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62 results on '"MESH: Colonic Neoplasms"'

1. Determining PD-L1 Status in Patients With Triple-Negative Breast Cancer: Lessons Learned From IMpassion130

Author: Jary, Marine, Liu, Wen-Wei, Yan, Dongyao, Bai, Isaac, Muranyi, Andrea, Colle, Elise, Brocheriou, Isabelle, Turpin, Anthony, Radosevic-Robin, Nina, Bourgoin, Pierre, Penault-Llorca, Frédérique, Cohen, Romain, Vernerey, Dewi, André, Thierry, Borg, Christophe, Shanmugam, Kandavel, Svrcek, Magali, Liu, Wen‐wei, Cooperator Multidisciplinary Oncology Group (GERCOR), CHU Clermont-Ferrand, Ventana Medical Systems, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'oncologie médicale (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Saint-Antoine [AP-HP], Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Translational Cancer Research Unit [Antwerp], Philipps Universität Marburg = Philipps University of Marburg, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), University of the Sunshine Coast (USC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Pathology, Aberdeen University Medical School, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), VU Medical Center, Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], Institute for Surgical Pathology, University hospital of Zurich [Zurich], Service de pathologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'Oncologie Médicale [CHU Saint -Antoine], Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Oncologie Médicale [CHU Saint-Antoine], HAL-SU, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: Cancer Research, Biopsy, Best practice, BluePrint 80-gene signature, Predictive, DNA Mismatch Repair, pMMR, B7-H1 Antigen, Cohort Studies, Breast cancer, MESH: Tumor Microenvironment, Tumor Microenvironment, MESH: B7-H1 Antigen, Prospective Studies, MESH: Lymphocytes, Tumor-Infiltrating, MESH: Cohort Studies, Oligometastatic colorectal cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, high/low risk, immune profile, General Medicine, Immunohistochemistry, External quality assessment, 3. Good health, MESH: DNA Mismatch Repair, Oncology, Cytological techniques, Colonic Neoplasms, Molecular Medicine, HER2-low, Colorectal Neoplasms, PD-L1, Histology, Serum proteins, T lymphocytes, [SDV.CAN]Life Sciences [q-bio]/Cancer, Prognostic, Non-small cell lung carcinoma, Lymphocytes, Tumor-Infiltrating, Molecular diagnostics, Genetics, Humans, early breast cancer, MESH: Colonic Neoplasms, MESH: Humans, Liquid biopsy, gene expression profiles, MammaPrint 70-gene signature, Plasma proteins, Biomarker, MESH: Prospective Studies, digestive system diseases, Next-generation sequencing, Trastuzumab-deruxtecan, MESH: Tissue Fixation, hallmarks of cancer, MESH: Colorectal Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri-operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein-1 (PD-1, invasive front, stromal, intra-epithelial compartments), and programmed death-ligand 1 (PD-L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD-L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD-L1 expressions on immune cells were predictive of better disease-free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD-L1 expression and tumor-infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.
Published: 2022
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2. A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

Author: Alex Pezzotta, Anna Pistocchi, Patrick Mehlen, Andrea Paradisi, Anna Di Matteo, Federico Forneris, Daniele Campolungo, Costanza Giampietro, Elisa Belloni, Gianluca Deflorian, Nina Volf, Antonella Chiapparino, Michael Rehman, William Vermi, Maria Paola Paronetto, Mattia Bugatti, Davide Pradella, Claudia Ghigna, Anne Eichmann, Matteo Campioni, Serena Zacchigna, Luigi Scietti, Paradisi, Andrea, Consiglio Nazionale delle Ricerche (CNR), Università degli Studi di Pavia = University of Pavia (UNIPV), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano = University of Milan (UNIMI), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Centre Léon Bérard [Lyon], University of Brescia, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Heidelberg University, Swiss Federal Laboratories for Materials Science and Technology [Dübendorf] (EMPA), International Centre for Genetic Engineering and Biotechnology (ICGEB) (Trieste), Yale School of Medicine [New Haven, Connecticut] (YSM), Università degli studi di Trieste = University of Trieste, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], University of Rome 'Foro Italico', Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pradella, D., Deflorian, G., Pezzotta, A., Di Matteo, A., Belloni, E., Campolungo, D., Paradisi, A., Bugatti, M., Vermi, W., Campioni, M., Chiapparino, A., Scietti, L., Forneris, F., Giampietro, C., Volf, N., Rehman, M., Zacchigna, S., Paronetto, M. P., Pistocchi, A., Eichmann, A., Mehlen, P., Ghigna, C., University of Pavia, University of Milan, Yale University School of Medicine, University of Trieste, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Netrin Receptor, Angiogenesis, Regulator, General Physics and Astronomy, Apoptosis, RNA-binding protein, RNA-Binding Protein, 0302 clinical medicine, Netrin, Morphogenesis, RNA Isoforms, MESH: Animals, MESH: Endothelial Cells, MESH: Nerve Tissue Proteins, Zebrafish, Colonic Neoplasm, Endothelial Cell, 0303 health sciences, Multidisciplinary, Neovascularization, Pathologic, Chemistry, MESH: Alternative Splicing, RNA-Binding Proteins, RNA Isoform, Netrin-1, Cell biology, MESH: Survival Analysis, 030220 oncology & carcinogenesis, embryonic structures, Colonic Neoplasms, RNA splicing, Survival Analysi, Netrin Receptors, Human, Gene isoform, animal structures, Blood Vessel, Science, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Neuro-Oncological Ventral Antigen, Morphogenesi, Animals, Humans, Alternative Splicing, Blood Vessels, Endothelial Cells, Survival Analysis, MESH: Zebrafish, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Neovascularization, 030304 developmental biology, Pathologic, MESH: Colonic Neoplasms, MESH: Humans, Animal, MESH: Apoptosis, fungi, Alternative splicing, MESH: Blood Vessels, General Chemistry, MESH: Netrin Receptors, MESH: RNA Isoforms, MESH: Morphogenesis, Exon skipping, MESH: RNA-Binding Proteins, nervous system, MESH: Netrin-1, Nerve Tissue Protein, MESH: Neovascularization, Pathologic, Tumour angiogenesis
Abstract: The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis., Nature Communications, 12, ISSN:2041-1723
Published: 2021
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3. Artificial intelligence-guided tissue analysis combined with immune infiltrate assessment predicts stage III colon cancer outcomes in PETACC08 study

Author: S. Nguyen, Quentin Klopfenstein, Oana Cojocarasu, Francis Fein, Mohamed Gasmi, Cynthia Reichling, Pierre-Laurent Puig, Karine Le Malicot, Jean Paul Lagasse, Côme Lepage, Pierre-Luc Etienne, Jean-Marc Gornet, Julien Taieb, Jean-François Emile, Hakim Becheur, Dominique Luet, François Ghiringhelli, André Vanoli, Hervé Perrier, Marie Christine Kaminsky, Valentin Derangère, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER
Subjects: 0301 basic medicine, Colorectal cancer, Lymphocyte, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, immunohistopathology, MESH: Lymphocytes, Tumor-Infiltrating, biology, Gastroenterology, MESH: Neoplasm Staging, Prognosis, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Colonic Neoplasms, Stromal cell, CD3, adjuvant treatment, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Disease-Free Survival, MESH: Prognosis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, computerised image analysis, Stroma, Artificial Intelligence, Image Interpretation, Computer-Assisted, Humans, MESH: Artificial Intelligence, Neoplasm Invasiveness, Pathological, Neoplasm Staging, MESH: Colonic Neoplasms, MESH: Humans, business.industry, MESH: Adenocarcinoma, MESH: Neoplasm Invasiveness, medicine.disease, 030104 developmental biology, MESH: Disease-Free Survival, biology.protein, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, MESH: Image Interpretation, Computer-Assisted, CD8
Abstract: ObjectiveDiagnostic tests, such as Immunoscore, predict prognosis in patients with colon cancer. However, additional prognostic markers could be detected on pathological slides using artificial intelligence tools.DesignWe have developed a software to detect colon tumour, healthy mucosa, stroma and immune cells on CD3 and CD8 stained slides. The lymphocyte density and surface area were quantified automatically in the tumour core (TC) and invasive margin (IM). Using a LASSO algorithm, DGMate (DiGital tuMor pArameTErs), we detected digital parameters within the tumour cells related to patient outcomes.ResultsWithin the dataset of 1018 patients, we observed that a poorer relapse-free survival (RFS) was associated with high IM stromal area (HR 5.65; 95% CI 2.34 to 13.67; pConclusionThese findings suggest that artificial intelligence can potentially improve patient care by assisting pathologists in better defining stage III colon cancer patients’ prognosis.
Published: 2020
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4. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

Author: Jorge Joven, Sara Verdura, Salvador Fernández-Arroyo, Elisa Blanco-González, Javier A. Menendez, Maria Montes-Bayón, Jan Stursa, R Á-F García, Elisabet Cuyàs, Benoit Viollet, Lukas Werner, Jiri Neuzil, Program Against Cancer Therapeutic Resistance/Metabolism & Cancer Group [Catalonia, Spain] (ProCURE), Catalan Institute of Oncology-Girona (ICO-Girona), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Unitat de Recerca Biomedica [Reus, Spain], Hospital Universitari de Sant Joan [Reus, Spain]-Rovira i Virgili University [Reus, Spain] (IISPV), The Campus of International Excellence Southern Catalonia [Tarragona, Spain], Department of Physical and Analytical Chemistry oviedo [Oviedo, Spain] ( Faculty of Chemistry), University of Oviedo, Institute of Chemical Technology [Prague, Czech Republic], Institute of Biotechnology [Prague-West, Czech Republic], Czech Academy of Sciences [Prague] (CAS), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Medical Science [Queensland, Australia], Griffith University [Brisbane], and Viollet, Benoit
Subjects: 0301 basic medicine, S-Adenosylmethionine, Cancer Research, Methyltransferase, AMP-Activated Protein Kinases, Mitochondrion, MESH: Metformin, Mice, MESH: DNA Methylation, Tumor Cells, Cultured, MESH: Animals, MESH: AMP-Activated Protein Kinases, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Regulation of gene expression, MESH: Electron Transport Complex I, Biguanide, MESH: Follow-Up Studies, MESH: Gene Expression Regulation, Neoplastic, Methylation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, S-Adenosylhomocysteine, Metformin, Mitochondria, Cell biology, Gene Expression Regulation, Neoplastic, Colonic Neoplasms, DNA methylation, Female, MESH: Biomarkers, Tumor, Reprogramming, medicine.drug, MESH: S-Adenosylhomocysteine, MESH: Mitochondria, medicine.drug_class, MESH: Carbon, Breast Neoplasms, Biology, 03 medical and health sciences, MESH: Hypoglycemic Agents, Biomarkers, Tumor, Genetics, medicine, Animals, Humans, Hypoglycemic Agents, MESH: Tumor Cells, Cultured, MESH: Mice, Molecular Biology, MESH: Genome, Human, MESH: Colonic Neoplasms, MESH: Humans, Electron Transport Complex I, Genome, Human, MESH: S-Adenosylmethionine, DNA Methylation, Carbon, 030104 developmental biology, MESH: Female, MESH: Breast Neoplasms, Follow-Up Studies
Abstract: International audience; The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM:SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity. By increasing the contribution of one-carbon units to the SAM from folate stores while decreasing SAH in response to AMPK-sensed energetic crisis, metformin can operate as a metabolo-epigenetic regulator capable of reprogramming one of the key conduits linking cellular metabolism to the DNA methylation machinery.
Published: 2017
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5. The Cytotoxic Effect of Apis mellifera Venom with a Synergistic Potential of Its Two Main Components—Melittin and PLA2—On Colon Cancer HCT116 Cell Lines

Author: Ziad Fajloun, Bruno Coutard, Dany El-Obeid, Jean-Marc Sabatier, Mariam Rifi, Carole Yaacoub, Hiba Mawlawi, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Cell Death, Pharmaceutical Science, Venom, Pharmacology, MESH: Drug Synergism, MESH: Bees, Analytical Chemistry, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Drug Discovery, Cytotoxic T cell, MESH: Animals, Cytotoxicity, MESH: Phospholipases A2, Chromatography, High Pressure Liquid, 0303 health sciences, Cell Death, biology, Chemistry, Drug Synergism, Bees, bee venom, 3. Good health, MESH: Cell Survival, MESH: Melitten, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Colonic Neoplasms, Molecular Medicine, lipids (amino acids, peptides, and proteins), Apis mellifera, MESH: HCT116 Cells, Cell Survival, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, in vitro anticancer effect, Melittin, lcsh:QD241-441, 03 medical and health sciences, Phospholipase A2, lcsh:Organic chemistry, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Viability assay, Physical and Theoretical Chemistry, MESH: Chromatography, High Pressure Liquid, neoplasms, 030304 developmental biology, MESH: Colonic Neoplasms, PLA2, MESH: Humans, HCT116 cell lines, Organic Chemistry, HCT116 Cells, Melitten, In vitro, Phospholipases A2, melittin, Cancer cell, biology.protein
Abstract: Colon carcinogenesis is ranked second globally among human diseases after cardiovascular failures. Bee venom (BV) has been shown to possess in vitro anticancer effects against several types of cancer cells. The two main biopeptides of Apis mellifera BV, namely, melittin (MEL) and phospholipase A2 (PLA2), are suspected to be the biomolecules responsible for the anticancer activity. The present work aims to evaluate the cytotoxic effect of the A. mellifera venom on human colon carcinoma cells (HCT116), and to assess the synergistic effect of MEL and PLA2 on these cells. After analyzing, through high-pressure liquid chromatography, the proportions of MEL and PLA2 on BV, we have established a cell viability assay to evaluate the effect of BV, MEL, PLA2, and a mixture of MEL and PLA2 on the HCT116 cells. Results obtained showed a strong cytotoxicity effect induced by the A. mellifera venom and to a lower extent MEL or PLA2 alone. Remarkably, when MEL and PLA2 were added together, their cytotoxic effect was greatly improved, suggesting a synergistic activity on HCT116 cells. These findings confirm the cytotoxic effect of the A. mellifera venom and highlight the presence of synergistic potential activities between MEL and PLA2, possibly inducing membrane disruption of HCT116 cancer cells. Altogether, these results could serve as a basis for the development of new anticancer treatments.
Published: 2021
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6. Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression

Author: Frederick Masson, Tracy L Putoczki, Oliver M. Sieber, Yelena Khakham, Cary Tsui, Lotta Burstroem, Ashleigh R Poh, Matthias Ernst, Clifford A. Lowell, Robert J.J. O'Donoghue, Adele Preaudet, Lachlan Whitehead, Guillaume Lessene, Simon Monard, Christopher G. Love, Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia, and The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
Subjects: 0301 basic medicine, MESH: Signal Transduction, Cancer Research, Colorectal cancer, [SDV]Life Sciences [q-bio], Cell, Inbred C57BL, medicine.disease_cause, MESH: Mice, Knockout, Mice, 0302 clinical medicine, tyrosine kinase inhibitor, 2.1 Biological and endogenous factors, MESH: Animals, Src family kinase, Aetiology, Cancer, Mice, Knockout, MESH: STAT3 Transcription Factor, MESH: Macrophage Activation, Hematology, MESH: Gene Expression Regulation, Neoplastic, Colo-Rectal Cancer, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, colitis-associated colon cancer, hematopoietic cell kinase, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Pyrroles, Proto-Oncogene Proteins c-hck, Female, Signal transduction, Colorectal Neoplasms, MESH: Proto-Oncogene Proteins c-hck, alternative macrophage polarization, Signal Transduction, STAT3 Transcription Factor, MESH: Xenograft Model Antitumor Assays, Knockout, SRC family kinases, mouse model, Oncology and Carcinogenesis, colorectal cancer, Biology, stat3, Article, 03 medical and health sciences, Rare Diseases, MESH: Mice, Inbred C57BL, medicine, tumor microenvironment, Animals, Humans, Pyrroles, Oncology & Carcinogenesis, xenograft, MESH: Colonic Neoplasms, Neoplastic, Tumor microenvironment, MESH: Humans, Oncogene, Neurosciences, Cell Biology, Macrophage Activation, medicine.disease, Xenograft Model Antitumor Assays, Mice, Inbred C57BL, 030104 developmental biology, Pyrimidines, Gene Expression Regulation, MESH: Pyrimidines, Cancer research, MESH: Stromal Cells, Stromal Cells, Digestive Diseases, Carcinogenesis, MESH: Female, MESH: Colorectal Neoplasms
Abstract: International audience; Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.
Published: 2017
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7. Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate

Author: Emily J. Greenspan, Gérard Lambeau, Daniel W. Rosenberg, Carine M. Mounier, Wendum D, Fléjou Jf, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Center for Molecular Medicine, University of Connecticut (UCONN), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Male, Cancer Research, Pathology, Colorectal cancer, Gene Expression, Polymerase Chain Reaction, 0302 clinical medicine, MESH: Aged, 80 and over, Intestinal mucosa, MESH: Colitis, MESH: Up-Regulation, MESH: Group III Phospholipases A2, Intestinal Mucosa, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, secreted phospholipase A2, MESH: Phospholipases A2, Secretory, Group III Phospholipases A2, Middle Aged, Colitis, Immunohistochemistry, 3. Good health, Up-Regulation, qPCR, Real-time polymerase chain reaction, Oncology, colon cancer, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Intestinal Mucosa, Biomarker (medicine), Adenocarcinoma, biomarker, Female, Adult, medicine.medical_specialty, MESH: Gene Expression, Colon, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Survivin, medicine, Biomarkers, Tumor, Humans, Matrilysin, MESH: Colon, Phospholipases A2, Secretory, Molecular Diagnostics, 030304 developmental biology, Aged, MESH: Colonic Neoplasms, MESH: Humans, MESH: Adenocarcinoma, Cancer, MESH: Adult, MESH: Immunohistochemistry, MESH: Polymerase Chain Reaction, medicine.disease, MESH: Male, MESH: Tumor Markers, Biological, Cancer research, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Recent studies suggest that secreted phospholipases A2 (sPLA2s) represent attractive potential tumour biomarkers and therapeutic targets for various cancers. As a first step to address this issue in human colorectal cancer, we examined the expression of the full set of sPLA2s in sporadic adenocarcinomas and normal matched mucosa from 21 patients by quantitative PCR and immunohistochemistry. In normal colon, PLA2G2A and PLA2G12A were expressed at high levels, PLA2G2D, PLA2G5, PLA2G10 and PLA2G12B at moderate levels, and PLA2G1B, PLA2G2F and PLA2G3 at low levels. In adenocarcinomas from left and right colon, the expression of PLA2G3 was increased by up to 40-fold, while that of PLA2G2D and PLA2G5 was decreased by up to 23- and 14-fold. The variations of expression for sPLA2-IID, sPLA2-III and sPLA2-V were confirmed at the protein level. The expression pattern of these sPLA2s appeared to be linked respectively to the overexpression of interleukin-8, defensin alpha6, survivin and matrilysin, and downregulation of SFRP-1 and RLPA-1, all these genes being associated to colon cancer. This original sPLA2 profile observed in adenocarcinomas highlights the potential role of certain sPLA2s in colon cancer and suggests that sPLA2-III might be a good candidate as a novel biomarker for both left and right colon cancers.
Published: 2008
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8. Structural basis for recognition of breast and colon cancer epitopes Tn antigen and Forssman disaccharide by Helix pomatia lectin

