Descriptor: "MESH: Colonic Neoplasms" / Language: english - Searchworks@Jio Institute Digital Library Search Results

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48 results on '"MESH: Colonic Neoplasms"'

1. 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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2. 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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3. Women at a Disadvantage in Fluorouracil Treatment

Author: Joseph Ciccolini, Gérard Milano, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Internal medicine, Humans, Medicine, Dihydrouracil Dehydrogenase (NADP), Disadvantage, ComputingMilieux_MISCELLANEOUS, MESH: Colonic Neoplasms, Sex Characteristics, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Humans, business.industry, MESH: Polymorphism, Single Nucleotide, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, MESH: Male, 030104 developmental biology, Fluorouracil, 030220 oncology & carcinogenesis, Colonic Neoplasms, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Dihydrouracil Dehydrogenase (NADP), business, MESH: Female, MESH: Fluorouracil, [PHYS.PHYS.PHYS-DATA-AN]Physics [physics]/Physics [physics]/Data Analysis, Statistics and Probability [physics.data-an], medicine.drug, MESH: Sex Characteristics
Abstract: International audience
Published: 2016
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4. Ochratoxin A and T-2 Toxin Induce Clonogenicity and Cell Migration in Human Colon Carcinoma and Fetal Lung Fibroblast Cell Lines

Author: Abassi, Haila, Ayed-Boussema, Imen, Shirley, Sarah, Abid, Salwa, Bacha, Hassen, Laboratoire de Recherche sur les Substances Biologiquement Compatibles [Monastir] ( LRSBC ), Faculté de médecine dentaire de Monastir [Tunisie] ( FMDM ), 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 ), Ministère Tunisien de l'Enseignement Supérieur et de la Recherche Scientifique et de la Technologie (Laboratoire de Recherche sur les Substances Biologiquement Compatibles (LRSBC), UMR 866 Lipides, Nutrition Cancer (Dijon), Laboratoire de Recherche sur les Substances Biologiquement Compatibles [Monastir] (LRSBC), Faculté de Médecine Dentaire de Monastir [Tunisie] (FMDM), Lipides - Nutrition - Cancer (U866) (LNC), and 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)
Subjects: MESH : Cell Line, MESH: Cell Line, Tumor, Aflatoxin B1, MESH : Lung, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, MESH : Wound Healing, MESH: T-2 Toxin, MESH : Mycotoxins, MESH: Mycotoxins, Cell Migration, Cell Line, MESH : Aflatoxin B1, Cell Movement, Cell Line, Tumor, T2-Toxin, MESH : T-2 Toxin, MESH : Ochratoxins, Humans, MESH : Cell Movement, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Clonogenicity, MESH: Cell Movement, Lung, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Colonic Neoplasms, Wound Healing, MESH: Humans, MESH : Cell Line, Tumor, MESH: Aflatoxin B1, MESH : Humans, MESH: Ochratoxins, Ochratoxin A, Mycotoxins, Ochratoxins, MESH: Cell Line, MESH: Wound Healing, T-2 Toxin, MESH : Colonic Neoplasms, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Colonic Neoplasms
Abstract: IF 3.02; International audience; T-2 toxin and Ochratoxin A (OTA) are toxic secondary metabolites produced by various fungi, and together they contaminate feedstuffs worldwide. T-2 toxin and OTA may exert carcinogenic action in rodent. Despite the various in vivo experiments, carcinogenicity of these two mycotoxins has not yet been proven for human. In this current study, we proposed to investigate, in Human colon carcinoma cells and fetal lung fibroblast-like cells transfected with MYC, the effect of T-2 toxin and OTA on cell clonogenicity and cell migration. Results of the present investigation showed that T2-toxin as well as OTA has an important clonogenic effect in all cell lines, suggesting that these mycotoxins could promote the transcription of c-myc gene. Furthermore, T-2 toxin and OTA enhanced the migration effect of HCT116 cells at very low concentrations, proposing that these mycotoxins may exhibit carcinogenesis-like properties in the studied cells.
Published: 2016
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5. PRODIGE 34-FFCD 1402-ADAGE: Adjuvant chemotherapy in elderly patients with resected stage III colon cancer: A randomized phase 3 trial

Author: Aparicio , Thomas, Francois , Eric, Cristol-Dalstein , Laurence, Carola , Elisabeth, Maillard , Emilie, Paillaud , Elena, Retornaz , Frédérique, Faroux , Roger, André , Thierry, Bedenne , Laurent, Seitz , Jean-François, Service de Gastro-entérologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), CRLCC Val d'Aurelle - Paul Lamarque, CH Creil/Senlis, Fédération Francophone de la Cancérologie Digestive, FFCD, 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 ), Unité de médecine gériatrique ( Gériatrie - Henri Mondor ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Gérontologique Départemental de Marseille ( CGD 13 ), Service de chirurgie digestive (CH de La Roche-sur-Yon), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Ligue Nationale Contre le Cancer, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Lipides - Nutrition - Cancer (U866) (LNC), 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, Unité de médecine gériatrique (Gériatrie - Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Gérontologique Départemental de Marseille (CGD 13), 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), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Male, Organoplatinum Compounds, Oxaloacetates, MESH : Antineoplastic Combined Chemotherapy Protocols, Leucovorin, MESH : Aged, MESH : Leucovorin, Deoxycytidine, Activities of Daily Living, Antineoplastic Combined Chemotherapy Protocols, MESH : Neoplasm Staging, MESH : Female, Digestive System Surgical Procedures, MESH: Treatment Outcome, MESH: Digestive System Surgical Procedures, MESH: Aged, MESH: Organoplatinum Compounds, MESH : Chemotherapy, Adjuvant, MESH: Neoplasm Staging, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, MESH : Colonic Neoplasms, MESH: Chemotherapy, Adjuvant, Chemotherapy, Adjuvant, Colonic Neoplasms, MESH : Fluorouracil, MESH : Disease-Free Survival, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fluorouracil, Efficacy, MESH : Male, MESH : Treatment Outcome, MESH : Organoplatinum Compounds, MESH : Capecitabine, Disease-Free Survival, MESH : Deoxycytidine, Humans, MESH : Digestive System Surgical Procedures, Capecitabine, Aged, Neoplasm Staging, MESH: Colonic Neoplasms, MESH: Humans, MESH: Activities of Daily Living, MESH: Deoxycytidine, MESH : Humans, MESH: Capecitabine, MESH: Quality of Life, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Quality of Life, MESH: Male, MESH: Disease-Free Survival, Quality of Life, MESH: Leucovorin, MESH : Activities of Daily Living, MESH: Fluorouracil, MESH: Female
Abstract: IF 2.719; International audience
Published: 2016
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6. 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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7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. 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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14. Cisplatin-induced apoptosis involves a Fas-ROCK-ezrin-dependent actin remodelling in human colon cancer cells

