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6 results on '"LIVER-CANCER"'

1. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]

Subjects
Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Published
2021
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2. Hepatitis B virus preS2Δ38–55 variants: A newly identified risk factor for hepatocellular carcinoma

Author

Fabien Zoulim, Pierre Simon Garcia, Valentin Tilloy, Saunab Ghosh, Yusuke Shimakawa, Maud Lemoine, Janet Hall, Céline Brochier-Armanet, Njie Ramou, Anaëlle Dubois, Nora Kakwata-Nkor Deluce, Damien Cohen, Clément Guillot, Sophie Alain, Geoffroy Durand, Isabelle Chemin, Maimuna Mendy, Mark Thursz, Florence Le Calvez-Kelm, Umberto D'Alessandro, Catherine Voegele, Gibril Ndow, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Dupuytren [CHU Limoges], London School of Hygiene and Tropical Medicine [Fajara, Gambia], London School of Hygiene and Tropical Medicine (LSHTM), Hospices Civils de Lyon (HCL), Imperial College London, European Commission (FP7), Agence Nationale de Recherches sur le Sida et les Hepatites Virales (12357), the ARC Santé from the Region Auvergne Rhône-Alpes, NIHR Imperial Biomedical Research Centre., Imperial College Healthcare NHS Trust: Research Capability Funding (RCF), Medical Research Council (MRC), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université (HESAM)-HESAM Université (HESAM)

Subjects
WT, wild type, HBsAg, Aflatoxin B1, Carcinogenesis, Hepatocellular carcinoma, NBS1, Nijmegen breakage syndrome 1, LSM, liver stiffness measurement, medicine.disease_cause, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Liver disease, 0302 clinical medicine, PreS deletion, Genotype, INFECTION, Immunology and Allergy, LIVER-CANCER, SSA, sub-Saharan Africa, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, 0303 health sciences, education.field_of_study, AFP, alpha-fetoprotein, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Gastroenterology, GAMBIA, CARRIERS, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cirrhosis, 030211 gastroenterology & hepatology, Liver cancer, Viral load, Life Sciences & Biomedicine, AFB1, aflatoxin B1, Research Article, Hepatitis B virus, PROTEINS, Population, ER, endoplasmic reticulum, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal Medicine, medicine, lcsh:RC799-869, education, 030304 developmental biology, Science & Technology, Hepatology, Gastroenterology & Hepatology, business.industry, DNA, medicine.disease, GENOTYPES, Virology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, GENE, PROLIFICA, Prevention of Liver Fibrosis and Cancer in Africa, digestive system diseases, SUBGENOTYPE, ROC, receiver operating characteristic, DELETIONS, NGS, next-generation sequencing, OR, odds ratio, Africa, lcsh:Diseases of the digestive system. Gastroenterology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background & Aims Although HBV is a major cause of death in Africa, its genetic variability has been poorly documented. This study aimed to address whether HBV genotype and surface gene variants are associated with HBV-related liver disease in The Gambia. Methods We conducted a case-control study nested in the Prevention of Liver Fibrosis and Cancer in Africa programme. Consecutive treatment-naive patients with chronic HBV infection and detectable viral load were recruited: 211 controls with no significant liver disease and 91 cases (56 cirrhosis and 35 HCC cases). HBV genotypes and surface gene variants were determined by Sanger sequencing or next-generation sequencing (NGS) in serum DNA. Aflatoxin B1 (AFB1)-specific codon 249 TP53 mutation was determined by NGS in circulating cell-free plasma DNA. Results In phylogenetic analysis, 85% of individuals carried HBV genotype E, 14% genotype A, and 1% A/E recombinant viruses. Surface gene variants were more frequently observed in cases (43% and 57% in cirrhosis and HCC cases, respectively) than controls (25%; p 2,000 IU/ml (OR 22.7 [8.0–64.9]), HBsAg levels, Graphical abstract, Highlights • The rarer HBV genotype A (vs. E) is associated with a higher risk of HCC (odds ratio 5.2). • A genotype-independent deletion hotspot was found in the preS2 domain (preS2Δ38–55). • PreS2Δ38–55 was significantly associated with HCC and is an independent risk factor.

Published
2020
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3. Retrodifferentiation of human tumor hepatocytes to stem cells leads to metabolic reprogramming and chemoresistance