Author: Jean-Luc Coll, Anne Imberty, Aymeric Audfray, Julien Lescar, Edward P. Mitchell, Christelle Breton, Jean-Frederic Sanchez, Centre de Recherches sur les Macromolécules Végétales (CERMAV), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), European Synchrotron Radiation Facility (ESRF), Salas, Danielle, Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Acetylgalactosamine, MESH: Epitopes, Tn antigen, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disaccharides, Biochemistry, Epitope, Metastasis, Epitopes, 03 medical and health sciences, MESH: Lectins, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Forssman Antigen, Antigen, Lectins, MESH: Disaccharides, medicine, Humans, Antigens, Tumor-Associated, Carbohydrate, 030304 developmental biology, Forssman Antigen, MESH: Colonic Neoplasms, 0303 health sciences, MESH: Humans, MESH: Antigens, Tumor-Associated, Carbohydrate, biology, Cancer, Lectin, Helix pomatia, biology.organism_classification, medicine.disease, Forssman antigen, Molecular biology, 3. Good health, 030220 oncology & carcinogenesis, Colonic Neoplasms, biology.protein, Female, MESH: Acetylgalactosamine, MESH: Female, MESH: Breast Neoplasms
Abstract: International audience; Helix pomatia agglutinin (HPA) is a lectin that has been used extensively in histopathology, since its binding to tissue sections from breast and colon cancers is correlated with the worst prognosis for the patients. The lectin recognizes alpha-d-N-acetylgalactosamine (alphaGalNAc) containing epitopes which are only present in cancer cell lines having a high likelihood to undergo metastasis, such as the HT29 cancer colon cell line. Several breast cancer cell lines have also been shown to be labeled, although IGROV1, an ovarian cancer cell line, is not. Inhibition studies, using GalNAc monosaccharides, are reported here, showing that the labeling is dependent upon the presence of carbohydrate epitopes. The crystal structures of the lectin complexed with two GalNAc containing epitopes associated with cancer, the Tn (alphaGalNAc-Ser) and Forssman (alphaGalNAc1-3GalNAc) antigens, show the lectin's specificity for GalNAc is due to a particular network of hydrogen bonds. A histidine residue makes hydrophobic contact with the aglycon, rationalizing the preference for GalNAc bearing an additional sugar or amino acid in the alpha position. These structures provide the molecular basis for the use of HPA in metastasis research.
Published: 2007
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9. Differential involvement of destrin and cofilin‐1 in the control of invasive properties of Isreco1 human colon cancer cells

Author: Yann Estornes, Fabien Gay, Jean‐Claude Gevrey, Séverine Navoizat, Mimoun Nejjari, Jean‐Yves Scoazec, Jean‐Alain Chayvialle, Jean‐Christophe Saurin, Jacques Abello, Tumeurs endocrines digestives : mécanismes de la tumorigenèse et de la progression tumorale, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), and Hospices Civils de Lyon (HCL)
Subjects: Cofilin 1, Cancer Research, Pathology, medicine.medical_specialty, MESH: Cell Line, Tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, MESH: Extracellular Matrix, Biology, MESH: Cell Adhesion, Cell Movement, Cell Line, Tumor, MESH: RNA, Small Interfering, Cell Adhesion, medicine, Humans, Neoplasm Invasiveness, MESH: Bombesin, Phosphorylation, RNA, Small Interfering, Cell adhesion, MESH: Cell Movement, MESH: Colonic Neoplasms, Matrigel, MESH: Humans, MESH: Phosphorylation, MESH: Neoplasm Invasiveness, MESH: Cofilin 1, MESH: Gene Expression Regulation, Neoplastic, Cofilin, Actin cytoskeleton, Extracellular Matrix, Cell biology, MESH: Crk-Associated Substrate Protein, MESH: Destrin, Gene Expression Regulation, Neoplastic, Crk-Associated Substrate Protein, Destrin, Oncology, Actin depolymerizing factor, Colonic Neoplasms, Bombesin, Lamellipodium
Abstract: International audience; Actin depolymerizing factor (ADF)/cofilin family proteins are key regulators of actin filament turnover and cytoskeleton reorganization. The role of cofilin-1 in cell motility has been demonstrated in several cell types but remained poorly documented in the case of colon cancer. In addition, the putative function of destrin (also known as ADF) had not been explored in this context despite the fact that it is expressed in all colon cancer cell lines examined. We were therefore prompted to evaluate the respective contributions of these proteins to the invasive properties of the human colon cancer Isreco1 cell line, which expresses a comparatively high destrin/cofilin ratio. Reduction of cofilin-1 or destrin expression in Isreco1 cells using RNA interference led to an increase of the number of multinucleated cells and altered polarized lamellipodium protrusion and distribution of paxillin-containing adhesions. Both cofilin-1 and destrin silencing enhanced cell adhesion to extracellular matrix components. However, only destrin appeared to be required for cell migration on collagen I and for cell invasion through Matrigel in response to the proinvasive neuroendocrine peptide bombesin. This differential functional involvement was supported by a destrin-dependent, cofilin-independent phosphorylation of p130Crk-associated substrate (p130Cas) upon cell adhesion to collagen I or Matrigel. Taken together, our results suggest that destrin is a significant regulator of various processes important for invasive phenotype of human colon cancer Isreco1 cells whereas cofilin-1 may be involved in only a subset of them.
Published: 2007
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10. Inhibitor of Growth 4 Suppresses Cell Spreading and Cell Migration by Interacting with a Novel Binding Partner, Liprin α1

Author: Motoko Unoki, Jiang Cheng Shen, Damien Ythier, Kensuke Kumamoto, Alain Duperray, Rémy Pedeux, Lyuba Varticovski, Curtis C. Harris, Duperray, Alain, Laboratory of Human Carcinogenesis, National Institutes of Health [Bethesda] (NIH), Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, and Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, MESH: Cell Line, Tumor, Motility, Cell Cycle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, Article, MESH: Glioma, Cell membrane, MESH: Cell Cycle Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Cell Line, Tumor, MESH: RNA, Small Interfering, MESH: Homeodomain Proteins, medicine, Humans, MESH: Protein Binding, MESH: Tumor Suppressor Proteins, RNA, Small Interfering, Cell Cycle Protein, MESH: Cell Movement, Adaptor Proteins, Signal Transducing, MESH: Adaptor Proteins, Signal Transducing, Homeodomain Proteins, MESH: Colonic Neoplasms, MESH: Humans, biology, Cell growth, Tumor Suppressor Proteins, MESH: Transfection, Cell Membrane, Cell migration, Glioma, Vinculin, Cell biology, medicine.anatomical_structure, Oncology, Cytoplasm, Colonic Neoplasms, biology.protein, Lamellipodium, Protein Binding, MESH: Cell Membrane
Abstract: Inhibitor of growth 4 (ING4) is a candidate tumor suppressor that plays a major role in gene regulation, cell cycle control, apoptosis, and angiogenesis. ING4 expression is down-regulated in glioblastoma cells and head and neck squamous cell carcinoma. Here, we identified liprin α1/PPFIA1, a cytoplasmic protein necessary for focal adhesion formation and axon guidance, as a novel interacting protein with ING4. ING4 and liprin α1 colocalized at lamellipodia in the vicinity of vinculin. Overexpressed ING4 suppressed cell spreading and cell migration. In contrast, overexpressed liprin α1 enhanced cell spreading and cell migration. Knockdown of endogenous ING4 with RNA interference induced cell motility, whereas knockdown of endogenous liprin α1 suppressed cell motility. ING4 also suppressed cell motility that was enhanced by liprin α1. However, ING4 did not further suppress cell motility when liprin α1 was suppressed with RNA interference, suggesting a functional and mechanistic interdependence between these proteins. In addition to its nuclear functions, cytoplasmic ING4 interacts with liprin α1 to regulate cell migration and, with its known antiangiogenic function, may prevent invasion and metastasis. [Cancer Res 2007;67(6):2552–8]
Published: 2007
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11. The tumor suppressor activity induced by adenovirus-mediated BRCA1 overexpression is not restricted to breast cancers

Author: Voahangy Randrianarison, Michel Perricaudet, Jean Feunteun, N Elie, Paule Opolon, Nicolas Foray, Didier Marot, S Brailly-Tabard, Elisabeth Connault, Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Génétique oncologique (GO - UMR 8125), Rayonnement Synchrotron et Recherche Medicale (RSRM), Université Joseph Fourier - Grenoble 1 (UJF)-European Synchrotron Radiation Facility (ESRF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and European Synchrotron Radiation Facility (ESRF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Lung Neoplasms, Angiogenesis, Genes, BRCA1, Apoptosis, MESH: Cell Cycle, Injections, Intralesional, Retinoblastoma Protein, Mice, 0302 clinical medicine, MESH: Genetic Vectors, Genes, Tumor Suppressor, MESH: Animals, 0303 health sciences, Cell Cycle, MESH: Genetic Predisposition to Disease, MESH: Adenoviridae, MESH: Gene Expression Regulation, Neoplastic, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Colonic Neoplasms, Molecular Medicine, Female, HT29 Cells, G1 phase, MESH: Cell Line, Tumor, Tumor suppressor gene, Genetic Vectors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: G1 Phase, Adenoviridae, 03 medical and health sciences, Breast cancer, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, E2F, Molecular Biology, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: HT29 Ce, Cell growth, MESH: Apoptosis, G1 Phase, Genetic Therapy, MESH: Genes, Tumor Suppressor, medicine.disease, Androgen receptor, Cancer research, MESH: Gene Therapy, MESH: Genes, BRCA1, MESH: Female, Neoplasm Transplantation
Abstract: International audience; The BRCA1 (breast cancer 1) breast cancer susceptibility gene is recognized as responsible for most familial breast and ovarian cancers and is suggested to be a tissue-specific tumor suppressor gene. In this report, we investigated the tissue specificity of tumor inhibitory activities induced by a recombinant adenovirus coding for wild-type BRCA1 (wtAdBRCA1). We demonstrated a pronounced in vitro antiproliferative effect on H1299 lung and HT29 colon cells upon infection with AdBRCA1. We describe a prolonged G1 cell cycle arrest associated with a decrease in the hyperphosphorylated form of Rb, suggesting that the Rb/E2F pathway is implicated in BRCA1-induced cell growth arrest. We also observed a significant antitumor effect in these pre-established subcutaneous tumors after in situ delivery of AdBRCA1, although these two tumors do not express wt p53, and also estrogen alpha and beta, progesterone and androgen receptors. Moreover, BRCA1 can induce a strong prolonged cell cycle arrest and apoptotic cell death but no significant antiangiogenic effect in H1299 tumors. Finally, our data indicate that intratumor administration of wtAdBRCA1 significantly inhibits growth of lung and colon steroid hormone-independent tumors.
Published: 2005
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12. Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases

Author: Eric Guérin, Marie-Christine Rio, Athanasios Yiotakis, Bernard Rousseau, Magdalini Matziari, Anne Boulay, Vincent Dive, Fabrice Beau, Kumari L. Andarawewa, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, MESH: Matrix Metalloproteinases, Matrix metalloproteinase inhibitor, MESH: Nitrosomethylurethane, medicine.medical_treatment, Apoptosis, Matrix metalloproteinase, MESH: Dose-Response Relationship, Drug, Mice, 0302 clinical medicine, Medicine, MESH: Animals, Enzyme Inhibitors, MESH: Lymphocytes, Tumor-Infiltrating, MESH: Peptide Fragments, Mice, Inbred BALB C, 0303 health sciences, MESH: Kinetics, Effective dose (pharmacology), 3. Good health, MESH: Alkylating Agents, Oncology, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Oligopeptides, Disease Progression, MESH: Disease Progression, Oligopeptides, Alkylating Agents, medicine.medical_specialty, Ratón, MESH: Mice, Inbred BALB C, Matrix Metalloproteinase Inhibitors, MESH: Drug Administration Schedule, Drug Administration Schedule, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Nitrosomethylurethane, Pharmacokinetics, In vivo, MESH: Cell Proliferation, Internal medicine, Animals, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Colonic Neoplasms, Chemotherapy, Dose-Response Relationship, Drug, business.industry, MESH: Apoptosis, Therapeutic effect, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Matrix Metalloproteinases, Peptide Fragments, Kinetics, Endocrinology, business
Abstract: International audience; The in vivo disposition and antitumor efficacy of a newly developed phosphinic matrix metalloproteinase inhibitor (RXP03) were examined. RXP03 potently inhibits MMP-11, MMP-8 and MMP-13, but not MMP-1 and MMP-7. Twenty-four hours after i.p. injection into mice, most of the RXP03 was recovered intact in plasma, feces (biliary excretion) and tumor tissue. Pharmacokinetic parameters indicated that, after an i.p. dose of 100 microg/day, the plasma concentration of RXP03 over 24 hr remained higher than the Ki values determined for MMP-11, MMP-8 and MMP-13. Efficacy of RXP03 on the growth of primary tumors induced by s.c. injection of C(26) colon carcinoma cells in mice was observed to depend both on RXP03 doses and treatment schedules. Tumor volumes in mice treated for 18 days with 50, 100 and 150 microg/day of RXP03 were decreased compared with control tumor volumes, 100 microg/day being the most effective dose. Treatment at higher dose (600 microg/day) did not significantly reduce the tumor size as compared to control. Short treatments with RXP03 100 microg/day, 3 to 7 days after C(26) inoculation, were more effective on tumor growth than continuous treatment over 18 days. Strikingly, RXP03 treatment started 6 days after the C(26) injection and continued until day 18 led to stimulation of tumor growth, as compared to control. These paradoxical effects, depending on the RXP03 treatment schedule, underline the need to define carefully the spatiotemporal function of each MMP at various stages of tumor growth to achieve optimal therapeutic effects by MMP inhibitor treatment.
Published: 2004
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13. A role for peroxisome proliferator-activated receptor gamma in resveratrol-induced colon cancer cell apoptosis