Author: Odile Sergent, Amélie Rébillard, Xavier Tekpli, Mathieu Pizon, Dominique Lagadic-Gossmann, Patrick Legembre, Elodie Jouan, Marie-Thérèse Dimanche-Boitrel, David Gilot, S. Jouan-Lanhouet, Environmental and food chemical toxicants membrane and gene targets, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-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 )-École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), 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)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2, ifr 66, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Ligue Nationale Contre le Cancer (Côte d'Armor, Ille et Vilaine et Loire-Atlantique Comités), Rennes Métropole et la 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 )-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 )-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR)-Université de Rennes (UR), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC)
Subjects: MESH: Signal Transduction, Cancer Research, RHOA, MESH: Cytoskeletal Proteins, Apoptosis, Ezrin, Fas ligand, 0302 clinical medicine, RNA interference, Tumor Cells, Cultured, FADD, Membrane fluidity, Cytoskeleton, 0303 health sciences, biology, Actin cytoskeleton, RhoA-GTP, Fas receptor, Colon cancer, MESH: Antigens, CD95, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Signal Transduction, Fas Ligand Protein, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, ROCK, Humans, fas Receptor, MESH: Tumor Cells, Cultured, Lipid rafts, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Apoptosis, Fas, MESH: Fas Ligand Protein, Cytoskeletal Proteins, MESH: Cisplatin, biology.protein, Cancer research, MESH: Antineoplastic Agents, Cisplatin
Abstract: International audience; In human colon cancer cells, cisplatin-induced apoptosis involves the Fas death receptor pathway independent of Fas ligand. The present study explores the role of ezrin and actin cytoskeleton in relation with Fas receptor in this cell death pathway. In response to cisplatin treatment, a rapid and transient actin reorganisation is observed at the cell membrane by fluorescence microscopy after Phalloidin-FITC staining. This event is dependent on the membrane fluidification studied by electron paramagnetic resonance and necessary for apoptosis induction. Moreover, early after the onset of cisplatin treatment, ezrin co-localised with Fas at the cell membrane was visualised by membrane microscopy and was redistributed with Fas, FADD and procaspase-8 into membrane lipid rafts as shown on Western blots. In fact, cisplatin exposure results in an early small GTPase RhoA activation demonstrated by RhoA-GTP pull down, Rho kinase (ROCK)-dependent ezrin phosphorylation and actin microfilaments remodelling. Pretreatment with latrunculin A, an inhibitor of actin polymerisation, or specific extinction of ezrin or ROCK by RNA interference prevents both cisplatin-induced actin reorganisation and apoptosis. Interestingly, specific extinction of Fas receptor by RNA interference abrogates cisplatin-induced ROCK-dependent ezrin phosphorylation, actin reorganisation and apoptosis suggesting that Fas is a key regulator of cisplatin-induced actin remodelling and is indispensable for apoptosis. Thus, these findings show for the first time that phosphorylation of ezrin by ROCK via Fas receptor is involved in the early steps of cisplatin-induced apoptosis.
Published: 2010
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15. 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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16. The first extracellular domain of the tumour stem cell marker CD133 contains an antigenic ganglioside-binding motif

Author: Xiao-Jun Guo, Nouara Yahi, Nicolas Garmy, Marc Maresca, Nadira Taïeb, Jacques Fantini, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut méditerranéen de Recherche en Nutrition : Biochimie et Biologie de la Nutrition (IMRN), Université Paul Cézanne - Aix-Marseille 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and Université Paul Cézanne - Aix-Marseille 3-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, MESH: HT29 Cells, MESH: Membrane Microdomains, MESH: Amino Acid Sequence, Stem cell marker, Epitope, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Complementary, Gangliosides, AC133 Antigen, Tumor Markers, Lipid raft, MESH: Antigens, CD, 0303 health sciences, MESH: Peptides, MESH: G(M1) Ganglioside, CD, 3. Good health, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, embryonic structures, Neoplastic Stem Cells, lipids (amino acids, peptides, and proteins), MESH: Caco-2 Cells, Stem cell, HT29 Cells, Protein Structure, DNA, Complementary, Molecular Sequence Data, MESH: Glycoproteins, G(M1) Ganglioside, Biology, 03 medical and health sciences, Membrane Microdomains, Antigens, CD, Ganglioside binding, Cancer stem cell, Biomarkers, Tumor, Humans, Amino Acid Sequence, Antigens, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], neoplasms, Glycoproteins, 030304 developmental biology, MESH: Gangliosides, MESH: Colonic Neoplasms, Binding Sites, Ganglioside, MESH: Humans, MESH: Molecular Sequence Data, DNA, MESH: DNA, Complementary, Biological, Molecular biology, MESH: Neoplastic Stem Cells, Protein Structure, Tertiary, carbohydrates (lipids), MESH: Binding Sites, MESH: Tumor Markers, Biological, Caco-2 Cells, Peptides, Tertiary
Abstract: International audience; Prominin 1/CD133 is a marker of transplantable cancer stem cells. We have generated anti-peptide antibodies against a N-terminal epitope of CD133 belonging to a ganglioside-binding domain. The labelling of colon cancer cells with these antibodies was inhibited by various gangliosides including GM1 and GD3, but not GT1b. CD133 immunolabelling progressively decreased to undetectable levels in post-confluent cultures, possibly through ganglioside-mediated epitope masking since the staining was partially recovered after chemical disruption of lipid rafts. We suggest that selected gangliosides could modulate the accessibility of CD133 and regulate cell-cell contacts involving CD133(+) stem cells at the earliest steps of tumour development.
Published: 2009
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17. 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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18. 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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19. 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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20. 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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21. 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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22. 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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23. 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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24. 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