Author: Dominique Delmas, Emeric Limagne, Alessandra Scagliarini, Virginie Aires, Annie Carlier, Bertrand Brassart, Eric Solary, Laurent Martiny, Stéphane Mandard, Michel Tarpin, Chimiothérapie et réponse immunitaire anti-tumorale (U866, Cancer, équipe 1), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Istituto Nazionale di Fisica Nucleare, Sezione di Roma Tor Vergata (INFN, Sezione di Roma Tor Vergata), Istituto Nazionale di Fisica Nucleare (INFN), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), URCA - UFR Sciences exactes et naturelles (URCA UFR SEN), Université de Reims Champagne-Ardenne (URCA), Ligue Inter-régionale Grand-Est Contre le Cancer, Conseil Régional de Bourgogne, FEDER, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Matrice extracellulaire et dynamique cellulaire - UMR 7369 ( MEDyC ), Université de Reims Champagne-Ardenne ( URCA ) -SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ) -Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des Sciences de l'Environnement Marin (LEMAR) ( LEMAR ), Institut de Recherche pour le Développement ( IRD ) -Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ) -Université de Brest ( UBO ) -Institut Universitaire Européen de la Mer ( IUEM ), Institut de Recherche pour le Développement ( IRD ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Istituto Nazionale di Fisica Nucleare, Sezione di Roma Tor Vergata ( INFN, Sezione di Roma Tor Vergata ), National Institute for Nuclear Physics ( INFN ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire SiRMa, Centre National de la Recherche Scientifique ( CNRS ), URCA - UFR Sciences exactes et naturelles ( URCA UFR SEN ), Université de Reims Champagne-Ardenne ( URCA ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Mandard, Stéphane
Subjects: endocrine system diseases, Colorectal cancer, Peroxisome proliferator-activated receptor, Apoptosis, Pharmacology, Resveratrol, resveratrol, MESH: Thiazolidinediones, PPAR, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, 0302 clinical medicine, MESH: Stilbenes, Stilbenes, MESH : Cell Proliferation, [ SHS.INFO ] Humanities and Social Sciences/Library and information sciences, Anilides, skin and connective tissue diseases, chemistry.chemical_classification, 0303 health sciences, food and beverages, Cell cycle, 3. Good health, MESH : Thiazolidinediones, MESH : Colonic Neoplasms, colon cancer, 030220 oncology & carcinogenesis, Colonic Neoplasms, S Phase Cell Cycle Checkpoints, Rosiglitazone, hormones, hormone substitutes, and hormone antagonists, Biotechnology, medicine.drug, MESH : PPAR gamma, MESH: Cell Line, Tumor, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Anilides, [SHS.INFO] Humanities and Social Sciences/Library and information sciences, MESH : Anilides, MESH : Stilbenes, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, MESH: Cell Proliferation, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH : S Phase Cell Cycle Checkpoints, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, polyphenols, 030304 developmental biology, Cell Proliferation, MESH: Colonic Neoplasms, MESH: Humans, Cell growth, MESH : Cell Line, Tumor, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, organic chemicals, MESH: Apoptosis, MESH : Humans, medicine.disease, PPAR gamma, MESH: S Phase Cell Cycle Checkpoints, chemistry, MESH: PPAR gamma, Cancer cell, Thiazolidinediones, MESH : Apoptosis, Food Science
Abstract: Scope Resveratrol may function as a chemopreventive agent. A recent clinical study demonstrates a reduction in tumor cell proliferation in colorectal patients receiving repeated oral ingestion of resveratrol. However, gaps remain in our knowledge of the molecular mechanisms by which resveratrol exerts its chemopreventive effect. We have previously demonstrated that resveratrol induces apoptosis in colon cancer cells and that resveratrol can sensitize chemoresistant colon cancer cells to various drugs. Based on its ability to activate peroxisome proliferator-activated receptor gamma (PPARγ) in colon cancer cells, we sought to determine the implication of this nuclear transcription factor in resveratrol-induced apoptosis. Methods and results Transient transfection of cancer cells with a dominant-negative PPARγ mutant or treatment with a PPARγ antagonist (GW9662) reversed the inhibitory effect of resveratrol. Moreover, GW9662 prevented disruption of the cell cycle induced by resveratrol and consequently abrogated resveratrol-induced apoptosis. Tumor cell death was potentiated by combining resveratrol with rosiglitazone, a PPARγ agonist. Conclusion The results show that PPARγ plays a role in resveratrol-induced apoptosis of colon carcinoma cells. The combination of resveratrol with a PPARγ agonist could be a promising pharmacological approach for treatment of colorectal cancer.
Published: 2014
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14. TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Author: Ludovic Cervera, Eric Vivier, Eric Gilson, Antonella Stoppacciaro, Karine Jamet, Thomas Kuilman, Laure Sabatier, François-Loïc Cosset, Jacqueline Marvel, Jean-Yves Scoazec, Jing Ye, Daniel S. Peeper, Angela Maria Rizzo, Annamaria Biroccio, Béatrice Horard, Thomas Simonet, Claire T Kint De Rodenbeeke, Carlo Leonetti, Els Verhoeyen, Renée Grataroli, Helene Duret, Mark J. Smyth, Aaron Mendez-Bermudez, Adeline Augereau, Gilles Pagès, Pasquale Zizza, Vincent Picco, Florian Lepinasse, Julien Cherfils-Vicini, Delphine Poncet, Erica Salvati, Arturo Londoño-Vallejo, Serge Bauwens, Michelle Ricoul, Céline Cognet, Sébastien Pinte, Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Énergies et Mécanique Théorique et Appliquée (LEMTA ), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Cell, Melanoma, Experimental, Apoptosis, MESH: Flow Cytometry, medicine.disease_cause, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: RNA, Small Interfering, Tumor Cells, Cultured, Telomeric Repeat Binding Protein 2, MESH: Animals, MESH: Discoidin Domain Receptor 1, RNA, Small Interfering, MESH: Lymphocytes, Tumor-Infiltrating, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, ZAP70, MESH: Telomeric Repeat Binding Protein 2, Natural killer T cell, Flow Cytometry, 3. Good health, Cell biology, Killer Cells, Natural, MESH: Melanoma, Experimental, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Colonic Neoplasms, Interleukin 12, Female, MESH: Receptor Protein-Tyrosine Kinases, Sulfotransferases, MESH: Killer Cells, Natural, MESH: DNA Primers, Blotting, Western, Mice, Nude, Breast Neoplasms, Biology, Real-Time Polymerase Chain Reaction, MESH: Cell Adhesion, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Discoidin Domain Receptor 1, MESH: Cell Proliferation, medicine, Cell Adhesion, MESH: Mice, Nude, Animals, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Tumor Cells, Cultured, MESH: Mice, 030304 developmental biology, Cell Proliferation, DNA Primers, MESH: RNA, Messenger, MESH: Colonic Neoplasms, Lymphokine-activated killer cell, MESH: Humans, Cell growth, MESH: Apoptosis, Receptor Protein-Tyrosine Kinases, Cell Biology, MESH: Sulfotransferases, Cancer cell, MESH: HeLa Cells, Carcinogenesis, MESH: Female, MESH: Breast Neoplasms, HeLa Cells
Abstract: International audience; Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4--a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4--was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.
Published: 2013
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15. Induction of colonic aberrant crypts in mice by feeding apparent N-nitroso compounds derived from hot dogs

Author: James L. Wisecarver, Valerie Shostrom, Michal P. Lisowyj, Lin Zhou, Michael E. Davis, Sidney S. Mirvish, Denis E. Corpet, Nathalie Naud, James M. Gulizia, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), NIH from the National Cancer Institute [RO3-CA-139533, RO1-CA-143460], Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), University of Nebraska Medical Center - UNMC (USA), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), and Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Subjects: Cancer Research, MESH: Meat Products, MDF, Colorectal cancer, Food Handling, Hot-dog, Medicine (miscellaneous), Gastroenterology, MESH: Carcinogens, chemistry.chemical_compound, Feces, Mice, 0302 clinical medicine, MESH: Nitroso Compounds, Aberrant Crypt Foci, hemic and lymphatic diseases, MESH: Animals, Colorectal, reproductive and urinary physiology, Cancer, 0303 health sciences, Nutrition and Dietetics, MESH: Feces, female genital diseases and pregnancy complications, 3. Good health, Meat Products, Nitroso-compounds, Oncology, 030220 oncology & carcinogenesis, Nitrosation, Alimentation et Nutrition, Colonic Neoplasms, Female, MESH: Azoxymethane, MESH: Food Handling, Aberrant crypt foci, Nitroso Compounds, medicine.medical_specialty, Processed meat, MESH: Sodium Nitrite, Azoxymethane, MESH: Nitrosation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Aberrant Crypt Foci, Article, Andrology, 03 medical and health sciences, Internal medicine, medicine, Animals, Sodium nitrite, MESH: Mice, Carcinogen, 030304 developmental biology, ACF, MESH: Colonic Neoplasms, Sodium Nitrite, Cured meat, Composés nitrosés, medicine.disease, Charcuterie, Médecine vétérinaire et santé animal, chemistry, Carcinogens, MESH: Female
Abstract: International audience; Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5 mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17-34 (ANC tests) wk. Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOM injections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5-6, with P < 0.01 for both ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon.
Published: 2012
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16. Red meat and colon cancer : should we become vegetarians, or can we make meat safer ?

Author: Denis E. Corpet, Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Saisissez le nom du laboratoire, du service ou du département., Ville service., and ProdInra, Migration
Subjects: Swine, Colorectal cancer, Epidemiology, cancer du colon, MESH: Lipid Peroxidation, fer, Lipid peroxidation, 0302 clinical medicine, Medicine, Processed meat, MESH: Animals, Food science, MESH: Swine, ComputingMilieux_MISCELLANEOUS, processed meat, MESH: Meat, 0303 health sciences, hème, heme iron, MESH: Nitrites, food and beverages, Safer meat, Epidémiologie, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Iron, Dietary, 030220 oncology & carcinogenesis, Nitrosation, épidémiologie, Hème, Iron, Dietary, MESH: Nitrosation, 03 medical and health sciences, Humans, Food and Nutrition, MESH: Meta-Analysis as Topic, viande rouge, MESH: Humans, haem, medicine.disease, Food safety, Calcium, Dietary, Meta-analysis, chemistry, Méta-analyse, Cattle, Food Additives, Lipid Peroxidation, Haem, MESH: Oxidation-Reduction, Food Handling, [SDV]Life Sciences [q-bio], alpha-Tocopherol, Heme iron, Viande rouge, Red meat, Colon cancer, Cancer colorectal, chemistry.chemical_compound, méta-analyse, vegetarisme, 2. Zero hunger, Diet, Vegetarian, MESH: Cattle, colon cancer, MESH: alpha-Tocopherol, charcuterie : cancer colorectal, Colonic Neoplasms, Alimentation et Nutrition, epidemiology, safer meat, Oxidation-Reduction, MESH: Calcium, Dietary, MESH: Food Handling, charcuterie, Meat, MESH: Rats, MESH: Food Additives, [SDV.CAN]Life Sciences [q-bio]/Cancer, Meta-Analysis as Topic, MESH: Diet, Animals, Nitrites, 030304 developmental biology, MESH: Colonic Neoplasms, business.industry, MESH: Diet, Vegetarian, Fer, Diet, Rats, meta-analysis, Charcuterie, business, Food Science
Abstract: International audience; The effect of meat consumption on cancer risk is a controversial issue. However, recent meta-analyses show that high consumers of cured meats and red meat are at increased risk of colorectal cancer. This increase is significant but modest (20-30%). Current WCRF-AICR recommendations are to eat no more than 500 g per week of red meat, and to avoid processed meat. Moreover, our studies show that beef meat and cured pork meat promote colon carcinogenesis in rats. The major promoter in meat is heme iron, via N-nitrosation or fat peroxidation. Dietary additives can suppress the toxic effects of heme iron. For instance, promotion of colon carcinogenesis in rats by cooked, nitrite-treated and oxidized high-heme cured meat was suppressed by dietary calcium and by α-tocopherol, and a study in volunteers supported these protective effects in humans. These additives, and others still under study, could provide an acceptable way to prevent colorectal cancer.
Published: 2011
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17. S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells

Author: Cindy Godard, Patrick Legembre, Selvakumar Subramaniam, Olivier Cauvard, Ali Bettaieb, Lissbeth Leon-Bollotte, Antonio Martinez–Ruiz, Jean-François Jeannin, Stéphanie Plenchette–Colas, Catherine Paul, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Servicio de Immunologia, Hospital Universitario de la Princesa-Instituto de Investigacion Sanitaria Princesa, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ligue Nationale Contre le Cancer (Comités de Sâone-et-Loire, de Nevers, de Côte d'Or, et le Cancéropole Grand Est), le gouvernement espagnol (grant CSD007-00020), Association pour la Recherche Contre le Cancer (L.L-B.), Institut National du Cancer (L.L-B.), la Région de Bourgogne (S.S.), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Hospital Universitario de La Princesa-Instituto de Investigacion Sanitaria del Hospital de la Princesa, Hospital Universitario de La Princesa, and Université de Rennes (UR)
Subjects: MESH: Nitroglycerin, MESH: Signal Transduction, Time Factors, MESH: Membrane Microdomains, Apoptosis, MESH : Fas Ligand Protein, Cytoplasmic part, MESH: Lipid A, Fas ligand, Mice, Nitroglycerin, 0302 clinical medicine, MESH : Protein Transport, MESH : Female, MESH: Animals, FADD, Lipid raft, 0303 health sciences, Tumor, biology, Colon Cancer, MESH : Lipid A, MESH : Biotinylation, Gastroenterology, Fas receptor, MESH: Antigens, CD95, Protein Transport, Lipid A, MESH : Colonic Neoplasms, MESH : Nitric Oxide, MESH : Nitric Oxide Donors, 030220 oncology & carcinogenesis, Colonic Neoplasms, Death-inducing signaling complex, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Mutation, MESH : Transfection, Signal Transduction, MESH : Time Factors, MESH: Protein Transport, Fas Ligand Protein, MESH : Mammary Neoplasms, Experimental, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Mammary Neoplasms, Experimental, Nitric Oxide, Transfection, Caspase 8, 03 medical and health sciences, Membrane Microdomains, Cell Line, Tumor, MESH : Mice, Animals, Humans, Biotinylation, Nitric Oxide Donors, MESH: Biotinylation, Cysteine, fas Receptor, MESH: Mice, MESH : Protein Processing, Post-Translational, 030304 developmental biology, MESH : Signal Transduction, MESH: Colonic Neoplasms, MESH : Cysteine, MESH: Humans, Hepatology, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH: Transfection, MESH : Humans, MESH: Time Factors, Mammary Neoplasms, Experimental, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cysteine, MESH: Nitric Oxide Donors, Molecular biology, Signaling, MESH: Fas Ligand Protein, MESH : Nitroglycerin, Localization, MESH: Nitric Oxide, MESH: Protein Processing, Post-Translational, Mutation, biology.protein, MESH : Membrane Microdomains, MESH : Animals, MESH : Antigens, CD95, Protein Processing, Post-Translational, MESH: Female, MESH : Apoptosis
Abstract: International audience; BACKGROUND & AIMS: Fas belongs to the family of tumor necrosis factor receptors which induce apoptosis. Many cancer cells express Fas but do not undergo Fas-mediated apoptosis. Nitric oxide reverses this resistance by increasing levels of Fas at the plasma membrane. We studied the mechanisms by which NO affects Fas function. METHODS: Colon and mammary cancer cell lines were incubated with the NO donor glyceryl trinitrate or lipid A; S-nitrosylation of Fas was monitored using the biotin switch assay. Fas constructs that contained mutations at cysteine residues that prevent S-nitrosylation were used to investigate the involvement of S-nitrosylation in Fas-mediated cell death. Apoptosis was monitored according to morphologic criteria. RESULTS: NO induced S-nitrosylation of cysteine residues 199 and 304 in the cytoplasmic part of Fas. In cancer cells that overexpressed wild-type Fas, S-nitrosylation induced Fas recruitment to lipid rafts and sensitized the cells to Fas ligand. In cells that expressed a mutant form of Fas in which cysteine 304 was replaced by valine residue, NO-mediated translocation of Fas to lipid rafts was affected and the death-inducing signal complex and synergistic effect of glyceryl trinitrate-Fas ligand were inhibited significantly. These effects were not observed in cells that expressed Fas with a mutation at cysteine 199. CONCLUSIONS: We identified post-translational modifications (S-nitrosylation of cysteine residues 199 and 304) in the cytoplasmic domain of Fas. S-nitrosylation at cysteine 304 promotes redistribution of Fas to lipid rafts, formation of the death-inducing signal complex, and induction of cell death.
Published: 2011
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18. A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor

Author: Stéphanie Brayer, Philippe Le Bouteiller, Nabila Jabrane-Ferrat, Fabienne Meggetto, Armand Bensussan, Salem Chouaib, Julie Tabiasco, Jean Kadouche, Olivier Chose, Maryse Aguerre-Girr, Muhammad Zaeem Noman, Sylvie Giuriato, Muriel Golzio, Sophie Chabot, Karine Bigot, Stéphane Galiacy, François Malecaze, Jérôme Giustiniani, Alexandra C. Provost, Jean-Philippe Jais, Elisabeth Bellard, Marc Abitbol, Justin Teissié, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'étude et de recherche thérapeutiques en ophtalmologie, Université Paris Descartes - Paris 5 (UPD5), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Ophtalmologie [Hopital Purpan - Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Cell Biology (DUMC), Duke University Medical Center, MAT Biopharma, MAT Ltd., Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Sciences et Technologies du Medicament de Toulouse Toulouse, France. (UMR2587, CNRS-PIERRE FABRE), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Fonctions Cellulaires et Moleculaires de l'Appareil Respiratoire et des Vaisseaux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de recherche biomédicale (IMRB), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Cell Biology ( DUMC ), Oncodermatologie, immunologie et cellules souches cutanées ( DIO U976 ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Pathology, MESH : Retinal Diseases, MESH : Antineoplastic Combined Chemotherapy Protocols, Angiogenesis, MESH: Rabbits, Fibroblast growth factor, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Neovascularization, Antibodies, Monoclonal, Murine-Derived, Mice, MESH : Fibroblast Growth Factor 2, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH : Receptors, Immunologic, Immunology and Allergy, MESH : Female, MESH: Animals, Receptors, Immunologic, Melanoma, MESH: Antigens, CD, MESH : Cyclophosphamide, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, 0303 health sciences, Neovascularization, Pathologic, MESH : Mice, Nude, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH : Colonic Neoplasms, MESH : Corneal Neovascularization, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Fibroblast Growth Factor 2, Rabbits, MESH : GPI-Linked Proteins, medicine.symptom, Intravital microscopy, Retinopathy, medicine.medical_specialty, MESH: Melanoma, MESH : Male, Immunology, MESH : Melanoma, MESH: Mice, Inbred BALB C, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, GPI-Linked Proteins, Article, 03 medical and health sciences, Retinal Diseases, Antigens, CD, Cell surface receptor, MESH : Mice, MESH : Antigens, CD, medicine, MESH: Mice, Nude, Animals, Humans, Corneal Neovascularization, MESH : Rabbits, Cyclophosphamide, MESH: Mice, MESH: Receptors, Immunologic, MESH : Mice, Inbred BALB C, MESH: Retinal Diseases, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Corneal Neovascularization, MESH: Fibroblast Growth Factor 2, MESH : Humans, MESH : Neovascularization, Pathologic, MESH: Cyclophosphamide, medicine.disease, eye diseases, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, MESH: Antibodies, Monoclonal, Murine-Derived, Corneal neovascularization, MESH : Animals, MESH: GPI-Linked Proteins, MESH: Neovascularization, Pathologic, MESH: Female
Abstract: A monoclonal anti-CD160 antibody inhibits the growth of new vessels in pathological ocular and tumor neoangiogenesis but not in healthy tissues., Angiogenesis plays an essential role in several diseases of the eye and in the growth of solid tumors, but existing antiangiogenic therapies have limited benefits in several cases. We report the antiangiogenic effects of a monoclonal antibody, CL1-R2, in several animal models of neovascularization. CL1-R2 recognizes human CD160, a membrane receptor which is conserved in various mammal species. We show that CD160 is expressed on the endothelial cells of newly formed blood vessels in human colon carcinoma and mouse B16 melanoma but not in vessels of healthy tissues. CL1-R2 reduced fibroblast growth factor 2–induced neovascularization in the rabbit cornea, in a mouse model of oxygen-induced retinopathy, and in a mouse Matrigel plug assay. Treatment of B16 melanoma-bearing mice with CL1-R2 combined with cyclophosphamide chemotherapy caused regression of the tumor vasculature and normalization of the remaining vessels as shown by Doppler ultrasonography, intravital microscopy, and histology. These studies validate CD160 as a potential new target in cases of human pathological ocular and tumor neoangiogenesis that do not respond or become resistant to existing antiangiogenic drugs.
Published: 2011
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19. Increase in intracellular PGE2 induces apoptosis in Bax-expressing colon cancer cell

Author: Christophe Olivier, Christophe Braud, François M. Vallette, François Pedelaborde, Lisenn Lalier, Jean Menanteau, Département de Biologie Oncologique, Centre de Lutte Contre le Cancer René Gauducheau, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Toxicologie, Université de Nantes (UN), and BMC, Ed.
Subjects: Cancer Research, MESH: Cyclooxygenase 2 Inhibitors, Colorectal cancer, Intracellular Space, Apoptosis, MESH: Microinjections, 0302 clinical medicine, Prostaglandin-E Synthases, bcl-2-Associated X Protein, 0303 health sciences, biology, MESH: Dinoprostone, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Intramolecular Oxidoreductases, Blot, MESH: Cell Survival, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Intracellular Space, lipids (amino acids, peptides, and proteins), MESH: Cyclooxygenase 2, Stem cell, Intracellular, Research Article, MESH: Cell Line, Tumor, Microinjections, Cell Survival, MESH: HCT116 Cells, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Dinoprostone, 03 medical and health sciences, Bcl-2-associated X protein, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Genetics, medicine, Humans, MESH: Blotting, Western, MESH: bcl-2-Associated X Protein, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, Cyclooxygenase 2 Inhibitors, business.industry, MESH: Apoptosis, Cancer, HCT116 Cells, medicine.disease, MESH: Intramolecular Oxidoreductases, digestive system diseases, Cyclooxygenase 2, Cell culture, Immunology, Cancer research, biology.protein, business
Abstract: Background NSAIDs exhibit protective properties towards some cancers, especially colon cancer. Yet, it is not clear how they play their protective role. PGE2 is generally shown as the only target of the NSAIDs anticancerous activity. However, PGE2 known targets become more and more manifold, considering both the molecular pathways involved and the target cells in the tumour. The role of PGE2 in tumour progression thus appears complex and multipurpose. Methods To gain understanding into the role of PGE2 in colon cancer, we focused on the activity of PGE2 in apoptosis in colon cancer cell lines. Results We observed that an increase in intracellular PGE2 induced an apoptotic cell death, which was dependent on the expression of the proapoptotic protein Bax. This increase was induced by increasing PGE2 intracellular concentration, either by PGE2 microinjection or by the pharmacological inhibition of PGE2 exportation and enzymatic degradation. Conclusions We present here a new sight onto PGE2 in colon cancer cells opening the way to a new prospective therapeutic strategy in cancer, alternative to NSAIDs.
Published: 2011
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20. Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Author: Paillas, Salome, Bibeau, Frédéric, Denouël, Amélie, Mollevi, Caroline, Causse, Annick, Denis, Vincent, Vezzio-Vié, Nadia, Marzi, Laetitia, Cortijo, Cédric, Ait-Arsa, Imade, Askari, Nadav, Pourquier, Philippe, Martineau, Pierre, Del Rio, Maguy, Gongora, Celine, Boissière, Florence, Vezzio-Vie, N., Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), EndoFrance [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cyclotron Réunion Océan Indien (CYROI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Sanford-Burnham Medical Research Institute, Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'anatomo-pathologie, CRLCC Val d'Aurelle - Paul Lamarque, Unité de biostatistiques, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), IDvet, Laboratoire d'Informatique, de Modélisation et d'optimisation des Systèmes (LIMOS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Mines de St Etienne, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, Pyridines, Colorectal cancer, [SDV]Life Sciences [q-bio], Cell, Leucovorin, Drug resistance, p38 Mitogen-Activated Protein Kinases, MESH: Drug Synergism, Mice, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MAPK p38, MESH: Protein Kinase Inhibitors, MESH: Animals, Phosphorylation, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Imidazoles, Drug Synergism, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Immunohistochemistry, MESH: Drug Resistance, Neoplasm, 3. Good health, Isoenzymes, MESH: Antineoplastic Combined Chemotherapy Protocols, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Isoenzymes, MESH: Camptothecin, Adenocarcinoma, Female, Fluorouracil, MESH: Imidazoles, medicine.drug, MESH: Xenograft Model Antitumor Assays, MAP Kinase Signaling System, MESH: HCT116 Cells, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Irinotecan, Article, 03 medical and health sciences, Downregulation and upregulation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, MESH: Mice, Nude, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Kinase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Phosphorylation, MESH: MAP Kinase Signaling System, MESH: Adenocarcinoma, MESH: Pyridines, Cancer, MESH: Immunohistochemistry, HCT116 Cells, medicine.disease, Xenograft Model Antitumor Assays, MESH: p38 Mitogen-Activated Protein Kinases, SN38, Drug Resistance, Neoplasm, Immunology, Cancer research, Camptothecin, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil
Abstract: Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer. Cancer Res; 71(3); 1041–9. ©2010 AACR.
Published: 2011
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21. Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma

Author: Paillas, Salomé, Boissière, Florence, Bibeau, Frédéric, Denouel, Amélie, Mollevi, Caroline, Causse, Annick, Denis, Vincent, Vezzio-Vié, Nadia, Marzi, Laetitia, Cortijo, Cédric, Ait-Arsa, Imade, Askari, Nadav, Pourquier, Philippe, Martineau, Pierre, del Rio, Maguy, Gongora, Céline, Le Ster, Yves, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire d'anatomo-pathologie, CRLCC Val d'Aurelle - Paul Lamarque, Unité de biostatistiques, Sanford-Burnham Medical Research Institute, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Xenograft Model Antitumor Assays, MESH: HCT116 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Drug Synergism, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Nude, MAPK p38, MESH: Protein Kinase Inhibitors, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, MESH: Colonic Neoplasms, MESH: Humans, MESH: Phosphorylation, MESH: MAP Kinase Signaling System, MESH: Adenocarcinoma, MESH: Pyridines, MESH: Immunohistochemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Drug Resistance, Neoplasm, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: p38 Mitogen-Activated Protein Kinases, SN38, MESH: Antineoplastic Combined Chemotherapy Protocols, Drug resistance, MESH: Isoenzymes, MESH: Camptothecin, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, MESH: Imidazoles
Abstract: International audience; Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer.
Published: 2011
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22. A gastrin precursor, gastrin-gly, upregulates VEGF expression in colonic epithelial cells through an HIF-1-independent mechanism

Author: Laurence Daulhac, Aline Kowalski-Chauvel, Souad Najib, Catherine Seva, Cécile Résa, Claudine Bertrand, Audrey Ferrand, Catherine Do, Timothy C. Wang, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie fondamentale et clinique de la douleur, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine, Memorial Sloane Kettering Cancer Center [New York], Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Signal Transduction, Vascular Endothelial Growth Factor A, Cancer Research, Colorectal cancer, Angiogenesis, Fluorescent Antibody Technique, MESH: Gastrins, Immunoenzyme Techniques, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Up-Regulation, Tumor Cells, Cultured, MESH: Animals, MESH: Fluorescent Antibody Technique, Gastrin, 0303 health sciences, MESH: Immunoblotting, Reverse Transcriptase Polymerase Chain Reaction, MESH: Enzyme-Linked Immunosorbent Assay, Up-Regulation, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Signal transduction, Signal Transduction, medicine.medical_specialty, MESH: Mice, Transgenic, Colon, Blotting, Western, Immunoblotting, Enzyme-Linked Immunosorbent Assay, Mice, Transgenic, Biology, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, Article, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, Gastrins, medicine, MESH: Blotting, Western, Animals, Humans, MESH: Tumor Cells, Cultured, RNA, Messenger, MESH: Colon, MESH: Immunoenzyme Techniques, Autocrine signalling, MESH: Mice, PI3K/AKT/mTOR pathway, MESH: RNA, Messenger, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, MESH: Vascular Endothelial Growth Factor A, MESH: 1-Phosphatidylinositol 3-Kinase, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Endocrinology, Cell culture, Cancer research, Proto-Oncogene Proteins c-akt
Abstract: International audience; One of the major angiogenic factor released by tumor cells is VEGF. Its high expression is correlated with poor prognosis in colorectal tumors. In colon cancer, gastrin gene expression is also upregulated. In these tumors, gastrin precursors are mainly produced and act as growth factors. Recently, a study has also shown that the gastrin precursor, G-gly induced in vitro tubules formation by vascular endothelial cells suggesting a potential proangiogenic role. Here, we demonstrate that stimulation of human colorectal cancer cell lines with G-gly increases the expression of the proangiogenic factor VEGF at the mRNA and protein levels. In addition, blocking the progastrin autocrine loop leads to a downregulation of VEGF. Although HIF-1 is a major transcriptional activator for VEGF our results suggest an alternative mechanism for VEGF regulation in normoxic conditions, independent of HIF-1 that involves the PI3K/AKT pathway. Indeed we show that G-gly does not lead to HIF-1 accumulation in colon cancer cells. Moreover, we found that G-gly activates the PI3K/AKT pathway and inhibition of this pathway reverses the effects of G-gly observed on VEGF mRNA and protein levels. In correlation with these results, we observed in vivo, on colon tissue sections from transgenic mice overexpressing G-gly, an increase in VEGF expression in absence of HIF-1 accumulation. In conclusion, our study demonstrates that gastrin precursors, known to promote colon epithelial cells proliferation and survival can also contribute to the angiogenesis process by stimulating the expression of the proangiogenic factor VEGF via the PI3K pathway and independently of hypoxia conditions.
Published: 2010
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23. Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

Author: Valérie Simon, Jean-François Bourgaux, Francisco Cruzalegui, L. Veracini, Frédéric Hollande, Christine Benistant, Audrey Sirvent, Serge Roche, Julie Pannequin, Dubois, Frederic, Centre de recherche en Biologie Cellulaire (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastroentérologie, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Division of Cancer Research and Drug Discovery, Institut de Recherches Servier, Equipe Labellisée 'Ligue Nationale contre le Cancer', Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, MESH: Membrane Microdomains, Down-Regulation, SRC Family Tyrosine Kinase, Biology, medicine.disease_cause, MESH: Membranes, MESH: Phosphoproteins, MESH: Protein-Tyrosine Kinases, MESH: Down-Regulation, CSK Tyrosine-Protein Kinase, 03 medical and health sciences, 0302 clinical medicine, Membrane Microdomains, Downregulation and upregulation, Cell Movement, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neoplasm Invasiveness, MESH: Cell Movement, Molecular Biology, 030304 developmental biology, MESH: Colonic Neoplasms, 0303 health sciences, MESH: Humans, Tyrosine-protein kinase CSK, Membranes, Kinase, MESH: Neoplasm Invasiveness, Protein-Tyrosine Kinases, Phosphoproteins, src-Family Kinases, MESH: src-Family Kinases, 030220 oncology & carcinogenesis, Immunology, Colonic Neoplasms, Cancer research, Phosphorylation, Carcinogenesis, Colorectal Neoplasms, Tyrosine kinase, MESH: Colorectal Neoplasms, Proto-oncogene tyrosine-protein kinase Src
Abstract: International audience; The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Csk-dependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.
Published: 2009
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24. KLF4-dependent, PPARgamma-induced expression of GPA33 in colon cancer cell lines

Author: Julie Rageul, Marc G. Denis, Frank J. Gonzalez, Anne Jarry, Christian L. Laboisse, Sandrine Théoleyre, Stéphanie Mottier, Yatrik M. Shah, D. Masson, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Biologie et physiopathologie intestinales. Pharmacologie nutritionnelle, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Cancer Research, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Cancer Research, MESH: Cyclin D1, MESH: Membrane Glycoproteins, Peroxisome proliferator-activated receptor, MESH: Down-Regulation, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: RNA, Small Interfering, Tumor Cells, Cultured, Cyclin D1, RNA, Small Interfering, chemistry.chemical_classification, MESH: Chromatin Immunoprecipitation, 0303 health sciences, Membrane Glycoproteins, Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Neoplastic, Oncology, KLF4, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Kruppel-Like Transcription Factors, Cyclin-Dependent Kinase Inhibitor p21, Chromatin Immunoprecipitation, medicine.medical_specialty, Blotting, Western, Kruppel-Like Transcription Factors, Down-Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, MESH: Cyclin-Dependent Kinase Inhibitor p21, Kruppel-Like Factor 4, 03 medical and health sciences, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Ciglitazone, medicine, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Tumor Cells, Cultured, 030304 developmental biology, MESH: RNA, Messenger, GPA33, MESH: Colonic Neoplasms, MESH: Humans, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, PPAR gamma, Endocrinology, chemistry, MESH: PPAR gamma, Cancer research, Chromatin immunoprecipitation
Abstract: International audience; The glycoprotein A33 (GPA33) is a colon cancer antigen. Phase I trials with 131I and 125I monoclonal antibody A33 in colon carcinoma patients showed excellent localization to colorectal cancer and some evidence of tumor response. Using DNA microarrays, we have identified the GPA33 gene as a target of PPARgamma in HT29-Cl.16E colon cancer cells. Treatment of HT29-Cl.16E, Caco2, SW1116 and LS174T colon cancer cells with the PPARgamma agonist GW7845 induced a 2- to 6-fold increase in GPA33 mRNA as determined by real-time PCR. This induction was also found in HT29-Cl.16E cells treated with rosiglitazone and ciglitazone and was prevented by cotreatment with the PPARgamma antagonist GW9662, indicating that this regulation was PPARgamma dependent. No canonical PPAR responsive element was found in the GPA33 promoter. We therefore analyzed the expression of transcription factors involved in GPA33 expression. CDXl, CDX2 and KLF5 expression was not modified by PPARgamma activation. By contrast, a significant increase in KLF4 was seen, both at mRNA and protein levels. Furthermore, chromatin immunoprecipitation studies demonstrated that an increased amount of KLF4 protein was bound to the GPA33 promoter in cells treated with rosiglitazone. Finally, downregulation of KLF4 expression by siRNA reduced rosiglitazone-induced GPA33 expression. This indicates that PPARgamma activation induces KLF4 expression, which in turn increases GPA33 expression. We also demonstrate that PPARgamma activation leads to increased (p21WAF1/Cip1 and keratin 19) or decreased (cyclin D1) expression of known KLF4 targets, suggesting that KLF4 is a nodal player in a network of PPARgamma-regulated genes.
Published: 2009
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25. Effects of resveratrol analogs on cell cycle progression, cell cycle associated proteins and 5fluoro-uracil sensitivity in human derived colon cancer cells

Author: Didier Colin, Jean-Claude Izard, Amandine Gimazane, Eric Solary, Dominique Delmas, Norbert Latruffe, Gérard Lizard, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Actichem, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), and Latruffe, Norbert
Subjects: Cancer Research, Cyclin A, Fluorescent Antibody Technique, Cell Cycle Proteins, MESH: Cell Cycle, MESH: Flow Cytometry, MESH : Blotting, Western, Resveratrol, medicine.disease_cause, Wine grape, MESH: Drug Synergism, Immunoenzyme Techniques, chemistry.chemical_compound, MESH: Phenols, MESH : Cell Cycle Proteins, MESH : Tumor Cells, Cultured, MESH: Stilbenes, Stilbenes, Tumor Cells, Cultured, MESH : Cell Proliferation, MESH: Fluorescent Antibody Technique, MESH: Antimetabolites, Antineoplastic, biology, Kinase, MESH : Antimetabolites, Antineoplastic, Cell Cycle, food and beverages, Drug Synergism, Cell cycle, Flow Cytometry, MESH : Colonic Neoplasms, Oncology, Biochemistry, Colonic Neoplasms, MESH : Fluorouracil, Fluorouracil, MESH : Phenols, Antimetabolites, Antineoplastic, MESH : Drug Synergism, MESH : Flow Cytometry, Blotting, Western, MESH : Immunoprecipitation, MESH : Stilbenes, MESH: Cell Cycle Proteins, Phenols, MESH : Immunoenzyme Techniques, MESH: Cell Proliferation, MESH : Cell Cycle, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Immunoprecipitation, MESH: Blotting, Western, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Tumor Cells, Cultured, Kinase activity, MESH: Immunoenzyme Techniques, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Benzofurans, Cell Proliferation, MESH: Colonic Neoplasms, MESH: Humans, MESH : Benzofurans, MESH: Immunoprecipitation, MESH : Humans, MESH: Benzofurans, MESH : Fluorescent Antibody Technique, chemistry, Cell culture, biology.protein, Carcinogenesis, MESH: Fluorouracil
Abstract: International audience; Epidemiological studies suggested that trans-resveratrol, a wine grape component, could prevent malignant tumor development. This compound also demonstrated cytostatic and cytotoxic effects on tumor cells in vitro. To obtain trans-resveratrol derivatives with a better cellular uptake and enhanced antiproliferative effects, we synthesized a triacetate derivative as well as an oligomer, epsilon-viniferin and its acetylated form, epsilon-viniferin penta-acetate. We also obtained vineatrol, a wine grape shoot extract that associates several polyphenols that may act synergistically, including trans-resveratrol and epsilon-viniferin. We show here that resveratrol triacetate and vineatrol are as efficient as trans-resveratrol in inducing the accumulation of human colon cancer cells in early S phase of the cell cycle. This effect is associated with a nuclear redistribution of cyclin A and the formation of a cyclin A/cyclin-dependent kinase 2 complex whose kinase activity is increased. In contrast, epsilon-viniferin and its acetylated form do not demonstrate any significant activity on these cells when tested alone. Interestingly, resveratrol triacetate and vineatrol dramatically enhance 5-Fluoro-Uracil-mediated inhibition of colon cancer cell proliferation. Thus, acetylated derivatives of resveratrol have retained the cytostatic and cytotoxic activities of the parental molecule and thus deserve to be tested as chemosensitizers in animal models.
Published: 2009
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26. Reverse transcription-quantitative polymerase chain reaction: description of a RIN-based algorithm for accurate data normalization