25. 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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26. Place of multidisciplinary consulting meetings and clinical trials in the management of colorectal cancer in France in 2000

Author: Brigitte Trétarre, Nabil Maarouf, Guy Launoy, Anne-Marie Bouvier, Patricia Delafosse, Michel Velten, A. Buemi, Arlette Danzon, Eric Bauvin, Pascale Grosclaude, Jean Faivre, N. Raverdy, Service de Biostatistique des Hospices Civils de Lyon, Hospices Civils de Lyon (HCL), Registre Bourguignon des Cancers Digestifs, 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)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), 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), Registre des cancers du Tarn, FRANCIM, Réseau des registres français du cancer, Registre général des cancers de la Somme, CHU Amiens-Picardie, Registre des cancers de la Manche, CHPC - Site Louis Pasteur, Centre Hospitalier Public du Cotentin (CHPC)-Centre Hospitalier Public du Cotentin (CHPC), Cancers et Populations : Facteurs de Risque, Depistage, Pratiques Diagnostiques et Therapeutiques, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Viala, Pascale, Hospices Civils de Lyon ( HCL ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Epidémiologie et analyses en santé publique :risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Registre des Cancers de la Somme, CHU Nord, Amiens, registre des cancers de la Manche, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), and 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 ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon )
Subjects: Male, MESH: Registries, Colorectal cancer, MESH : Aged, MESH : Referral and Consultation, MESH: Patient Participation, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hospitals, University, MESH: Hospitals, Public, MESH: Patient Care Team, Multidisciplinary approach, MESH : Population Surveillance, MESH : Neoplasm Staging, MESH : Female, Registries, MESH : Rectal Neoplasms, Referral and Consultation, MESH: Aged, education.field_of_study, Clinical Trials as Topic, Health Policy, Gastroenterology, Age Factors, General Medicine, MESH: Neoplasm Staging, MESH : Colonic Neoplasms, Population Surveillance, MESH: Hospitals, Private, Colonic Neoplasms, MESH : Hospitals, Private, Population study, Female, MESH: Health Policy, France, MESH : Health Policy, medicine.medical_specialty, MESH: Clinical Trials as Topic, MESH : Male, MESH : Sex Factors, Population, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hospitals, Private, MESH: Population Surveillance, MESH: Referral and Consultation, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Sex Factors, medicine, Humans, MESH: Patient Selection, Patient participation, MESH : France, education, MESH : Hospitals, University, Aged, Neoplasm Staging, MESH : Hospitals, Public, Patient Care Team, MESH: Age Factors, MESH: Colonic Neoplasms, MESH: Hospitals, University, MESH: Humans, MESH : Patient Care Team, business.industry, Hospitals, Public, Rectal Neoplasms, Patient Selection, MESH : Humans, Cancer, MESH: Rectal Neoplasms, MESH : Patient Selection, medicine.disease, MESH: Male, MESH : Patient Participation, Surgery, MESH : Clinical Trials as Topic, Clinical trial, MESH: France, Family medicine, MESH : Age Factors, Patient Participation, business, MESH: Female, MESH : Registries
Abstract: International audience; AIM: The 1998 consensus conference dealing with colon cancer, and the 2003 Cancer Plan underlined the need for multidisciplinary meetings and for including patients in therapeutic trials. The aim of this study, which pooled data from the French Cancer Registries operating within the Francim network, was to report on diagnostic and therapeutic practices in the general French population before implementation of the Cancer Plan. METHODS: The study population was composed of 2935 patients with colorectal cancer diagnosed in 2000 in twelve French administrative districts accounting for 15% of the geographical area of France. Data were collected using a standardized procedure. Three categories of place of diagnosis were defined: public university hospitals, public non-university hospitals, and private clinics. RESULTS: Overall, multidisciplinary meeting was conducted for 32.2% of patients with colorectal cancer. This proportion varied from 6.4% to 76.9%, depending on the geographical area (P75 years): 0.71, P
Published: 2007

27. Usefulness of autoantigens depletion to detect autoantibody signatures by multiple affinity protein profiling

Author: Ludovic Canelle, Geneviève Choquet-Kastylevsky, Michel Caron, Jean-Paul Lasserre, Raymonde Joubert-Caron, Céline Vlieghe, Julie Hardouin, Magalie Duchateau, Laboratoire de Biophysique Moléculaire Cellulaire et Tissulaire (BIOMOCETI), and Université Paris 13 (UP13)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Antibodies, Neoplasm, MESH: Antigens, Neoplasm, Peptide, MESH: Amino Acid Sequence, 01 natural sciences, Autoantigens, Chromatography, Affinity, Analytical Chemistry, Tandem Mass Spectrometry, MESH: Autoantibodies, chemistry.chemical_classification, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, Chemistry, MESH: Protein Array Analysis, Protein primary structure, Middle Aged, MESH: Chromatography, Affinity, 3. Good health, Biochemistry, MESH: Autoantigens, Colonic Neoplasms, Biomarker (medicine), MESH: Caco-2 Cells, Antibody, Molecular Sequence Data, Protein Array Analysis, Filtration and Separation, Adenocarcinoma, 03 medical and health sciences, Affinity chromatography, Antigens, Neoplasm, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, 030304 developmental biology, Aged, Autoantibodies, MESH: Colonic Neoplasms, Chromatography, MESH: Humans, MESH: Molecular Sequence Data, 010401 analytical chemistry, MESH: Adenocarcinoma, Autoantibody, Cancer, MESH: Tandem Mass Spectrometry, medicine.disease, 0104 chemical sciences, Protein profiling, MESH: Antibodies, Neoplasm, biology.protein, Caco-2 Cells
Abstract: International audience; Patients with cancer produce specific autoantibodies against protein antigens present in limited amount among a large background of immunoglobulins (Igs), nonrelevant as biomarkers, including natural antibodies. Multiple affinity protein profiling (MAPPing) that combines 2-D immunoaffinity chromatography, enzymatic digestion of the isolated proteins, and identification by MS/MS, may facilitate the identification of these so far unknown patient antibodies. The first immunoaffinity chromatography is crucial, as it is used for selectively removing proteins (autoantigens) recognized by natural antibodies. Application of this depletion step to colon cancer cell proteins is specifically described along with the identification of the natural autoantigens, as well as the coupling of this depletion step with the next steps. By enabling to separate antibody-binding proteins recognized by either natural autoantibodies or patient-specific antibodies this approach may contribute significantly towards the definition of autoantibody signatures.
Published: 2007
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28. 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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29. 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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30. 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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31. 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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32. 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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33. 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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34. 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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35. 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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36. 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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37. Correlation between invasiveness of colorectal tumor cells and adhesive potential under flow