Author: Marc Ychou, Florence Boissière-Michot, Evelyne Lopez-Crapez, Frédéric Bibeau, Dominic Cellier, Alexandre Ho-Pun-Cheung, Eric Assenat, Caroline Bascoul-Mollevi, Merck Santé - Lyon, Merck & Co. Inc, Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Laboratoire d'anatomo-pathologie, Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Le Ster, Yves
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Biopsy, RNA Stability, Statistics as Topic, MESH: Biopsy, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Gene expression, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, 0303 health sciences, lcsh:Cytology, Reverse Transcriptase Polymerase Chain Reaction, Methodology Article, MESH: RNA Stability, MESH: Gene Expression Regulation, 3. Good health, MESH: Reproducibility of Results, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Colonic Neoplasms, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Algorithm, Algorithms, Normalization (statistics), MESH: Cell Line, Tumor, lcsh:QH426-470, MESH: HCT116 Cells, Breast Neoplasms, MESH: Algorithms, Biology, Database normalization, 03 medical and health sciences, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, lcsh:QH573-671, Molecular Biology, MESH: Statistics as Topic, 030304 developmental biology, MESH: Colonic Neoplasms, Messenger RNA, MESH: Humans, Rectal Neoplasms, Reproducibility of Results, MESH: Rectal Neoplasms, RNA, HCT116 Cells, Reverse transcriptase, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, lcsh:Genetics, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, Gene Expression Regulation, MESH: Breast Neoplasms
Abstract: Background Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the gold standard technique for mRNA quantification, but appropriate normalization is required to obtain reliable data. Normalization to accurately quantitated RNA has been proposed as the most reliable method for in vivo biopsies. However, this approach does not correct differences in RNA integrity. Results In this study, we evaluated the effect of RNA degradation on the quantification of the relative expression of nine genes (18S, ACTB, ATUB, B2M, GAPDH, HPRT, POLR2L, PSMB6 and RPLP0) that cover a wide expression spectrum. Our results show that RNA degradation could introduce up to 100% error in gene expression measurements when RT-qPCR data were normalized to total RNA. To achieve greater resolution of small differences in transcript levels in degraded samples, we improved this normalization method by developing a corrective algorithm that compensates for the loss of RNA integrity. This approach allowed us to achieve higher accuracy, since the average error for quantitative measurements was reduced to 8%. Finally, we applied our normalization strategy to the quantification of EGFR, HER2 and HER3 in 104 rectal cancer biopsies. Taken together, our data show that normalization of gene expression measurements by taking into account also RNA degradation allows much more reliable sample comparison. Conclusion We developed a new normalization method of RT-qPCR data that compensates for loss of RNA integrity and therefore allows accurate gene expression quantification in human biopsies.
Published: 2009
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27. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH

Author: Nathalie M. Mazure, Frédéric Dayan, Jacques Pouysségur, Karine Ilc, Johanna Chiche, Julie Laferrière, Eric Trottier, M. Christiane Brahimi-Horn, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
Subjects: Male, Cancer Research, MESH: Hydrogen-Ion Concentration, Cytoplasm, MESH: Cell Hypoxia, MESH: Spheroids, Cellular, MESH: Antigens, Neoplasm, MESH: Cricetinae, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Cricetulus, Cricetinae, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Carbonic Anhydrases, chemistry.chemical_classification, 0303 health sciences, biology, Hydrogen-Ion Concentration, Cell Hypoxia, Oncology, Biochemistry, 030220 oncology & carcinogenesis, Enzyme Induction, MESH: Cell Growth Processes, Colonic Neoplasms, Acidosis, Intracellular, MESH: Enzyme Induction, MESH: Carbonic Anhydrases, MESH: Cell Line, Tumor, Intracellular pH, Bicarbonate, Mice, Nude, Cell Growth Processes, MESH: Acidosis, 03 medical and health sciences, Cricetulus, Antigens, Neoplasm, Carbonic anhydrase, Cell Line, Tumor, Spheroids, Cellular, MESH: Mice, Nude, Animals, Humans, Carbonic Anhydrase IX, MESH: Mice, 030304 developmental biology, MESH: Colonic Neoplasms, Tumor microenvironment, MESH: Humans, Cell growth, MESH: Cytoplasm, Carbonic Anhydrase 9, Fibroblasts, MESH: Male, Enzyme, chemistry, 13. Climate action, MESH: Fibroblasts, biology.protein, Cancer research
Abstract: Acidosis of the tumor microenvironment is typical of a malignant phenotype, particularly in hypoxic tumors. All cells express multiple isoforms of carbonic anhydrase (CA), enzymes catalyzing the reversible hydration of carbon dioxide into bicarbonate and protons. Tumor cells express membrane-bound CAIX and CAXII that are controlled via the hypoxia-inducible factor (HIF). Despite the recognition that tumor expression of HIF-1α and CAIX correlates with poor patient survival, the role of CAIX and CAXII in tumor growth is not fully resolved. To understand the advantage that tumor cells derive from expression of both CAIX and CAXII, we set up experiments to either force or invalidate the expression of these enzymes. In hypoxic LS174Tr tumor cells expressing either one or both CA isoforms, we show that (a) in response to a “CO2 load,” both CAs contribute to extracellular acidification and (b) both contribute to maintain a more alkaline resting intracellular pH (pHi), an action that preserves ATP levels and cell survival in a range of acidic outside pH (6.0–6.8) and low bicarbonate medium. In vivo experiments show that ca9 silencing alone leads to a 40% reduction in xenograft tumor volume with up-regulation of ca12 mRNA levels, whereas invalidation of both CAIX and CAXII gives an impressive 85% reduction. Thus, hypoxia-induced CAIX and CAXII are major tumor prosurvival pHi-regulating enzymes, and their combined targeting shows that they hold potential as anticancer targets. [Cancer Res 2009;69(1):358–68]
Published: 2009
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28. CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer

Author: Bruno Chauffert, Grégoire Lauvau, Eric Solary, Hideo Yagita, Laurence Zitvogel, François Martin, Stephan Roux, Fanny Chalmin, Pierre Emmanuel Puig, Grégoire Mignot, Sylvain Ladoire, François Ghiringhelli, Lionel Apetoh, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Immunologie des Maladies Infectieuses Allergiques et Autoimmunes, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Immunology, Juntendo University School of Medicine, We received grant support from Fondation pour la Recherche Médicale (to S. Roux and L. Apetoh), Association pour la Recherche contre le Cancer (to G. Mignot), and Institut National de la Santé et de la Recherche Médicale (to F. Ghiringhelli). This work was supported by special grants from the Ligue contre le Cancer de Bourgogne and the Association pour la Recherche contre le Cancer., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mignot, Grégoire, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: CD4-Positive T-Lymphocytes, Male, MESH : Rats, Inbred Strains, T-Lymphocytes, Regulatory, MESH : TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand, MESH : T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, Neoplasms, Cytotoxic T cell, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Neoplasms, IL-2 receptor, Cytotoxicity, Cells, Cultured, 0303 health sciences, Mice, Inbred BALB C, MESH: Dendritic Cells, MESH : Rats, MESH: CD4-Positive T-Lymphocytes, MESH : Mice, Nude, hemic and immune systems, General Medicine, MESH: Rats, Inbred Strains, 3. Good health, MESH : Colonic Neoplasms, MESH : CD4-Positive T-Lymphocytes, Colonic Neoplasms, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: TNF-Related Apoptosis-Inducing Ligand, MESH: Cells, Cultured, Research Article, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Rats, MESH : Male, MESH: Mice, Inbred BALB C, Mice, Nude, chemical and pharmacologic phenomena, Biology, 03 medical and health sciences, Immune system, Cell Line, Tumor, MESH : Cells, Cultured, MESH : Mice, MESH: Mice, Nude, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, MESH: Colonic Neoplasms, Innate immune system, MESH : Cell Line, Tumor, MESH: T-Lymphocytes, Regulatory, TLR9, Rats, Inbred Strains, Dendritic Cells, MESH : Neoplasms, MESH : Disease Models, Animal, MESH: Male, Rats, TLR2, Disease Models, Animal, MESH : Dendritic Cells, Immunology, TLR4, MESH : Animals, MESH: Disease Models, Animal, 030215 immunology
Abstract: International audience; Tumors that progress do so via their ability to escape the antitumor immune response through several mechanisms, including developing ways to induce the differentiation and/or recruitment of CD4(+)CD25(+) Tregs. The Tregs, in turn, inhibit the cytotoxic function of T cells and NK cells, but whether they have an effect on the cytotoxic function of tumor-infiltrating DCs (TIDCs) has not been determined. Here we have shown, in 2 rodent models of colon cancer, that CD4(+)CD25(+) Tregs inhibit the ability of CD11b(+) TIDCs to mediate TNF-related apoptosis-inducing ligand-induced (TRAIL-induced) tumor cell death. In both models of cancer, combination treatment with Mycobacterium bovis Bacillus Calmette-Guérin (BCG), which activates the innate immune system via TLR2, TLR4, and TLR9, and cyclophosphamide (CTX), which depletes Tregs, eradicated the tumors. Further analysis revealed that the treatment led to a marked increase in the number of CD11b(+) TIDCs that killed the tumor cells via a TRAIL-dependent mechanism. Furthermore, acquisition of TRAIL expression by the CD11b(+) TIDCs was induced by BCG and dependent on signaling through TLR2, TLR4, and TLR9. In vivo transfer of Tregs abrogated the ability of BCG to induce CD11b(+) TIDCs to express TRAIL and thereby nullified the efficacy of the CTX-BCG treatment. Our data have therefore delineated what we believe to be a novel mechanism by which Tregs inhibit the antitumor immune response.
Published: 2008
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29. Radiocurability by targeting tumor necrosis factor-alpha using a bispecific antibody in carcinoembryonic antigen transgenic mice

Author: André Pèlegrin, Bruno Robert, David Azria, Lore Santoro, Frédéric Bibeau, Sophie Gourgou, Christel Larbouret, Pierre Martineau, Isabelle Teulon, Christine Linard, Jean-Pierre Pouget, Immunociblage et radiobiologie en oncologie, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Unité de biostatistiques en Oncologie, CRLC Val d'Aurelle, Laboratoire d'anatomo-pathologie, CRLCC Val d'Aurelle - Paul Lamarque, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 'Comité de l'Hérault de la Ligue Nationale Contre le Cancer' and 'Fondation Gustave et Simone Prévot', and Le Ster, Yves
Subjects: Cancer Research, Pathology, MESH: Combined Modality Therapy, Necrosis, medicine.medical_treatment, Bispecific antibody, MESH: Random Allocation, Drug Evaluation, Preclinical, Mice, Random Allocation, 0302 clinical medicine, Carcinoembryonic antigen, Antibodies, Bispecific, MESH: Immunocompromised Host, MESH: Animals, Tumor Stem Cell Assay, Radiation, biology, MESH: Tumor Stem Cell Assay, synergism, Combined Modality Therapy, 3. Good health, Cytokine, Oncology, MESH: Cell Survival, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Drug Evaluation, Preclinical, Tumor necrosis factor alpha, Antibody, medicine.symptom, medicine.medical_specialty, MESH: Carcinoembryonic Antigen, Cell Survival, MESH: Mice, Transgenic, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunocompromised Host, 03 medical and health sciences, CEA-transgenic mice, MESH: Antibodies, Bispecific, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, In vivo, Tumor Necrosis FactorΑ, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, RNA, Messenger, Clonogenic assay, MESH: Mice, MESH: RNA, Messenger, MESH: Colonic Neoplasms, MESH: Humans, Tumor Necrosis Factor-alpha, business.industry, radiotherapy enhancement, Carcinoembryonic Antigen, MESH: Tumor Necrosis Factor-alpha, biology.protein, Cancer research, business, 030215 immunology
Abstract: International audience; PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) enhances radiotherapy (RT) killing of tumor cells in vitro and in vivo. To overcome systemic side effects, we used a bispecific antibody (BsAb) directed against carcinoembryonic antigen (CEA) and TNF-alpha to target this cytokine in a CEA-expressing colon carcinoma. We report the evaluation of this strategy in immunocompetent CEA-transgenic mice. METHODS AND MATERIALS: The murine CEA-transfected colon carcinoma MC-38 was used for all experiments. In vitro, clonogenic assays were performed after RT alone, TNF-alpha alone, and RT plus TNF-alpha. In vivo, the mice were randomly assigned to treatment groups: control, TNF-alpha, BsAb, BsAb plus TNF-alpha, RT, RT plus TNF-alpha, and RT plus BsAb plus TNF-alpha. Measurements of endogenous TNF-alpha mRNA levels and evaluation of necrosis (histologic evaluation) were assessed per treatment group. RESULTS: In vitro, combined RT plus TNF-alpha resulted in a significant decrease in the survival fraction at 2 Gy compared with RT alone (p < 0.00001). In vivo, we observed a complete response in 5 (50%) of 10, 2 (20%) of 10, 2 (18.2%) of 11, and 0 (0%) of 12 treated mice in the RT plus BsAb plus TNF-alpha, RT plus TNF-alpha, RT alone, and control groups, respectively. This difference was statistically significant when TNF-alpha was targeted with the BsAb (p = 0.03). The addition of exogenous TNF-alpha to RT significantly increased the endogenous TNF-alpha mRNA level, particularly when TNF-alpha was targeted with BsAb (p < 0.01). The percentages of necrotic area were significantly augmented in the RT plus BsAb plus TNF-alpha group. CONCLUSION: These results suggest that targeting TNF-alpha with the BsAb provokes RT curability in a CEA-expressing digestive tumor syngenic model and could be considered as a solid rationale for clinical trials.
Published: 2007
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30. Phosphatidylethanol Accumulation Promotes Intestinal Hyperplasia by Inducing ZONAB-Mediated Cell Density Increase in Response to Chronic Ethanol Exposure

Author: Frédéric Hollande, Jean-François Bourgaux, Dominique Joubert, Charbel Darido, Nathalie Delaunay, Maria S. Balda, Tangui Maurice, Julie Pannequin, Michael A. Frohman, Philippe Crespy, Karl Matter, Jean-Pierre Bali, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University College of London [London] (UCL), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Herrada, Anthony, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Mécanismes moléculaires dans les démences neurodégénératives (MMDN - U710 Inserm)
Subjects: Cancer Research, Cell Count, MESH: Alcohol Dehydrogenase, MESH: Heat-Shock Proteins, MESH: CCAAT-Enhancer-Binding Proteins, MESH: Claudin-1, Mice, chemistry.chemical_compound, 0302 clinical medicine, Claudin-1, MESH: Animals, Heat-Shock Proteins, 0303 health sciences, MESH: Zonula Occludens-1 Protein, biology, Hyperplasia, Endocytosis, 3. Good health, Cell biology, Intestines, Oncology, Biochemistry, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Endocytosis, MESH: Phospholipase D, MESH: Caco-2 Cells, MESH: Membrane Proteins, MESH: Intestines, MESH: Ethanol, Glycerophospholipids, Adenocarcinoma, MESH: Phosphoproteins, 03 medical and health sciences, Phospholipase D, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell adhesion, Molecular Biology, MESH: Mice, 030304 developmental biology, Alcohol dehydrogenase, MESH: Colonic Neoplasms, Ethanol, MESH: Humans, MESH: Hyperplasia, MESH: Cell Count, MESH: Adenocarcinoma, Alcohol Dehydrogenase, Acetaldehyde, Membrane Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Phosphoproteins, medicine.disease, MESH: Glycerophospholipids, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, chemistry, CCAAT-Enhancer-Binding Proteins, Zonula Occludens-1 Protein, Cancer research, biology.protein, Phosphatidylethanol, Caco-2 Cells
Abstract: Chronic alcohol consumption is associated with increased risk of gastrointestinal cancer. High concentrations of ethanol trigger mucosal hyperregeneration, disrupt cell adhesion, and increase the sensitivity to carcinogens. Most of these effects are thought to be mediated by acetaldehyde, a genotoxic metabolite produced from ethanol by alcohol dehydrogenases. Here, we studied the role of low ethanol concentrations, more likely to mimic those found in the intestine in vivo, and used intestinal cells lacking alcohol dehydrogenase to identify the acetaldehyde-independent biological effects of ethanol. Under these conditions, ethanol did not stimulate the proliferation of nonconfluent cells, but significantly increased maximal cell density. Incorporation of phosphatidylethanol, produced from ethanol by phospholipase D, was instrumental to this effect. Phosphatidylethanol accumulation induced claudin-1 endocytosis and disrupted the claudin-1/ZO-1 association. The resulting nuclear translocation of ZONAB was shown to mediate the cell density increase in ethanol-treated cells. In vivo, incorporation of phosphatidylethanol and nuclear translocation of ZONAB correlated with increased proliferation in the colonic epithelium of ethanol-fed mice and in adenomas of chronic alcoholics. Our results show that phosphatidylethanol accumulation after chronic ethanol exposure disrupts signals that normally restrict proliferation in highly confluent intestinal cells, thus facilitating abnormal intestinal cell proliferation. (Mol Cancer Res 2007;5(11):1147–57)
Published: 2007
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31. Cyclin-dependent kinase 2/cyclin E complex is involved in p120 catenin (p120ctn)-dependent cell growth control: a new role for p120ctn in cancer

Author: M. Laine, Christiane Oddou, C Marie, Muriel R. Jacquier-Sarlin, Benjamin Ducarouge, Marc R. Block, Nicolas T. Chartier, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des systèmes d'adhérence et différenciation (DySAD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ARC Ligue Nationale contre le cancer, and Block, Marc
Subjects: Cancer Research, Cytoplasm, Delta Catenin, Cyclin E, Cyclin D, Cyclin A, MESH: HT29 Cells, Cyclin B, MESH: Cell Cycle, MESH: Centrosome, MESH: Gene Amplification, 0302 clinical medicine, MESH: Up-Regulation, Phosphorylation, 0303 health sciences, biology, MESH: Genomic Instability, Cell Cycle, Catenins, 16. Peace & justice, 3. Good health, Cell biology, Up-Regulation, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Cell Growth Processes, Disease Progression, MESH: Cell Adhesion Molecules, MESH: Disease Progression, HT29 Cells, animal structures, MESH: Cyclin-Dependent Kinase 2, Recombinant Fusion Proteins, Green Fluorescent Proteins, Cell Growth Processes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Phosphoproteins, Article, Genomic Instability, 03 medical and health sciences, MESH: Green Fluorescent Proteins, MESH: Recombinant Fusion Proteins, Humans, Mitosis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Catenins, 030304 developmental biology, Centrosome, MESH: Colonic Neoplasms, MESH: Humans, MESH: Phosphorylation, MESH: Cytoplasm, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 2, Gene Amplification, Phosphoproteins, MESH: Cyclin E, Cyclin-dependent kinase complex, biology.protein, Cancer research, Cell Adhesion Molecules, Cyclin A2
Abstract: Depending on its cellular localization, p120 catenin (p120ctn) can participate in various processes, such as cadherin-dependent cell-cell adhesion, actin cytoskeleton remodeling, and intracellular trafficking. Recent studies also indicate that p120ctn could regulate cell proliferation and contact inhibition. This report describes a new function of p120ctn in the regulation of cell cycle progression. Overexpression of the p120ctn isoform 3A in human colon adenocarcinoma cells (HT-29) results in cytoplasmic accumulation of the protein, as observed in many tumors. This cytoplasmic increase is correlated with a reduction in proliferation and inhibition of DNA synthesis. Under these conditions, experiments on synchronized cells revealed a prolonged S phase associated with cyclin E stabilization. Both confocal microscopy and biochemical analysis showed that cyclin E and cyclin-dependent kinase 2 colocalized with p120ctn in centrosomes during mitosis. These proteins are associated in a functional complex evidenced by coimmunoprecipitation experiments and the emergence of Thr199-phosphorylated nucleophosmin/B23. Such post-translational modification of this centrosomal target has been shown to trigger the initiation of centrosome duplication. Therefore, p120ctn-mediated accumulation of cyclin E in centrosomes may participate in abnormal amplification of centrosomes and the inhibition of DNA replication, thus leading to aberrant mitosis and polyploidy. Because these modifications are often observed in cancer, p120ctn may represent a new therapeutic target for future therapy. [Cancer Res 2007;67(20):9781–90]
Published: 2007
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32. Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer

Author: Pierre Levy, Nicole Maurin, Marie-Elisabeth Forgue-Lafitte, Bettina Fabiani, Jean-François Fléjou, Jacques Bara, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Cancer Research, Pathology, Colorectal cancer, Mucin 5AC, MESH: Mucins, Gastroenterology, 0302 clinical medicine, fluids and secretions, Medicine, Intestinal Mucosa, 0303 health sciences, MESH: Middle Aged, MESH: Mucin 5AC, Diverticulitis, Middle Aged, respiratory system, Ulcerative colitis, Immunohistochemistry, 3. Good health, MESH: Precancerous Conditions, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, MESH: Intestinal Mucosa, Adenocarcinoma, Immunoradiometric Assay, Aberrant crypt foci, medicine.medical_specialty, Colon, MESH: Colitis, Ulcerative, digestive system, 03 medical and health sciences, MESH: Diverticulitis, Internal medicine, Humans, MESH: Colon, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, business.industry, Mucin, Mucins, Cancer, MESH: Immunohistochemistry, medicine.disease, Mucus, digestive system diseases, Colitis, Ulcerative, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Immunoradiometric Assay, business, Precancerous Conditions
Abstract: International audience; The abnormal expression of gastric M1/MUC5AC mucin in precancerous lesions and colon cancer evidenced by immunohistochemistry led us to check for its presence in the mucus obtained directly from patients undergoing surgery for cancerous (adenocarcinoma) or inflammatory (diverticulitis or ulcerative colitis) diseases. In parallel, the authors quantified aberrant crypt foci (ACF) and their immunolabelling by M1/MUC5AC in mucosae of cancer and diverticulitis patients. Immuno-Radio-Metric Assay of M1/MUC5AC mucin developed by the authors was used to detect M1/MUC5AC mucin in the colonic mucus scraped from surgical specimens. M1/MUC5AC mucin was detected in the mucus of 51/69 (74%) patients with colon adenocarcinoma, versus 7/27 (26%) patients with diverticulitis (threshold: 30 units of M1 mucin per mg protein, area under ROC curve: 0.80). M1/MUC5AC was present in significantly (p < 0.001) larger amounts in the mucus of cancer versus diverticulitis patients. All (10/10) patients with ulcerative colitis tested showed levels above the threshold and their mucosae were strongly labelled with the anti-M1/MUC5AC antibody by immunohistochemistry. Patients with cancer exhibited 3 fold more ACF than those with diverticulitis, but no significant difference was observed in the mean size and M1/MUC5AC expression pattern of ACF between these two groups. The expression of M1/MUC5AC was in correlation with their size. In macroscopically normal mucosa, ACF were the most important source of M1/MUC5AC mucin. Testing of M1/MUC5AC can enhance the detection of precancerous lesions and colon cancer.
Published: 2007
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33. Cisplatin-induced apoptosis involves membrane fluidification via inhibition of NHE1 in human colon cancer cells

Author: Morgane Gorria, Marie-Thérèse Dimanche-Boitrel, Bernd Kaina, Erich Gulbins, Martine Chevanne, Markus Christmann, Olivier Meurette, Laurent Vernhet, Odile Sergent, Laurent Counillon, Amélie Rébillard, Gwenaëlle LeMoigne-Muller, Dominique Lagadic-Gossmann, Xavier Tekpli, Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Biology, Ligue Nationale Contre le Cancer (the Côte d'Armor, Ille et Vilaine and Loire-Atlantique Comittees), Rennes Métropole, Région Bretagne., École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Cancer Research, MESH: Drug Interactions, MESH: HT29 Cells, MESH: Membrane Microdomains, cisplatin, Apoptosis, Guanidines, Cell membrane, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, Membrane fluidity, Drug Interactions, Sulfones, acid sphingomyelinase, Cation Transport Proteins, Lipid raft, 0303 health sciences, Sodium-Hydrogen Exchanger 1, membrane fluidity, MESH: Sulfones, 3. Good health, Cell biology, MESH: Guanidines, Cholesterol, medicine.anatomical_structure, Oncology, Biochemistry, colon cancer, 030220 oncology & carcinogenesis, Colonic Neoplasms, NHE1, Acid sphingomyelinase, Sphingomyelin, HT29 Cells, Intracellular, medicine.drug, Ceramide, Sodium-Hydrogen Exchangers, MESH: HCT116 Cells, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Cation Transport Proteins, Membrane Microdomains, medicine, Humans, 030304 developmental biology, Cisplatin, MESH: Colonic Neoplasms, MESH: Humans, MESH: Sodium-Hydrogen Antiporter, MESH: Apoptosis, HCT116 Cells, chemistry, MESH: Cisplatin, MESH: Antineoplastic Agents, MESH: Membrane Fluidity
Abstract: We have previously shown that cisplatin triggers an early acid sphingomyelinase (aSMase)-dependent ceramide generation concomitantly with an increase in membrane fluidity and induces apoptosis in HT29 cells. The present study further explores the role and origin of membrane fluidification in cisplatin-induced apoptosis. The rapid increase in membrane fluidity following cisplatin treatment was inhibited by membrane-stabilizing agents such as cholesterol or monosialoganglioside-1. In HT29 cells, these compounds prevented the early aggregation of Fas death receptor and of membrane lipid rafts on cell surface and significantly inhibited cisplatin-induced apoptosis without altering drug intracellular uptake or cisplatin DNA adducts formation. Early after cisplatin treatment, Na+/H+ membrane exchanger-1 (NHE1) was inhibited leading to intracellular acidification, aSMase was activated, and ceramide was detected at the cell membrane. Treatment of HT29 cells with Staphylococcus aureus sphingomyelinase increased membrane fluidity. Moreover, pretreatment with cariporide, a specific inhibitor of NHE1, inhibited cisplatin-induced intracellular acidification, aSMase activation, ceramide membrane generation, membrane fluidification, and apoptosis. Finally, NHE1-expressing PS120 cells were more sensitive to cisplatin than NHE1-deficient PS120 cells. Altogether, these findings suggest that the apoptotic pathway triggered by cisplatin involves a very early NHE1-dependent intracellular acidification leading to aSMase activation and increase in membrane fluidity. These events are independent of cisplatin-induced DNA adducts formation. The membrane exchanger NHE1 may be another potential target of cisplatin, increasing cell sensitivity to this compound. [Cancer Res 2007;67(16):7865–74]
Published: 2007
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34. Expression of TFF3 during multistep colon carcinogenesis

Author: John, R., El-Rouby, N. M., Catherine Tomasetto, Rio, M. C., Karam, S. M., Biologie moléculaire et génie génétique (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Peney, Maité, and Laboratoire de Biologie structurale
Subjects: Adult, MESH: Adenocarcinoma, Mucinous, Colon, MESH: Adenoma, Villous, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Proliferating Cell Nuclear Antigen, MESH: Cell Proliferation, MESH: Colitis, Adenoma, Villous, Humans, Neoplasm Invasiveness, MESH: Colon, Cell proliferation, Cell Proliferation, MESH: Colonic Neoplasms, MESH: Humans, MESH: Middle Aged, MESH: Peptides, MESH: Immunohistochemistry, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Neoplasm Invasiveness, Middle Aged, Colitis, Adenocarcinoma, Mucinous, Immunohistochemistry, MESH: Adenomatous Polyposis Coli, digestive system diseases, Colon cancer, 616 - Patología. Medicina clínica. Oncología, Cell Transformation, Neoplastic, MESH: Proliferating Cell Nuclear Antigen, Adenomatous Polyposis Coli, MESH: Cell Transformation, Neoplastic, Colonic Neoplasms, Disease Progression, MESH: Disease Progression, Trefoil Factor-3, Peptides
Abstract: The pathogenesis of colon cancer is not well understood. This common type of cancer is generally believed to occur in a multistep process which involves alterations of various tumor suppressor genes and oncogenes during the progression through benign lesions towards carcinoma. TFF3 is a product of the colonic epithelium and has been implicated in colonic mucosal protection and also in the aggressiveness of colon cancer cells. The aim of this study was to analyze the expression of TFF3 during propagation towards cancer development in the human colon. Colonic tissues representing colitis, adenomatous polyposis, tubulovillous adenoma, and mucoid/adeno-carcinomas were processed for immunohistochemistry using an antibody specific for human TFF3. The results were correlated with those of PCNA-labeling, quantified, and compared with those of control tissues obtained from the safe margin of macroscopically normal colonic mucosa of patients with colon cancer. The data showed marked down-regulation of TFF3 expression in adenomatous polyposis, then TFF3 expression returns to about control level during adenoma and remains high during mucoidand adeno-carcinomas. Colonic tissues with highly invasive cancer cells were characterized by statistically significant down-regulation of TFF3 expression. The changes observed in expression of TFF3 showed an inverse correlation with cell proliferation and suggest that it might play a protective role against colon carcinogenesis. Key words
Published: 2007

35. Nitric oxide inhibits Shiga-toxin synthesis by enterohemorrhagic Escherichia coli

Author: Alain P. Gobert, Marjolaine Vareille, Thibaut de Sablet, Thomas Hindré, Christine Martin, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), and Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Genes, Viral, medicine.disease_cause, IMMUNOLOGIE, Virulence factor, chemistry.chemical_compound, hemic and lymphatic diseases, SOS response, 0303 health sciences, MESH: Gene Expression Regulation, Bacterial, MESH: Genes, Viral, Multidisciplinary, MESH: Mitomycin, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Shiga toxin, Biological Sciences, Bacteriophage lambda, 3. Good health, INFECTIONS, MESH: Epithelial Cells, MESH: Escherichia coli O157, LEXA PROTEIN, Colonic Neoplasms, GENES, MESH: Cell Line, Tumor, Mitomycin, MESH: Shiga Toxin, Repressor, COMPLETE NUCLEOTIDE-SEQUENCE, Biology, Escherichia coli O157, Nitric Oxide, Nitric oxide, Microbiology, O157-H7, Shiga Toxin, MESH: Coculture Techniques, 03 medical and health sciences, MESH: Bacteriophage lambda, Cell Line, Tumor, medicine, Humans, Nitric Oxide Donors, RNA, Messenger, Escherichia coli, METHIONINE BIOSYNTHESIS, 030304 developmental biology, REGULATORS, MESH: RNA, Messenger, MESH: Colonic Neoplasms, Innate immune system, MESH: Humans, 030306 microbiology, Mutagenesis, Epithelial Cells, Gene Expression Regulation, Bacterial, MESH: Nitric Oxide Donors, Molecular biology, BACTERIAL INFECTION, MUCOSAL IMMUNOLOGY, Coculture Techniques, MODEL, Mutagenesis, Insertional, chemistry, MESH: Mutagenesis, Insertional, MESH: Nitric Oxide, biology.protein, HEMOLYTIC-UREMIC SYNDROME, SAKAI OUTBREAK
Abstract: Shiga-toxin (Stx) is the cardinal virulence factor of enterohemorrhagic Escherichia coli (EHEC). The genes encoding Stx are carried by a lambdoid phage integrated in the bacterial genome and are fully expressed after a bacterial SOS response induced by DNA-damaging agents. Because nitric oxide (NO) is an essential mediator of the innate immune response of infected colonic mucosa, we aimed to determine its role in Stx production by EHEC. Here we demonstrate that chemical or cellular sources of NO inhibit spontaneous and mitomycin C-induced stx mRNA expression and Stx synthesis, without altering EHEC viability. The synthesis of stx phage is also reduced by NO. This inhibitory effect apparently occurs through the NO-mediated sensitization of EHEC because mutation of the NO sensor nitrite-sensitive repressor results in loss of NO inhibiting activity on stx expression. Thus our findings identify NO as an inhibitor of stx expressing-phage propagation and Stx release and thus as a potential protective factor limiting the development of hemolytic syndromes.
Published: 2007
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36. Progression of tumors arising from large ACF is associated with the MUC5AC expression during rat colon MNNG carcinogenis

Author: Nicole Maurin, Marie-Elisabeth Forgue-Lafitte, Jacques Bara, A. Zimber, Pierre Levy, Service d'oto-rhino-laryngologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Maurin N, Forgue-Lafitte ME, Levy P, Zimber A, Bara J., Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, Cancer Research, Pathology, Time Factors, Colorectal cancer, Mucin 5AC, MESH: Mucins, medicine.disease_cause, MESH: Antibodies, Monoclonal, 0302 clinical medicine, Gene expression, Medicine, MESH: Animals, Intestinal Mucosa, 0303 health sciences, MESH: Mucin 5AC, Antibodies, Monoclonal, respiratory system, Immunohistochemistry, 3. Good health, Colon carcinogenesis, MESH: Precancerous Conditions, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Disease Progression, MESH: Intestinal Mucosa, MESH: Disease Progression, Human colon, Aberrant crypt foci, Adenoma, medicine.medical_specialty, Methylnitronitrosoguanidine, MESH: Rats, Adenocarcinoma, digestive system, 03 medical and health sciences, Animals, Rats, Wistar, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Adenoma, business.industry, Mucin, MESH: Adenocarcinoma, MESH: Time Factors, Mucins, MESH: Methylnitronitrosoguanidine, MESH: Immunohistochemistry, MESH: Rats, Wistar, medicine.disease, digestive system diseases, MESH: Male, Rats, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Carcinogenesis, Precancerous Conditions
Abstract: International audience; Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomas, precursors of colon cancer. The gastric M1/MUC5AC mucin has also been described as an early marker of colon carcinogenesis in the human and in the rat. To study changes in mucin expression associated with the genesis of tumors, Wistar rats were treated by intrarectal instillations of MNNG, twice a week for 2 weeks, and were sacrificed 10 (n = 20), 14 (n = 20), 22 (n = 20), 30 (n = 10) and 66 (n = 16) weeks after the beginning of the treatment. In the treated rats, the MUC5AC mucin was mainly expressed in ACF compared with the histologically normal mucosae, which showed few isolated MUC5AC-positive normal crypts. During carcinogenesis, the percentage of large ACF [> or =10 aberrant crypts] increased and the number of MUC5AC-positive (NCs) decreased. At Week 30, small tumors were observed arising from large ACF, both types of lesions expressing MUC5AC. At Week 66, large tumors showed remnants of MUC5AC-positive ACF in their adjacent mucosae. This observation suggests that the expression of MUC5AC is associated with the ACF/adenoma sequence and supports the notion of large ACF as precursors of adenomas/adenocarcinomas. Moreover, the expression of MUC5AC in the transitional mucosa adjacent to both rat and human colon tumors suggests that some human tumors could arise from large ACF, and reinforces the concept of the premalignant potential of these lesions.
Published: 2007
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37. Colitis and Colitis-Associated Cancer Are Exacerbated in Mice Deficient for Tumor Protein 53-Induced Nuclear Protein 1▿

Author: Sylvia Pietri, Bernard Malissen, Carla E. Cano, Juan L. Iovanna, Stéphane Garcia, Meritxell Gironella, Julien Gommeaux, Marcel Culcasi, Marie-Josèphe Pébusque, Alice Carrier, Nelson Dusetti, Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie, biologie et radicaux libres - UMR 6517 (CBRL), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Colorectal cancer, MESH: NF-kappa B, medicine.disease_cause, Inflammatory bowel disease, MESH: Mice, Knockout, MESH: Lipid Peroxidation, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Colitis, MESH: Animals, Nuclear protein, Mice, Knockout, 0303 health sciences, MESH: Oxidative Stress, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Dextran Sulfate, NF-kappa B, MESH: Reactive Oxygen Species, Nuclear Proteins, Articles, Colitis, 3. Good health, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Acute Disease, Colonic Neoplasms, MESH: Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Mutation, MESH: Carrier Proteins, Biology, 03 medical and health sciences, medicine, Animals, Molecular Biology, MESH: Mice, Acute colitis, Carcinogen, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Dextran Sulfate, Azoxymethane, MESH: Chronic Disease, Cell Biology, medicine.disease, Oxidative Stress, chemistry, MESH: Cell Transformation, Neoplastic, Immunology, Chronic Disease, Mutation, Cancer research, Lipid Peroxidation, Carcinogenesis, Carrier Proteins, Reactive Oxygen Species, MESH: Nuclear Proteins
Abstract: Tumor protein 53-induced nuclear protein 1 (TP53INP1) is an antiproliferative and proapoptotic protein involved in cell stress response. To address its physiological roles in colorectal cancer and colitis, we generated and tested the susceptibility of Trp53inp1-deficient mice to the development of colorectal tumors induced by injection of the carcinogen azoxymethane followed by dextran sulfate sodium (DSS)-induced chronic colitis. Trp53inp1-deficient mice showed an increased incidence and multiplicity of tumors compared to those of wild-type (WT) mice. Furthermore, acute colitis induced by DSS treatment was more severe in Trp53inp1-deficient mice than in WT mice. Treatment with the antioxidant N-acetylcysteine prevented colitis and colitis-associated tumorigenesis more efficiently in WT mice than in Trp53inp1-deficient mice, suggesting a higher oxidative load in the latter. Consistently, we demonstrated by electron spin resonance and spin trapping that colons derived from deficient mice produced more free radicals than those of the WT during colitis and that the basal blood level of the antioxidant ascorbate was decreased in Trp53inp1-deficient mice. Collectively, these results indicate that the oxidative load is higher in Trp53inp1-deficient mice than in WT mice, generating a more-severe DSS-induced colitis, which favors development of colorectal tumors in Trp53inp1-deficient mice. Therefore, TP53INP1 is a potential target for the prevention of colorectal cancer in patients with inflammatory bowel disease.
Published: 2007
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38. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Author: Franck J. Barrat, Jean Bourhis, Patrick Saulnier, Carla Ortiz, Laurence Zitvogel, Grégoire Mignot, Sebastian Amigorena, Bernard Ryffel, Guido Kroemer, Catherine Noguès, Alfredo Criollo, Suzette Delaloge, Huan Yang, Francis Lévi, Michel Obeid, Agnès Chompret, Paul Saftig, Françoise Clavel-Chapelon, Jean-Paul Mira, M. Chiara Maiuri, Fabrice Andre, Lionel Apetoh, Evelyn Ullrich, Antoine Tesniere, François Ghiringhelli, Virginie Joulin, T. Tursz, Rosette Lidereau, Apetoh, L, Ghiringhelli, F, Tesniere, A, Obeid, M, Ortiz, C, Criollo, A, Mignot, G, Maiuri, MARIA CHIARA, Ullrich, E, Saulnier, P, Yang, H, Amigorena, S, Ryffel, B, Barrat, Fj, Saftig, P, Levi, F, Lidereau, R, Nogues, C, MIRA J., P, Chompret, A, Joulin, V, CLAVEL CHAPELON, F, Bourhis, J, Andr, F, Delaloge, S, Kroemer, G, Zitvogel, L., Institut Gustave Roussy (IGR), Immunologie et Embryologie Moléculaires (IEM), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Cell Line, Tumor, MESH: Osteosarcoma, medicine.medical_treatment, MESH: Mice, Inbred BALB C, Immunoadjuvant, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Medicine, MESH: Animals, MESH: Neoplasms, MESH: Mice, MESH: Colonic Neoplasms, Toll-like receptor, MESH: Humans, business.industry, MESH: Organoplatinum Compounds, MESH: Pyridines, Abscopal effect, Cancer, General Medicine, MESH: Toll-Like Receptor 4, medicine.disease, MESH: Bone Neoplasms, 3. Good health, Radiation therapy, 030220 oncology & carcinogenesis, Immunology, Immunogenic cell death, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Disease Models, Animal, business, 030215 immunology
Abstract: Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.
Published: 2007
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39. TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions

Author: Olivier Micheau, Dominique Lagadic-Gossmann, Laurence Huc, Delphine Merino, Gwenaelle Le Moigne, Olivier Meurette, Amélie Rébillard, Marie-Thérèse Dimanche-Boitrel, Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Laboratoire Mouvement Sport Santé ( M2S ), École normale supérieure - Cachan ( ENS Cachan ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Université de Brest ( UBO ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Ligue Nationale Contre le Cancer (the Morbihan, Côte d'Armor and Ille et Vilaine Comittees), Région Bretagne, Rennes Métropole, Dimanche-Boitrel, Marie-Thérèse, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: Cancer Research, MESH: Hydrogen-Ion Concentration, Necrosis, MESH: HT29 Cells, MESH: NF-kappa B, TRAIL, MESH : RNA, Small Interfering, MESH: Benzoquinones, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, chemistry.chemical_compound, 0302 clinical medicine, MESH: RNA, Small Interfering, Benzoquinones, RNA, Small Interfering, Caspase, 0303 health sciences, biology, pH, NF-kappa B, Geldanamycin, Hydrogen-Ion Concentration, MESH : Lactams, Macrocyclic, 3. Good health, MESH : Colonic Neoplasms, Oncology, 030220 oncology & carcinogenesis, Caspases, Receptor-Interacting Protein Serine-Threonine Kinases, MESH : NF-kappa B, Colonic Neoplasms, medicine.symptom, MESH : Transfection, MESH: TNF-Related Apoptosis-Inducing Ligand, HT29 Cells, Programmed cell death, MESH: Enzyme Activation, Lactams, Macrocyclic, MESH: Receptor-Interacting Protein Serine-Threonine Kinases, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, Tumor cells, 03 medical and health sciences, MESH : HT29 Cells, MESH : Hydrogen-Ion Concentration, Extracellular, medicine, Humans, Kinase activity, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Necrosis, MESH: Caspases, MESH: Humans, MESH: Transfection, MESH : Humans, MESH : Receptor-Interacting Protein Serine-Threonine Kinases, MESH: Lactams, Macrocyclic, MESH : Benzoquinones, Molecular biology, MESH : Necrosis, Enzyme Activation, chemistry, Apoptosis, RIP, Cancer cell, biology.protein, MESH : Caspases, MESH : Enzyme Activation
Abstract: Tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pHe), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown that cancer cells, resistant to TRAIL-induced apoptosis at physiologic pHe (7.4), could be sensitized to TRAIL at acidic pHe (6.5). However, at this acidic pHe, cell death was necrotic. We show here that, in spite of a necrosis-like cell death morphology, caspases are activated and are necessary for TRAIL-induced cell death at acidic pHe in HT29 human colon cancer cells. Furthermore, we observed that, whereas receptor-interacting protein (RIP) was cleaved following TRAIL treatment at physiologic pHe (7.4), it was not cleaved following TRAIL treatment at acidic pHe (6.5). Moreover, RIP degradation by geldanamycin or decrease expression of RIP by small RNA interference transfection inhibited TRAIL-induced necrosis at acidic pHe, showing that RIP was necessary for this necrotic cell death pathway. We also show that RIP kinase activity was essential for this cell death pathway. Altogether, we show that, under acidic pHe conditions, TRAIL induces a necrosis-like cell death pathway that depends both on caspases and RIP kinase activity. Thus, our data suggest for the first time that RIP-dependent necrosis might be a major death pathway in TRAIL-based therapy in solid tumors with acidic pHe. [Cancer Res 2007;67(1):218–26]
Published: 2007
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40. Calreticulin exposure dictates the immunogenicity of cancer cell death

Author: Laurence Zitvogel, Jean-Luc Perfettini, Didier Métivier, Mauro Piacentini, François Ghiringhelli, Maria Castedo, Michel Obeid, Peter van Endert, Grégoire Mignot, Lionel Apetoh, Nathanael Larochette, Gian Maria Fimia, Theoharis Panaretakis, Antoine Tesniere, Noelia Casares, Guido Kroemer, Fabiola Ciccosanti, Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11) - Institut National de la Santé et de la Recherche Médicale (INSERM), National Institute for Infectious Diseases, Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biology, Università degli Studi di Roma Tor Vergata [Roma], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mignot, Grégoire
Subjects: Cell, Apoptosis, Cell Cycle Proteins, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, Protein Phosphatase 1, MESH: Animals, Anthracyclines, Electrophoresis, Gel, Two-Dimensional, MESH: Anthracyclines, MESH: Phagocytosis, Etoposide, MESH: Etoposide, 0303 health sciences, Mice, Inbred BALB C, biology, MESH: Dendritic Cells, MESH: Immunoblotting, Immunogenicity, MESH: Mitomycin, General Medicine, Recombinant Proteins, 3. Good health, Cell biology, Protein Transport, medicine.anatomical_structure, MESH: Neoplasms, Experimental, 030220 oncology & carcinogenesis, MESH: Antigens, Differentiation, Colonic Neoplasms, Immunogenic cell death, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA Interference, medicine.drug, MESH: Protein Transport, Settore BIO/06, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Calreticulin, Mitomycin, MESH: RNA Interference, Immunoblotting, MESH: Mice, Inbred BALB C, Mice, Nude, Antineoplastic Agents, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, MESH: Cell Cycle Proteins, Phagocytosis, Cell Line, Tumor, medicine, MESH: Mice, Nude, Animals, MESH: Mice, 030304 developmental biology, MESH: Colonic Neoplasms, business.industry, MESH: Apoptosis, Mitomycin C, Cell Membrane, Dendritic Cells, Neoplasms, Experimental, MESH: Electrophoresis, Gel, Two-Dimensional, Antigens, Differentiation, Cancer cell, Cancer research, biology.protein, MESH: Antineoplastic Agents, business, Calreticulin, MESH: Cell Membrane
Abstract: International audience; Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.
Published: 2006
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41. Glycine-extended gastrin activates two independent tyrosine-kinases in upstream of p85/p110 phosphatidylinositol 3-kinase in human colonic tumour cells

Author: Aline Kowalski-Chauvel, Julie Pannequin, Audrey Ferrand, Claudine Bertrand, Daniel Fourmy, Catherine Seva, Marlène Dufresne, Biologie et Pathologie Digestive, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Melbourne, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Herrada, Anthony
Subjects: MESH: Signal Transduction, MESH: Gastrins, MESH: Janus Kinase 2, chemistry.chemical_compound, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Gastrin, 0303 health sciences, Janus kinase 2, biology, Kinase, Gastroenterology, General Medicine, Protein-Tyrosine Kinases, 3. Good health, Colon cancer, JAK2, 030220 oncology & carcinogenesis, embryonic structures, Colonic Neoplasms, Glycine-extended gastrin, Electrophoresis, Polyacrylamide Gel, Signal transduction, Tyrosine kinase, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, Src, MESH: Enzyme Activation, animal structures, MESH: HCT116 Cells, Proto-Oncogene Proteins pp60(c-src), [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Protein-Tyrosine Kinases, 03 medical and health sciences, Enzyme activator, [SDV.CAN] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins, MESH: Cell Proliferation, Gastrins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Immunoprecipitation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphatidylinositol, 030304 developmental biology, Cell Proliferation, Colorectal Cancer, MESH: Colonic Neoplasms, MESH: Humans, MESH: Immunoprecipitation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Proto-Oncogene Proteins pp60(c-src), Janus Kinase 2, HCT116 Cells, Molecular biology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Enzyme Activation, MESH: Proto-Oncogene Proteins, chemistry, MESH: Phosphatidylinositol 3-Kinases, biology.protein, Phosphatidylinositol 3-kinase, MESH: Electrophoresis, Polyacrylamide Gel
Abstract: To investigate whether Src, JAK2 and phosphatidylinositol 3-kinase (PI3K) pathways are involved in the proliferation of human colonic tumour cells induced by glycine-extended gastrin (G-gly), the precursor of the mature amidated gastrin and to elucidate the molecular interaction between these three kinases in response to this peptide.Using the human colonic tumour cell line HCT116 as a model, we first measured the activation of PI3K, p60-Src and JAK2 in response to G-gly by in vitro kinase assays. Then we investigated the involvement of these kinases in G-gly-induced cell proliferation by MTT test.G-gly stimulation induced p60-Src, JAK2 and PI3K activation in HCT116. The different pathways were involved in proliferation of human colon cancer cells induced by G-gly. Furthermore, we found that both Src and JAK2 were necessary to PI3K regulation by this peptide. However, we did not find any cross-talk between the two tyrosine kinases.Our results suggest that the p60-Src/PI3K and JAK2/PI3K pathways act independently to mediate G-gly proliferative effect on human colonic tumour cells.
Published: 2006
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42. [Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas]

Author: Olschwang, S., Bonaiti, C., Feingold, J., Frebourg, T., Grandjouan, S., Lasset, C., Pierre Laurent-Puig, Lecuru, F., Millat, B., Sobol, H., Thomas, G., Eisinger, F., Kaniewski, Nadine, Genetique des Tumeurs, Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie génétique, CHU Rouen, Normandie Université (NU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Léon Bérard [Lyon], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de cancérologie et d'immunologie de Marseille (ICIM), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique épidémiologique et structures des populations humaines ( Inserm U535 ), Epidémiologie, sciences sociales, santé publique ( IFR 69 ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Cochin [AP-HP], Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Institut de cancérologie et d'immunologie de Marseille ( ICIM ), and Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], MESH: Mutation, MESH: Disease Susceptibility, Adenocarcinoma, MESH : Adenocarcinoma, MESH : Disease Susceptibility, MESH : Colorectal Neoplasms, Hereditary Nonpolyposis, Humans, MESH : Female, MESH : France, MESH : Rectal Neoplasms, MESH: Colonic Neoplasms, MESH: Humans, Rectal Neoplasms, MESH : Humans, MESH: Adenocarcinoma, MESH: Rectal Neoplasms, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Colorectal Neoplasms, Hereditary Nonpolyposis, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Endometrial Neoplasms, MESH: France, MESH : Colonic Neoplasms, MESH : Endometrial Neoplasms, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Colonic Neoplasms, Mutation, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Disease Susceptibility, France, MESH: Endometrial Neoplasms, MESH : Mutation, MESH: Female
Abstract: BACKGROUND: The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. METHODS: Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. MAIN RECOMMENDATIONS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.
Published: 2006
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43. Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front

Author: Catherine Tomasetto, Elena Roza Motrescu, Marie-Pierre Chenard, Marie-Christine Rio, Kumari L. Andarawewa, Anne Gansmuller, Isabelle Stoll, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Cancer Research, Cell Communication, Metastasis, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Matrix Metalloproteinase 11, Adipocyte, Adipocytes, MESH: Animals, 0303 health sciences, Mice, Inbred BALB C, Adipogenesis, Metalloendopeptidases, Cell Differentiation, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Mice, Inbred BALB C, Connective tissue, MESH: Metalloendopeptidases, Breast Neoplasms, Biology, 03 medical and health sciences, Matrix Metalloproteinase 11, Internal medicine, MESH: Cell Communication, medicine, Animals, Humans, Neoplasm Invasiveness, adipocyte protein 2, Autocrine signalling, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Embryo, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Neoplasm Invasiveness, Fibroblasts, medicine.disease, Embryo, Mammalian, MESH: Male, Endocrinology, chemistry, MESH: Fibroblasts, Cancer cell, Cancer research, biology.protein, MESH: Adipogenesis, MESH: Female, MESH: Breast Neoplasms
Abstract: The initial invasive processes during cancer development remain largely unknown. Stromelysin-3/matrix metalloproteinase 11 (ST3/MMP11) is associated with tumor invasion and poor prognosis. We present novel evidence that adipocytes present at human breast tumor invasive front are induced by cancer cells to express ST3. Using mouse syngeneic model, light and electron microscopy showed that in ST3-deficient mice but not in wild-type mice, forced cancer cell-adipocyte interaction/crosstalk results in adipocyte membrane alteration, allowing cancer cell fat infiltration and death. Thus, adipocytes are involved in initial cancer cell survival into connective tissue, and this effect is ST3 mediated. This suggested that ST3 might play a role in adipocyte metabolism. Accordingly, ST3-deficient mice exhibited fat excess and increased mRNA levels of peroxisome proliferator-activated receptor γ (PPARγ) and adipocyte protein 2 (aP2) adipogenic markers, indicating that, in vivo, ST3 negatively regulates fat homeostasis. Moreover, ST3-deficient mouse embryonic fibroblasts exhibited a dramatic enhanced potential to differentiate into adipocytes associated with increased PPARγ and aP2 expression, and recombinant ST3 treatment reverted their differentiation. Thus, in vitro, ST3 reduces adipocyte differentiation in an autocrine manner. High fibroblasts/adipocytes ratio is a stroma feature, and peritumoral fibroblast origin remains debated. Our results support the concept that invading cancer cells aberrantly restore the negative ST3 function on adipogenesis into proximal adipocytes/preadipocytes, leading to the accumulation/maintenance of a particular peritumoral fibroblast subpopulation. Accordingly, in human breast tumors, we observed that ST3-expressing peritumoral fibroblasts are distinct from α-smooth muscle actin-expressing myofibroblasts. This constitutes the first report of implication of a MMP in cancer cell-adipocyte interaction/crosstalk during early steps of connective tissue invasion.
Published: 2005
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44. Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation

Author: Benoit Lhermitte, Claire Domon-Dell, Isabelle Duluc, Elisabeth Martin, Jean-Noël Freund, Isabelle Gross, Michèle Kedinger, Christian Gaiddon, Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), and Gillot, Isabelle
Subjects: Cancer Research, Transcription, Genetic, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Enzyme Inhibitor, Serine, Mice, 0302 clinical medicine, MESH: Alkaline Phosphatase, Ubiquitin, Chlorocebus aethiops, CDX2 Transcription Factor, Genes, Tumor Suppressor, MESH: Animals, Enzyme Inhibitors, Intestinal Mucosa, Phosphorylation, Conserved Sequence, 0303 health sciences, Alanine, MESH: Conserved Sequence, Kinase, MESH: Amino Acid Substitution, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, MESH: COS Cells, Jejunum, Biochemistry, 030220 oncology & carcinogenesis, COS Cells, Colonic Neoplasms, embryonic structures, MESH: Caco-2 Cells, Homeotic gene, Proteasome Endopeptidase Complex, Tumor suppressor gene, MESH: Alanine, MESH: Cyclin-Dependent Kinase 2, Molecular Sequence Data, Glycine, Biology, Adenocarcinoma, 03 medical and health sciences, Consensus Sequence, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, MESH: Consensus Sequence, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, MESH: Colonic Neoplasms, Sequence Homology, Amino Acid, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 2, MESH: Adenocarcinoma, Alkaline Phosphatase, MESH: Cercopithecus aethiops, digestive system diseases, Amino Acid Substitution, biology.protein, Mutagenesis, Site-Directed, Caco-2 Cells, Carcinogenesis, Protein Processing, Post-Translational, Transcription Factors
Abstract: The Caudal-related homeodomain transcription factor Cdx2 plays a key role in intestinal cell fate determination. Reduction of Cdx2 expression is a feature of many human colon carcinomas and inactivation of one cdx2 allele facilitates the development of invasive adenocarcinoma in the murine colon. Here, we investigated the post-translational regulation of Cdx2. We showed that various forms of Cdx2 coexist in the intestine and colon cancer cell lines, some of them being phosphorylated forms. We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. Using site-specific mutagenesis, we identified serine 281 as a new key residue for Cdx2 phosphorylation. Intriguingly, serine 281 belongs to a conserved motif of four evenly spaced serines (the 4S motif) similar to the one controlling beta-catenin degradation by the proteasome pathway. A nonphosphorylated mutant Cdx2 lacking the 4S motif (4S>A) exhibited reduced polyubiquitination upon proteasome inhibition and increased stability compared to wild-type Cdx2. In addition, we found that this mutant was less efficient to suppress colony formation than wild-type Cdx2. Thus, our data highlight a novel post-translational mechanism controlling Cdx2 degradation via phosphorylation and polyubiquitination, which may be of importance for intestinal development and cancer.
Published: 2005
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45. CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways

Author: Jean-Yves Blay, Laurent Alberti, Nathalie Voorzanger-Rousselot, Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by The Breast Cancer Research Foundation, La Ligue contre le Cancer (Comités Départementaux de la Drôme, de l'Ardèche, du Rhône et de la Savoie)., and Autard, Delphine
Subjects: MESH: Carcinoma, Male, Cancer Research, CD30, Apoptosis, immune system diseases, hemic and lymphatic diseases, Tumor Cells, Cultured, Cytotoxic T cell, Caspase 8, Caspase 3, Lymphoma, Non-Hodgkin, MESH: Carcinoma, Renal Cell, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, BCL10, Caspase 9, Drug Resistance, Multiple, Kidney Neoplasms, Oncology, Caspases, Colonic Neoplasms, Female, Breast carcinoma, Research Article, CD40 Ligand, Antineoplastic Agents, Breast Neoplasms, Ceramides, lcsh:RC254-282, MESH: Drug Resistance, Multiple, MESH: Gene Expression Profiling, MESH: Cell Proliferation, medicine, Carcinoma, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Carcinoma, Renal Cell, MESH: CD40 Ligand, Cell Proliferation, MESH: Colonic Neoplasms, MESH: Humans, MESH: Caspases, Cell growth, business.industry, MESH: Apoptosis, Gene Expression Profiling, Prostatic Neoplasms, medicine.disease, MESH: Ceramides, Lymphoma, Cancer research, MESH: Antineoplastic Agents, MESH: Kidney Neoplasms, business, MESH: Lymphoma, MESH: Female, MESH: Breast Neoplasms
Abstract: BackgroundCD40L was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism. Whether this represents a general mechanism for other tumor types is unknown.MethodsThe resistance induced by CD40L against apoptosis induced by a panel of cytotoxic chemotherapeutic drugs in non Hodgkin's lymphoma and breast carcinoma cell lines was investigated.ResultsDoxorubicin, cisplatyl, etoposide, vinblastin and paclitaxel increased apoptosis in a dose-dependent manner in breast carcinoma as well as in non Hodgkin's lymphoma cell lines. Co-culture with irradiated L cells expressing CD40L significantly reduced the percentage of apoptotic cells in breast carcinoma and non Hodgkin's lymphoma cell lines treated with these drugs. In breast carcinoma cell lines, these 5 drugs induced an inconsistent increase of caspase-3/7 activity, while in non Hodgkin's lymphoma cell lines all 5 drugs increased caspase-3/7 activity up to 28-fold above baseline. Co-culture with CD40L L cells reduced (-39% to -89%) the activation of caspase-3/7 induced by these agents in all 5 non Hodgkin's lymphoma cell lines, but in none of the 2 breast carcinoma cell lines. Co culture with CD40L L cells also blocked the apoptosis induced by exogenous ceramides in breast carcinoma and non Hodgkin's lymphoma cell lines through a caspase-3-like, 8-like and 9-like dependent pathways.ConclusionThese results indicate that CD40L expressed on adjacent non tumoral cells induces multidrug resistance to cytotoxic agents and ceramides in both breast carcinoma and non Hodgkin's lymphoma cell lines, albeit through a caspase independent and dependent pathway respectively.
Published: 2005
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46. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men

Author: Fabrice Pierre, Denis E. Corpet, Xénobiotiques, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique - INRA (FRANCE), Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Dietary Fiber, Cancer Research, Pathology, Colon-carcinogenesis, MESH: Rodentia, Pharmacology, Wheat bran, medicine.disease_cause, MESH: Carcinogens, Mice, chemistry.chemical_compound, Chemically-induced, 0302 clinical medicine, MESH: Animals, Randomized Controlled Trials as Topic, Cancer, 0303 health sciences, Aspirin, beta Carotene, 3. Good health, Min mice, Oncology, MESH: Models, Animal, 030220 oncology & carcinogenesis, Meta-analysis, MESH: Calcium, Colonic Neoplasms, Models, Animal, Chemoprophylaxis, MESH: beta Carotene, medicine.drug, medicine.medical_specialty, Adenoma, MESH: Rats, Azoxymethane, Rodentia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, Chemoprevention, 03 medical and health sciences, medicine, Animals, Humans, Animal model, b-carotene, MESH: Aspirin, MESH: Mice, Carcinogen, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, business.industry, B-carotene, medicine.disease, MESH: Sensitivity and Specificity, Rats, Diet, MESH: Randomized Controlled Trials as Topic, chemistry, MESH: Dietary Fiber, Carcinogens, Systematic review, Calcium, Carcinogenesis, business
Abstract: International audience; Tumours in rodent and human colon share many histological and genetic features. To know if rodent models of colon carcinogenesis are good predictors of chemopreventive efficacy in humans, we conducted a meta-analysis of aspirin, beta-carotene, calcium, and wheat bran studies. Controlled intervention studies of adenoma recurrence in human volunteers were compared with chemoprevention studies of carcinogen-induced tumours in rats, and of polyps in Min (Apc(+/-)) mice: 6714 volunteers, 3911 rats and 458 mice were included in the meta-analyses. Difference between models was small since most global relative risks were between 0.76 and 1.00. A closer look showed that carcinogen-induced rat studies matched human trials for aspirin, calcium, carotene, and were compatible for wheat bran. Min mice results were compatible with human results for aspirin, but discordant for calcium and wheat bran (no carotene study). These few results suggest that rodent models roughly predict effect in humans, but the prediction is not accurate for all agents. Based on three cases only, the carcinogen-induced rat model seems better than the Min mouse model. However, rodent studies are useful to screen potential chemopreventive agents, and to study mechanisms of carcinogenesis and chemoprevention.
Published: 2005
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47. A CpG island hypermethylation profile of primary colorectal carcinomas and colon cancer cell lines

Author: Lind, Guro E, Thorstensen, Lin, Løvig, Tone, Meling, Gunn I, Hamelin, Richard, Rognum, Torleiv O, Esteller, Manel, Lothe, Ragnhild A, Department of Genetics, Norwegian Radium Hospital-Institute for Cancer Research, Institute of Forensic Medicine, University of Oslo (UiO)-National Hospital, Akershus University Hospital [Lørenskog], Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cancer Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), GEL is a Research Fellow and LT a Post-Doctoral Fellow of the Norwegian Cancer Society. TL is Post-Doctoral Fellow of the Norwegian Foundation for Health and Rehabilitation. The study was funded by grants from the Norwegian Cancer Society (A95068 and D97127 RAL)., Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Maylin, Françoise
Subjects: Male, MGMT, MESH: Neoplasm Proteins, hMLH1, p16, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Cadherins, p14, MESH: DNA Methylation, Tumor Suppressor Protein p14ARF, TP53, colorectal carcinomas, Promoter Regions, Genetic, MESH: CpG Islands, E-cadherin, MESH: Genes, APC, Nuclear Proteins, MESH: Comparative Study, Cadherins, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MESH: Nu, Neoplasm Proteins, MESH: Cyclin-Dependent Kinase Inhibitor p16, Colonic Neoplasms, CpG methylation, Female, Colorectal Neoplasms, MutL Protein Homolog 1, Genes, APC, MESH: Cell Line, Tumor, KRAS, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, O(6)-Methylguanine-DNA Methyltransferase, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, colon cancer cell lines, Humans, APC, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, MSI, Adaptor Proteins, Signal Transducing, MSS, MESH: Colonic Neoplasms, MESH: Humans, Research, DNA Methylation, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, digestive system diseases, MESH: Male, CpG Islands, MESH: Microsatellite Repeats, Carrier Proteins, MESH: Female, MESH: Colorectal Neoplasms, Microsatellite Repeats
Abstract: Background Tumor cell lines are commonly used as experimental tools in cancer research, but their relevance for the in vivo situation is debated. In a series of 11 microsatellite stable (MSS) and 9 microsatellite unstable (MSI) colon cancer cell lines and primary colon carcinomas (25 MSS and 28 MSI) with known ploidy stem line and APC, KRAS, and TP53 mutation status, we analyzed the promoter methylation of the following genes: hMLH1, MGMT, p16INK4a (CDKN2A α-transcript), p14ARF (CDKN2A β-transcript), APC, and E-cadherin (CDH1). We compared the DNA methylation profiles of the cell lines with those of the primary tumors. Finally, we examined if the epigenetic changes were associated with known genetic markers and/or clinicopathological variables. Results The cell lines and primary tumors generally showed similar overall distribution and frequencies of gene methylation. Among the cell lines, 15%, 50%, 75%, 65%, 20% and 15% showed promoter methylation for hMLH1, MGMT, p16INK4a, p14ARF, APC, and E-cadherin, respectively, whereas 21%, 40%, 32%, 38%, 32%, and 40% of the primary tumors were methylated for the same genes. hMLH1 and p14ARF were significantly more often methylated in MSI than in MSS primary tumors, whereas the remaining four genes showed similar methylation frequencies in the two groups. Methylation of p14ARF, which indirectly inactivates TP53, was seen more frequently in tumors with normal TP53 than in mutated samples, but the difference was not statistically significant. Methylation of p14ARF and p16INK4a was often present in the same primary tumors, but association to diploidy, MSI, right-sided location and female gender was only significant for p14ARF. E-cadherin was methylated in 14/34 tumors with altered APC further stimulating WNT signaling. Conclusions The present study shows that colon cancer cell lines are in general relevant in vitro models, comparable with the in vivo situation, as the cell lines display many of the same molecular alterations as do the primary carcinomas. The combined pattern of epigenetic and genetic aberrations in the primary carcinomas reveals associations between them as well as to clinicopathological variables, and may aid in the future molecular assisted classification of clinically distinct stages.
Published: 2004
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48. Beef meat and blood sausage promote the formation of azoxymethane-induced mucin-depleted foci and aberrant crypt foci in rat colons

Author: Fabrice Pierre, Sylviane Taché, Denis E. Corpet, Roelof van der Meer, Amanda Freeman, Xénobiotiques, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Wageningen Centre for Food Sciences (NIZO), NIZO [Ede, Netherlands], Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and NIZO
Subjects: MDF, Colorectal cancer, Medicine (miscellaneous), MESH: Mucins, medicine.disease_cause, MESH: Carcinogens, MESH: Lipid Peroxidation, chemistry.chemical_compound, 0302 clinical medicine, prevention, rat, MESH: Animals, Food science, Heme, 2. Zero hunger, MESH: Meat, 0303 health sciences, Nutrition and Dietetics, MESH: Chickens, 3. Good health, MESH: Cattle, 030220 oncology & carcinogenesis, MESH: Heme, Colonic Neoplasms, Red meat, Female, MESH: Azoxymethane, Aberrant crypt foci, Meat, MESH: Rats, Azoxymethane, beef meat, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, black pudding, blood sausage, 03 medical and health sciences, MESH: Diet, medicine, Animals, Feces, 030304 developmental biology, ACF, MESH: Colonic Neoplasms, MESH: Rats, Inbred F344, food, Mucins, promotion, medicine.disease, colorectal carcinogenesis, Rats, Inbred F344, Diet, Rats, chemistry, Carcinogens, Cattle, Hemoglobin, Lipid Peroxidation, Carcinogenesis, chicken meat, MESH: Female, Chickens
Abstract: International audience; Red meat intake is associated with colon cancer risk. Puzzlingly, meat does not promote carcinogenesis in rat studies. However, we demonstrated previously that dietary heme promotes aberrant crypt foci (ACF) formation in rats given a low-calcium diet. Here, we tested the hypothesis that heme-rich meats promote colon carcinogenesis in rats treated with azoxymethane and fed low-calcium diets (0.8 g/kg). Three meat-based diets were formulated to contain varying concentrations of heme by the addition of raw chicken (low heme), beef (medium heme), or black pudding (blood sausage; high heme). The no-heme control diet was supplemented with ferric citrate and the heme control diet with hemoglobin to match iron and heme concentrations in the beef diet, respectively. After 100 d, colons were scored for ACF and mucin-depleted foci (MDF). Fecal water was assayed for lipoperoxides and cytotoxicity. Only diets with heme promoted the formation of MDF, but all meat diets promoted ACF formation. The number of MDF/colon was 0.55 +/- 0.68 in controls, but 1.2 +/- 0.6 (P = 0.13), 1.9 +/- 1.4 (P < 0.01), and 3.0 +/- 1.2 (P < 0.001) in chicken-, beef-, and black pudding-fed rats. MDF promotion by the high-heme black pudding diet was greater than that by the medium-heme beef diet. The number of ACF/colon was 72 +/- 16 in controls, but 91 +/- 18, 100 +/- 13, and 103 +/- 14 in chicken-, beef-, and black pudding-fed rats (all P < 0.001). ACF and MDF did not differ between rats fed the beef diet and those fed the heme control diet. MDF promotion was correlated with high fecal water lipoperoxides and cytotoxicity (r = 0.65, P < 0.01). This is the first study to show the promotion of experimental carcinogenesis by dietary meat and the association with heme intake.
Published: 2004

49. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes

Author: Philippe Blache, Claire Domon, Isabelle Duluc, Jean-Noël Freund, Hans Clevers, Marc van de Wetering, Philippe Berta, Philippe Jay, Hubrecht Institute for Developmental Biology and Stem Cell Research, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hubrecht Laboratory, Centre for Biomedical Genetics, Ontogénèse et pathologie du système digestif : rôle du microenvironnement cellulaire et moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the C.N.R.S., the I.N.S.E.R.M., and French Cancer Research Association grants (ARC 4293 and ARC 3286) as well as a Ligue against Cancer grant to P.J., and Jay, Philippe
Subjects: MESH: Carcinoma, SOX9, Wnt, CDX2, intestinal epithelium, differentiation, Transcription, Genetic, MESH: Cytoskeletal Proteins, Cellular differentiation, Mice, 0302 clinical medicine, MESH: Animals, Intestinal Mucosa, 0303 health sciences, Wnt signaling pathway, SOX9 Transcription Factor, MESH: Transcription Factors, Immunohistochemistry, MESH: Image Processing, Computer-Assisted, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, MESH: Cell Nucleus, endocrine system, Blotting, Western, Transfection, MESH: Phenotype, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, stem cells, MESH: Homeodomain Proteins, Humans, MESH: Blotting, Northern, MESH: Blotting, Western, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Mucins, DNA, Cytoskeletal Proteins, MESH: Epithelium, Microscopy, Fluorescence, Neoplasm Transplantation, Transcription Factors, MESH: Signal Transduction, MESH: beta Catenin, MESH: Microscopy, Fluorescence, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Mucins, Epithelium, MESH: Reverse Transcriptase Polymerase Chain Reaction, Image Processing, Computer-Assisted, CDX2 Transcription Factor, beta Catenin, Research Articles, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Reverse Transcriptase Polymerase Chain Reaction, High Mobility Group Proteins, MESH: DNA, Cell Differentiation, MESH: Gene Expression Regulation, Neoplastic, Intestinal epithelium, Phenotype, medicine.anatomical_structure, Colonic Neoplasms, embryonic structures, Signal Transduction, MESH: Intestines, MESH: Cell Differentiation, Beta-catenin, MESH: Cell Line, Tumor, MESH: Trans-Activators, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Stem Cells, WNT, MESH: RNA, Cell Line, Tumor, medicine, Animals, Transcription factor, MESH: Mice, 030304 developmental biology, Cell Nucleus, Homeodomain Proteins, MESH: Colonic Neoplasms, Mucin-2, MESH: Transcription, Genetic, MESH: Transfection, Carcinoma, MESH: Immunohistochemistry, Cell Biology, Blotting, Northern, MESH: High Mobility Group Proteins, Molecular biology, MUC2, Trans-Activators, biology.protein, RNA, MESH: Neoplasm Transplantation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; TCF and SOX proteins belong to the high mobility group box transcription factor family. Whereas TCFs, the transcriptional effectors of the Wnt pathway, have been widely implicated in the development, homeostasis and disease of the intestine epithelium, little is known about the function of the SOX proteins in this tissue. Here, we identified SOX9 in a SOX expression screening in the mouse fetal intestine. We report that the SOX9 protein is expressed in the intestinal epithelium in a pattern characteristic of Wnt targets. We provide in vitro and in vivo evidence that a bipartite beta-catenin/TCF4 transcription factor, the effector of the Wnt signaling pathway, is required for SOX9 expression in epithelial cells. Finally, in colon epithelium-derived cells, SOX9 transcriptionally represses the CDX2 and MUC2 genes, normally expressed in the mature villus cells of the intestinal epithelium, and may therefore contribute to the Wnt-dependent maintenance of a progenitor cell phenotype.
Published: 2004
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50. Tissue concentrations of platelet-activating factor in colorectal carcinoma: inverse relationships with Dukes' stage of patients

Author: Cubertafond P, Laurence Guglielmi, Yves Denizot, Murielle Mathonnet, Gainant A, Stephane Bouvier, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)
Subjects: platelet-activating factor, Cancer Research, medicine.medical_specialty, NLM, Colorectal cancer, receptor, Biology, medicine.disease_cause, acetylhydrolase activity, Phospholipases A, chemistry.chemical_compound, MESH: 1-Alkyl-2-acetylglycerophosphocholine Esterase, Phospholipase A2, colorectal carcinoma, Internal medicine, Biomarkers, Tumor, Genetics, medicine, Carcinoma, Humans, Platelet Activating Factor, Receptor, Molecular Biology, health care economics and organizations, Neoplasm Staging, MESH: Colonic Neoplasms, Phospholipase A, MESH: Platelet Activating Factor, MESH: Humans, Platelet-activating factor, Cancer, MESH: Neoplasm Staging, respiratory system, medicine.disease, Endocrinology, chemistry, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Colonic Neoplasms, MESH: Tumor Markers, Biological, Cancer research, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), phospholipase A2, MESH: Phospholipases A, Colorectal Neoplasms, Carcinogenesis, MESH: Colorectal Neoplasms
Abstract: The lipid mediator platelet-activating factor (PAF) plays a role in cancer. We investigated its presence in human colon carcinoma by assessing the levels of tissue phospholipase A(2) (PLA(2), the key enzyme in the generation of the lyso-PAF precursor), lyso-PAF, PAF and acetylhydrolase activity (AHA, the key enzyme in PAF degradation) in colorectal cancer patients and by correlating them with Dukes' classification. The results highlighted that the tumour tissues of Dukes' A and B patients had significantly higher PLA(2), lyso-PAF, PAF and AHA levels as compared with nontumour tissues. Dukes' C patients had higher PLA(2), lyso-PAF and AHA levels but unchanged PAF. Dukes' D patients had higher AHA levels but unchanged PLA(2), lyso-PAF and PAF. A pathophysiological role for PAF is suggested in human colon carcinoma.
Published: 2003
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