Author: Benoliel, A. M., Pirro, N., Marin, V., Consentino, B., Pierre Bongrand, Vitte, J., Bongrand, P., Sielezneff, I., Sastre, B., Adhésion et Inflammation (LAI), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Chirurgie Digestive (AP-HM), Université de la Méditerranée - Aix-Marseille 2, Bongrand, Pierre, and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Antigens, CD29, MESH: E-Selectin, Vascular Cell Adhesion Molecule-1, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, MESH: Flow Cytometry, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Cadherins, MESH: Cell Adhesion, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Cell Adhesion, Humans, Neoplasm Invasiveness, MESH: Antigens, CD, MESH: Antigens, CD18, MESH: Colonic Neoplasms, MESH: Humans, MESH: Stress, Mechanical, Rectal Neoplasms, Integrin beta1, MESH: Vascular Cell Adhesion Molecule-1, MESH: Biological Markers, MESH: Rectal Neoplasms, MESH: Neoplasm Invasiveness, Cadherins, Flow Cytometry, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, CD18 Antigens, Colonic Neoplasms, MESH: Cell Adhesion Molecules, Stress, Mechanical, E-Selectin, Cell Adhesion Molecules, Biomarkers
Abstract: International audience; BACKGROUND: Tumor cell adhesiveness is involved in metastatic dissemination, and adhesive behavior may be different under static and dynamic conditions. MATERIALS AND METHODS: Patients undergoing primary colorectal cancer excision were tested for: i) serum concentration of sE-selectin, sICAM-1 and sVCAM-1, ii) expression of CD18, CD29d and E-cadherin on tumor cells and iii) efficiency of tumor cell adhesion to ECV304 monolayers under flow and resistance to detachment by shear. RESULTS: Twenty out of 31 patients were free of detectable relapse 12 months later. Relapsing and non-relapsing patients had similar levels of soluble adhesion molecules. E-cadherin was detected on tumor cells from three non-relapsing patients, but no relapsing one. Unexpectedly, significant CD18 labeling was found on two relapsing patients and one non-relapsing patient. Cells from relapsing patients displayed significantly increased (p < 0.05 two-sided, p < 0.025 one-sided) capacity to adhere to test monolayers under flow. CONCLUSION: Cancer invasion is related to tumor cell adhesiveness, and the flow chamber provides a practical way of measuring adhesive parameters with a potential value for relapse prediction.
Published: 2003

38. 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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39. Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system

Author: Corpet, Denis E, Pierre, Fabrice, Xénobiotiques, Institut National de la Recherche Agronomique (INRA)-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 (FRANCE), and Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE)
Subjects: MESH: Chemoprevention, MESH: Rats, MESH: Mice, Mutant Strains, Colon-carcinogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Chemoprevention, Chemically-induced, MESH: Diet, MESH: Anticarcinogenic Agents, chemoprevention, colon-carcinogenesis, MESH: Animals, MESH: Mice, Cancer, MESH: Colonic Neoplasms, MESH: Humans, Animal-model, Diet, MESH: Precancerous Conditions, MESH: Randomized Controlled Trials as Topic, chemically-induced, animal-model, MESH: Disease Models, Animal, diet, MESH: Azoxymethane, Min-mice
Abstract: International audience; The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.
Published: 2003

40. Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system

Author: Corpet, Denis E., Pierre, Fabrice H.F., 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), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: MESH: Colonic Neoplasms, MESH: Chemoprevention, MESH: Humans, MESH: Rats, MESH: Mice, Mutant Strains, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Precancerous Conditions, MESH: Randomized Controlled Trials as Topic, MESH: Diet, MESH: Anticarcinogenic Agents, chemically-induced, chemoprevention, colon-carcinogenesis, MESH: Animals, animal-model, MESH: Disease Models, Animal, diet, MESH: Azoxymethane, MESH: Mice, Min-mice
Abstract: International audience; The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.
Published: 2003

41. Most effective colon cancer chemopreventive agents in rats: a systematic review of aberrant crypt foci and tumor data, ranked by potency

Author: Denis E. Corpet, Sylviane Taché, Institut National de la Recherche Agronomique - INRA (FRANCE), Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Xénobiotiques, Institut National de la Recherche Agronomique (INRA)-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, Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Cancer Research, Pathology, Colorectal cancer, Carcinogenesis, Phytochemicals, Medicine (miscellaneous), phytochemical, Pharmacology, AGPI n-3, Intestin, Cancer prevention, 0302 clinical medicine, Aberrant crypt foci, Promotion, rat, MESH: Animals, DFMO, Anticarcinogen, database, Cancer, 0303 health sciences, Nutrition and Dietetics, NSAID, 3. Good health, Colon cancer, Intestine, MESH: Precancerous Conditions, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, aberrant crypt foci, Chimioprévention, carcinogenesis, medicine.drug, medicine.medical_specialty, N-3 PUFA, MESH: Rats, Diet therapy, Colon, AINS, review, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Piroxicam, Chemoprevention, Article, Database, 03 medical and health sciences, MESH: Anticarcinogenic Agents, medicine, Animals, Anticarcinogenic Agents, Potency, MESH: Colon, mouse, 030304 developmental biology, ACF, MESH: Colonic Neoplasms, business.industry, animal model, medicine.disease, PEG, digestive system diseases, Rats, Celecoxib, Oméga trois, Rat, business, Precancerous Conditions
Abstract: Potential chemopreventive agents for colorectal cancer are assessed in rodents. We speculated that the magnitude of the effect is meaningful and ranked all published agents according to their potency. Data were gathered systematically from 137 articles with the aberrant crypt foci (ACF) end point and from 146 articles with the tumor end point. The potency of each agent to reduce the number of ACF is listed in one table and the potency of each agent to reduce the tumor incidence in another table. Both tables are shown in this review and on a website with sorting abilities (http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html). Potency was estimated as the ratio of the value in control rats to the value in treated rats. From each article, only the most potent agent was kept, except in articles reporting the effect of more than seven agents. Among the 186 agents in the ACF table, the median agent reduced the number of ACF by one-half. The most potent agents to reduce azoxymethane-induced ACF were Pluronic, polyethylene glycol, perilla oil with beta-carotene, and sulindac sulfide. Among the 160 agents in the tumor table, the median agent reduced the tumor incidence in rats by one-half. The most potent agents to reduce the incidence of azoxymethane-induced tumors were celecoxib, a protease inhibitor from soy, difluoromethylornithine with piroxicam, polyethylene glycol, and a thiosulfonate. For the 57 agents present in both tables, a significant correlation (r) was found between the potencies against ACF and tumors (r = 0.45, P < 0.001); without celecoxib, a major outlying point in the correlation, r = 0.68 (P < 0.001, n = 56). In conclusion, this review gathers most known chemopreventive agents, ranks the most promising agents against colon carcinogenesis in rats or mice, and further supports the use of ACF as a surrogate end point for tumors in rats.
Published: 2002
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42. High density O-glycosylation of the MUC2 tandem repeat unit by N-acetylgalactosaminyltransferase-3 in colonic adenocarcinoma extracts

Author: Inoue, M., Takahashi, S., Yamashina, I., Kaibori, M., Okumura, T., Kamiyama, Y., Vichier-Guerre, S., Cantacuzène, D., Nakada, H., Departement of Biotechnology, Faculty of Engineering, Kyoto University [Kyoto], First Departement of Surgery, Kansai Medical University, Department of Medical Chemistry, Chimie Organique, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Kyoto University, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Acetylgalactosamine, Glycosylation, MESH: Isothiocyanates, Adenocarcinoma, MESH: Mucins, p-Dimethylaminoazobenzene, Isothiocyanates, Humans, Antigens, Tumor-Associated, Carbohydrate, RNA, Messenger, Intestinal Mucosa, MESH: Chromatography, High Pressure Liquid, Chromatography, High Pressure Liquid, MESH: Colonic Neoplasms, Mucin-2, MESH: N-Acetylgalacto, MESH: Humans, MESH: Antigens, Tumor-Associated, Carbohydrate, Tissue Extracts, MESH: Adenocarcinoma, Mucins, MESH: Indicators and Reagents, MESH: Glycosylation, Isoenzymes, carbohydrates (lipids), Tandem Repeat Sequences, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Colonic Neoplasms, MESH: Intestinal Mucosa, MESH: Isoenzymes, N-Acetylgalactosaminyltransferases, Indicators and Reagents, lipids (amino acids, peptides, and proteins), MESH: Acetylgalactosamine
Abstract: A synthetic peptide corresponding to the human MUC2 tandem repeat unit was glycosylated in vitro using UDP-GalNAc and extracts of colonic adenocarcinoma and paired normal mucosa, followed by fractionation of the products by reverse phase high-performance liquid chromatography. Several peaks of glycopeptides with different numbers of GalNAc residues attached were detected. It is notable that the adenocarcinoma extract was capable of glycosylating peptides to a much greater extent than was normal mucosa. The levels of mRNA for N-acetylgalactosaminyltransferases-1, -2, and -3 were determined by reverse transcription-PCR. Only N-acetylgalactosaminyltransferase-3 mRNA was expressed at a higher level in the adenocarcinoma than in the normal tissue. When the MUC2 tandem repeat peptide was glycosylated with a mixture of the normal mucosa extract and recombinant N-acetylgalactosaminyltransferase-3, larger amounts of glycopeptides with higher contents of GalNAc residues were produced. The MUC2 tandem repeat peptides glycosylated extensively by recombinant N-acetylgalactosaminyltransferase-1, -2, or -3 were prepared and characterized. Substitution at each Thr residue, as revealed by Edman degradation sequencing, in conjunction with evidence obtained on mass spectrometry indicated a heterogeneous pattern of site-specific glycosylation within the MUC2 tandem repeat. It was found that maximum numbers of 6, 8, and 11 GalNAc residues were incorporated by N-acetylgalactosaminyltransferases-1, -2, and -3, respectively, and that only N-acetylgalactosaminyltransferase-3 could completely glycosylate both consecutive sequences composed of three and five Thr residues in the MUC2 tandem repeat unit. These results suggest that O-glycosylation of the clustered Thr residues is a selective process controlled by N-acetylgalactosaminyltransferase-3 in the synthesis of clustered carbohydrate antigens.
Published: 2001

43. Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice

Author: Ginette Peiffer, Géraldine Parnaud, Denis E. Corpet, Sylviane Taché, 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)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Recherche Agronomique - INRA (FRANCE), National Cancer Institute (USA), and Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE)
Subjects: Male, Cancer Research, Pathology, potency, Colorectal cancer, efficacy, medicine.disease_cause, Polyethylene Glycols, chemistry.chemical_compound, 0302 clinical medicine, chemoprevention, MESH: Animals, Anticarcinogen, Cancer, 0303 health sciences, cancer prevention, MESH: Drug Screening Assays, Antitumor, Pluronic, 3. Good health, MESH: Precancerous Conditions, Oncology, colon cancer, laxative, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, aberrant crypt foci, poloxamer, colon-cancer, Aberrant crypt foci, medicine.medical_specialty, Colon-cancer, mice, chemoprevention, aberrant-crypt-foci, MESH: Rats, Colon, Ratón, Short Communication, polymer, block copolymer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chemoprevention, Excipients, 03 medical and health sciences, polyetylene glycol, PEG ratio, medicine, Animals, MESH: Colon, MESH: Mice, 030304 developmental biology, ACF, MESH: Excipients, Colorectal Cancer, MESH: Colonic Neoplasms, Azoxymethane, business.industry, MESH: Rats, Inbred F344, technology, industry, and agriculture, medicine.disease, MESH: Poloxamer, PEG, Rats, Inbred F344, MESH: Male, rats, pluronic, rat, chemistry, MESH: Polyethylene Glycols, Cancer research, Aberrant-crypt-foci, Rat, Drug Screening Assays, Antitumor, business, Carcinogenesis, Precancerous Conditions, MESH: Female
Abstract: Polyethylene-glycol (PEG) is a strong inhibitor of colon cancer in rats, and the most potent suppressor of aberrant crypt foci. 9 PEG-like block copolymers were tested in rodents, after an azoxymethane injection. Dietary pluronic F68 led to a 98.6% reduction in the number of aberrant crypt foci in a first rat study (P< 0.0001). Next 3 studies confirmed this pluronic efficacy in rats and mice. This non-toxic laxative seems roughly 5 times more potent than PEG for chemoprevention. © 2001 Cancer Research Campaign http://www.bjcancer.com
Published: 2001
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44. Cytostatic effect of polyethylene glycol on human colonic adenocarcinoma cells

Author: Laurence Gamet-Payrastre, Géraldine Parnaud, Denis E. Corpet, ProdInra, Migration, 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)-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Cancer Research, MESH: Flow Cytometry, Apoptosis, Sodium Chloride, Polyethylene Glycols, chemistry.chemical_compound, MESH: Osmolar Concentration, Tumor Cells, Cultured, Sorbitol, Osmotic pressure, MESH: Cell Size, colorectal, intestinal, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, cancer prevention, cytostatique, MESH: G0 Phase, Cell Differentiation, DNA, Neoplasm, Flow Cytometry, CANCER, HT29, 3. Good health, Oncology, Biochemistry, CaCo2, polyethylene glycol, Colonic Neoplasms, MESH: Cell Division, MESH: Caco-2 Cells, Cell Division, MESH: Cell Differentiation, MESH: Cell Nucleus, MESH: Sodium Chloride, PRESSION OSMOTIQUE, mechanism, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, macromolecular substances, Polyethylene glycol, Adenocarcinoma, Biology, MESH: G1 Phase, Resting Phase, Cell Cycle, Osmotic Pressure, anit-cancer, PEG ratio, Humans, AGENT CHEMOPREVENTIF, MESH: Tumor Cells, Cultured, Lactic Acid, Cell Size, MESH: Colonic Neoplasms, Cell Nucleus, MESH: Humans, colon, Osmotic concentration, Cell growth, MESH: Apoptosis, MESH: Adenocarcinoma, Cell Membrane, Osmolar Concentration, G1 Phase, technology, industry, and agriculture, MESH: Osmotic Pressure, PEG, Molecular biology, Culture Media, rats, MESH: Polyethylene Glycols, chemistry, Caco-2, Cell culture, Cancer cell, MESH: Culture Media, cells, MESH: Antineoplastic Agents, MESH: Lactic Acid, MESH: Sorbitol, Caco-2 Cells, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Cell Membrane
Abstract: International audience; Polyethylene glycol (PEG 8000) is a potent cancer chemopreventive agent. This osmotic laxative polymer markedly suppresses colon cancer in rats. To explain the mechanism, we have tested the in vitro effect of PEG on four human cell lines. Two poorly differentiated adenocarcinoma lines (HT29 and COLO205), a fetal mucosa line (FHC) and a differentiated line (post-confluent Caco-2) were incubated with various PEG concentrations for 2-5 days. Results show that PEG markedly and dose-dependently inhibited HT29 and COLO205 cell growth. This cytostatic effect was associated with a blocking of the cell cycle in G0/G1 phase. In addition, PEG decreased the viability of HT29 and COLO205 adenocarcinoma cells. In contrast, post-confluent intestinal-like Caco-2 cells and normal FHC cells were, respectively, not or little affected by PEG. Moreover, the lactate concentration increased twofold in the medium of PEG-treated HT29 cells compared with untreated cells. Microscopic observations showed that PEG induced cell shrinking, membrane blebbing and the condensation of nuclear chromatin. However, because no DNA ladder and no annexin staining were detected, we presume that PEG did not induce apoptosis. PEG increased the osmotic pressure of the culture medium. Hyperosmotic media with added NaCl or sorbitol also inhibited HT29 cell growth, and increased lactate release. These results suggest that PEG may be selectively cytostatic for proliferating cancer cells. This growth inhibition may be due to the high osmotic pressure induced by PEG in vitro. Because the osmotic pressure is high in feces of PEG-fed rats, it may explain the suppression of colon carcinogenesis by PEG.
Published: 2001

45. Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells

Author: Yolande Boilly-Marer, Eve Damiens, Geneviève Spik, Isabelle Duthille, Ikram El Yazidi, Joël Mazurier, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cyclin E, Time Factors, Cell Cycle Proteins, MESH: Cell Cycle, Biochemistry, MESH: Dose-Response Relationship, Drug, CDC2-CDC28 Kinases, Tumor Cells, Cultured, biology, Lactoferrin, Cell Cycle, Retinoblastoma protein, Cell cycle, Cyclin-Dependent Kinases, Cell biology, MESH: Cyclin-Dependent Kinases, MESH: Cyclin-Dependent Kinase Inhibitor p16, Colonic Neoplasms, MESH: Cell Division, Microtubule-Associated Proteins, Cell Division, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase Inhibitor p21, MESH: Time Factor, MESH: Cyclin-Dependent Kinase 4, MESH: Cyclin-Dependent Kinase 2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, MESH: G1 Phase, MESH: Protein-Serine-Threonine Kinases, MESH: Cyclin-Dependent Kinase Inhibitor p21, MESH: Cell Cycle Proteins, Cyclin-dependent kinase, Cyclins, Proto-Oncogene Proteins, MESH: Cyclin-Dependent Kinase Inhibitor p27, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, MESH: CDC2-CDC28 Kinases, Cyclin-Dependent Kinase Inhibitor p16, MESH: Colonic Neoplasms, MESH: Humans, Dose-Response Relationship, Drug, Cyclin-dependent kinase 4, Cell growth, Tumor Suppressor Proteins, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 2, G1 Phase, Cyclin-Dependent Kinase 4, Cell Biology, MESH: Cyclins, MESH: Cyclin E, MESH: Lactoferrin, MESH: Proto-Oncogene Proteins, MESH: Microtubule-Associated Proteins, biology.protein, Cancer research, MESH: Breast Neoplasms, Thymidine, MESH: Thymidine
Abstract: Lactoferrin inhibits cell proliferation and suppresses tumor growth in vivo. However, the molecular mechanisms underlying these effects remain unknown. In this in vitro study, we demonstrate that treatment of breast carcinoma cells MDA-MB-231 with human lactoferrin induces growth arrest at the G1 to S transition of the cell cycle. This G1 arrest is associated with a dramatic decrease in the protein levels of Cdk2 and cyclin E correlated with an inhibition of the Cdk2 kinase activity. Cdk4 activity is also significantly decreased in the treated cells and is accompanied by an increased expression of the Cdk inhibitor p21(CIP1). Furthermore, we show that lactoferrin maintains the cell cycle progression regulator retinoblastoma protein pRb in a hypophosphorylated form. Additional experiments with synchronized cells by serum depletion confirm the anti-proliferative activity of human lactoferrin. These effects of lactoferrin occur through a p53-independent mechanism both in MDA-MB-231 cells and other epithelial cell lines such as HBL-100, MCF-7, and HT-29. These findings demonstrate that lactoferrin induces growth arrest by modulating the expression and the activity of key G1 regulatory proteins.
Published: 1999

46. Glycemic index, nutrient density, and promotion of aberrant crypt foci in rat colon

Author: Ginette Peiffer, Sylviane Taché, Denis E. Corpet, Institut National de la Recherche Agronomique - INRA (FRANCE), Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Xénobiotiques, Institut National de la Recherche Agronomique (INRA)-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, ProdInra, Migration, Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Cancer Research, FIRI index, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Medicine (miscellaneous), Blood triglycerides, MESH: Rats, Sprague-Dawley, MESH: Energy Intake, MESH: Eating, Rats, Sprague-Dawley, chemistry.chemical_compound, Eating, Feces, Index glycémique, 0302 clinical medicine, MESH: Risk Factors, Dietary Sucrose, Risk Factors, insulin resistance, Glycemic index, Aberrant crypt foci, blood glucose, Promotion, rat, MESH: Animals, Nutrient density, ComputingMilieux_MISCELLANEOUS, Cancer, 0303 health sciences, Nutrition and Dietetics, MESH: Feces, Résistance à l'insuline, MESH: Nutritional Status, [SDV] Life Sciences [q-bio], MESH: Viscera, MESH: Glucose, MESH: Precancerous Conditions, Oncology, Adipose Tissue, Intestinal, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Calories vides, carcinogenesis, MESH: Adipose Tissue, empty calory, medicine.medical_specialty, MESH: Rats, Colon, nutrient density, Nutritional Status, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Carbohydrate metabolism, MESH: Dietary Sucrose, digestive system, Article, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Animals, Sucre, 030304 developmental biology, ACF, MESH: Colonic Neoplasms, Azoxymethane, Insulin, colorectal cancer : aberrant crypt foci, Body Weight, Fructose, promotion, medicine.disease, Colorectal cancer, digestive system diseases, MESH: Body Weight, Rats, blood insulin, Viscera, Endocrinology, Glucose, chemistry, azoxymethane, blood triglycerides, glycemic index, Rat, CARCINOGENESE, Energy Intake, MESH: Female, Precancerous Conditions
Abstract: International audience; We speculated that a diet with a high glycemic index (GI) or a diet with a low nutrient density (nutrient-to-calorie ratio) would enhance colon carcinogenesis, presumably via increased insulin resistance. Forty-eight Sprague-Dawley (SD) rats received an azoxymethane injection (20 mg/kg) and were randomized into five groups given an AIN-76 diet containing 1) 65% starch by weight, 2) 65% glucose (GI = 100), 3) 65% fructose (GI = 23), 4) 82% starch, or 5) 39% oil and 39% sucrose. The nutrient density of Diets 4 and 5 was one-half that of Diets 1-3. Promotion was assessed by the multiplicity (number of crypts) of aberrant crypt foci (ACF), an early marker of colon carcinogenesis. Insulin resistance was estimated by the FIRI index (blood insulin x blood glucose), by plasma triglycerides, and by visceral fat. To confirm the results in another rat strain, the experiment was duplicated in 48 Fischer (F344) rats. Results show that 1) the ACF multiplicity was not different in glucose- and fructose-fed rats (p > 0.7): diets with contrasting GI had the same effect on ACF growth; 2) diets of low nutrient density increased visceral fat (p < 0.05) but reduced the ACF size in F344 rats (p < 0.001, no reduction in SD rats); and 3) indirect insulin resistance markers (FIRI index, blood triglycerides, and visceral fat) did not correlate with ACF multiplicity. These results do not support the hypothesis that diets with a high GI or low nutrient density or diets that increase some indirect insulin resistance markers can promote colon carcinogenesis in F344 or SD rats.
Published: 1998

47. Effect of meat (beef, chicken, and bacon) on rat colon carcinogenesis

Author: Ginette Peiffer, Sylviane Taché, Denis E. Corpet, Géraldine Parnaud, Xénobiotiques, Institut National de la Recherche Agronomique (INRA)-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, Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Cancer Research, Swine, MESH: Random Allocation, Medicine (miscellaneous), Weight Gain, MESH: Eating, MESH: Carcinogens, chemistry.chemical_compound, Eating, Feces, Random Allocation, meat, 0302 clinical medicine, prevention, Risk Factors, MESH: Risk Factors, Casein, rat, MESH: Animals, Food science, MESH: Swine, processed meat, 2. Zero hunger, MESH: Meat, 0303 health sciences, MESH: Iron, Nutrition and Dietetics, Fatty Acids, MESH: Chickens, food and beverages, MESH: Feces, beef, 3. Good health, MESH: Fatty Acids, MESH: Viscera, MESH: Cattle, Oncology, Adipose Tissue, 030220 oncology & carcinogenesis, Colonic Neoplasms, Red meat, MESH: Weight Gain, Female, aberrant crypt foci, medicine.symptom, carcinogenesis, MESH: Azoxymethane, MESH: Adipose Tissue, MESH: Drinking, Aberrant crypt foci, MESH: Rats, White meat, Colon, Iron, chicken, Azoxymethane, Drinking, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Bile Acids and Salts, Biology, Article, Bile Acids and Salts, 03 medical and health sciences, MESH: Diet, medicine, Animals, MESH: Colon, 030304 developmental biology, ACF, MESH: Colonic Neoplasms, MESH: Rats, Inbred F344, promotion, Rats, Inbred F344, digestive system diseases, Rats, Viscera, chemistry, Carcinogens, Tumor promotion, Cattle, bacon, diet, Weight gain, Chickens, MESH: Female, porc
Abstract: International audience; High intake of red meat or processed meat is associated with increased risk of colon cancer. In contrast, consumption of white meat (chicken) is not associated with risk and might even reduce the occurrence of colorectal cancer. We speculated that a diet containing beef or bacon would increase and a diet containing chicken would decrease colon carcinogenesis in rats. One hundred female Fischer 344 rats were given a single injection of azoxymethane (20 mg/kg i.p.), then randomized to 10 different AIN-76-based diets. Five diets were adjusted to 14% fat and 23% protein and five other diets to 28% fat and 40% protein. Fat and protein were supplied by 1) lard and casein, 2) olive oil and casein, 3) beef, 4) chicken with skin, and 5) bacon. Meat diets contained 30% or 60% freeze-dried fried meat. The diets were given ad libitum for 100 days, then colon tumor promotion was assessed by the multiplicity of aberrant crypt foci [number of crypts per aberrant crypt focus (ACF)]. The ACF multiplicity was nearly the same in all groups, except bacon-fed rats, with no effect of fat and protein level or source (p = 0.7 between 8 groups by analysis of variance). In contrast, compared with lard- and casein-fed controls, the ACF multiplicity was reduced by 12% in rats fed a diet with 30% bacon and by 20% in rats fed a diet with 60% bacon (p < 0.001). The water intake was higher in bacon-fed rats than in controls (p < 0.0001). The concentrations of iron and bile acids in fecal water and total fatty acids in feces changed with diet, but there was no correlation between these concentrations and the ACF multiplicity. Thus the hypothesis that colonic iron, bile acids, or total fatty acids can promote colon tumors is not supported by this study. The results suggest that, in rats, beef does not promote the growth of ACF and chicken does not protect against colon carcinogenesis. A bacon-based diet appears to protect against carcinogenesis, perhaps because bacon contains 5% NaCl and increased the rats' water intake.
Published: 1998

48. Colonic protein fermentation and promotion of colon carcinogenesis by thermolyzed casein

Author: D. Stamp, Lilian U. Thompson, W. R. Bruce, Alan Medline, Michael C. Archer, Denis E. Corpet, Y. Yin, Xue-Ming Zhang, C. Rémésy, 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), Department of Nutritional Sciences, University of Toronto, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and ProdInra, Migration
Subjects: Cancer Research, Hot Temperature, MESH: Soybean Proteins, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), MESH: Vegetable Proteins, soy protein, casein, ammonia, Plant Proteins, Dietary, chemistry.chemical_compound, 0302 clinical medicine, heated, Casein, phenol, MESH: Animals, MESH: Proteins, Food science, para-cresol, scatol, Soy protein, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Nutrition and Dietetics, cooking, cancer prevention, MESH: Kinetics, Chemistry, cooked, food and beverages, Caseins, CANCER, 3. Good health, [SDV] Life Sciences [q-bio], ammonium, DHA, Oncology, Biochemistry, colon cancer, 030220 oncology & carcinogenesis, gut flora, Colonic Neoplasms, Soybean Proteins, Digestion, Female, aberrant crypt foci, butyric, MESH: Digestion, Egg white, Aberrant crypt foci, toxicology, MESH: Rats, Colon, Ovalbumin, MESH: Heat, [SDV.CAN]Life Sciences [q-bio]/Cancer, Butyrate, MESH: Caseins, MESH: Fermentation, Article, lysinoalanine, 03 medical and health sciences, AOM, dietary protein, thermolysed, indol-3-ol, Animals, MESH: Colon, 030304 developmental biology, cancer promotion, ACF, MESH: Colonic Neoplasms, egg white, MESH: Ovalbumin, Azoxymethane, MESH: Rats, Inbred F344, food, azoxyemetane, Proteins, LAL, dehydroalanine, butyrate, Colorectal cancer, digestive system diseases, Rats, Inbred F344, Rats, Kinetics, digestibility, Fermentation, RAT, CARCINOGENESE, diet, MESH: Female, cresol
Abstract: Thermolyzed casein is known to promote the growth of aberrant crypt foci (ACF) and colon cancer when it is fed to rats that have been initiated with azoxymethane. We speculated that the promotion was a consequence of increased colonic protein fermentation (i.e., that the thermolysis of the casein decreases its digestibility, increases the amount of protein reaching the colon, and increases colonic protein fermentation and that the potentially toxic products of this fermentation promote colon carcinogenesis). We found that the thermolysis of casein reduces its digestibility and increases colonic protein fermentation, as assessed by fecal ammonium and urinary phenol, cresol, and indol-3-ol. Thermolysis of two other proteins, soy and egg white protein, also increases colonic protein fermentation with increased fecal ammonia and urinary phenols, and thermolysis of all three proteins increases the levels of ammonia and butyric, valeric, and i-valeric acids in the cecal contents. We found, however, that the increased protein fermentation observed with thermolysis is not associated with promotion of colon carcinogenesis. With casein, the kinetics of protein fermentation with increasing thermolysis time are clearly different from the kinetics of promotion of ACF growth. The formation of the fermentation products was highest when the protein was thermolyzed for one hour, whereas promotion was highest for protein that had been thermolyzed for two or more hours. With soy and egg white, thermolysis increased colonic protein fermentation but did not promote colon carcinogenesis. Thus, although thermolysis of dietary casein increases colonic protein fermentation, products of this fermentation do not appear to be responsible for the promotion of colon carcinogenesis. Indeed, the results suggest that protein fermentation products do not play an important role in colon cancer promotion.
Published: 1995

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