Author

Orlando Musso, Anne Corlu, Bernard Fromenty, Karim Fekir, Florian Cabillic, Hélène Dubois-Pot-Schneider, Fabrice Morel, Romain Desert, Yoann Daniel, Claudine Rauch, Denise Glaise, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle Grand Ouest, Association pour la Recherche sur le CancerAssociation pour la Recherche sur le Cancer (ARC), University of Rennes, Ligue Contre le CancerLigue Contre le Cancer, Conseil Régional de BretagneConseil Régional de Bretagne (Brittany Council), Institut National de la Santé et de la Recherche MédicaleInstitut National de la Santé et de la Recherche Médicale (Inserm), 223317, Seventh Framework ProgrammeSeventh Framework Programme (FP7), 12688, Institut National Du CancerInstitut National Du Cancer (INCa), Centre National de la Recherche ScientifiqueCentre National de la Recherche Scientifique (CNRS), Contrat plan etat region, and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, Carcinoma, Hepatocellular, transdifferentiation, Cellular differentiation, [SDV]Life Sciences [q-bio], Apoptosis, Biology, growth-factor, advanced hepatocellular-carcinoma, Transcriptome, resistance, 03 medical and health sciences, 0302 clinical medicine, Side population, Cancer stem cell, liver-cancer, expression, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, metastasis, Progenitor cell, Cell Proliferation, angiopoietin-like 4, Liver Neoplasms, Cell Differentiation, Cellular Reprogramming, Prognosis, digestive system diseases, 3. Good health, Survival Rate, 030104 developmental biology, Oncology, Cell culture, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Hepatocytes, Neoplastic Stem Cells, sorafenib, regorafenib, Stem cell, Neoplasm Recurrence, Local
Abstract

Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies. Gene expression profiling of HepaRG-SP and HepaRG-Spheres revealed enriched signatures related to cancer stem cells, metastasis, and recurrence and showed that HepaRG progenitors could retrodifferentiate into an immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells expressed high levels of cytokines triggering retrodifferentiation and displayed high migration and invasion potential. They also showed changes in mitochondrial activity with reduced membrane potential, low ATP production, and high lactate production. These changes were, in part, related to angiopoietin-like 4 (ANGPTL4)–induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Upregulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Therefore, restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCC. Significance: Restoring mitochondrial function in human hepatocellular carcinomas overcomes cancer resistance.

Published
2019
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4. Transarterial Radioembolization (TARE) Agents beyond Y-90-Microspheres

Author

Etienne Garin, Pascal Loyer, Nicolas Lepareur, Julien Edeline, Christelle Bouvry, Valérie Ardisson, Xavier Palard, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CRLCC Eugène Marquis (CRLCC), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex IRON [ANR-11-LABX-0018], ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Jonchère, Laurent, and Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID

Subjects
medicine.medical_specialty, Carcinoma, Hepatocellular, Tare weight, Review Article, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Transarterial Radioembolization, serum-albumin microspheres, General Biochemistry, Genetics and Molecular Biology, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 030218 nuclear medicine & medical imaging, Microsphere, 03 medical and health sciences, 0302 clinical medicine, internal radiation-therapy, liver-cancer, hepatic-artery injection, Carcinoma, Medicine, Animals, Humans, Yttrium Radioisotopes, poly(l-lactic acid) microspheres, inoperable hepatocellular-carcinoma, ho-166 loaded microspheres, radionuclide therapy, intraarterial injection, i-131-labeled lipiodol, Chemoembolization, Therapeutic, Cause of death, Clinical Trials as Topic, General Immunology and Microbiology, business.industry, Liver Neoplasms, General Medicine, medicine.disease, Microspheres, 3. Good health, Clinical trial, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Radionuclide therapy, Radiology, business
Abstract

Liver malignancies, either primary tumours (mainly hepatocellular carcinoma and cholangiocarcinoma) or secondary hepatic metastases, are a major cause of death, with an increasing incidence. Among them, hepatocellular carcinoma (HCC) presents with a dark prognosis because of underlying liver diseases and an often late diagnosis. A curative surgical treatment can therefore only be proposed in 20 to 30% of the patients. However, new treatment options for intermediate to advanced stages, such as internal radionuclide therapy, seem particularly attractive. Transarterial radioembolization (TARE), which consists in the use of intra-arterial injection of a radiolabelled embolising agent, has led to very promising results. TARE with 90Y-loaded microspheres is now becoming an established procedure to treat liver tumours, with two commercially available products (namely, SIR-Sphere® and TheraSphere®). However, this technology remains expensive and is thus not available everywhere. The aim of this review is to describe TARE alternative technologies currently developed and investigated in clinical trials, with special emphasis on HCC.

Published
2018
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5. A Peculiar Mutation Spectrum Emerging from Young Peruvian Patients with Hepatocellular Carcinoma

Author

Stéphane Bertani, Eloy Ruiz, Eric Deharo, Pascal Pineau, Teresa Rojas Rojas, Agnès Marchio, Franco Doimi, Benoit Terris, Anne Dejean, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Instituto Nacional de Enfermedades Neoplasicas [Lima, Pérou] (INEN), Service d'Anatomie et de cytologie pathologiques [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pharmacochimie et Pharmacologie Pour le Développement ( PHARMA-DEV ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique ( CNRS ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Instituto Nacional de Enfermedades Neoplasicas, Banco de Tejidos Tumorales, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Departamento de Cirugia en Abdomen, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, and HAL AMU, Administrateur

Subjects
Male, Pathology, Epidemiology, DNA Mutational Analysis, lcsh:Medicine, NONCIRRHOTIC LIVER, TUMOR-SUPPRESSOR GENE, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Geographical Locations, Liver disease, CANCER STEM-CELLS, Peru, Medicine and Health Sciences, LIVER-CANCER, lcsh:Science, Aged, 80 and over, Multidisciplinary, Liver Neoplasms, LATIN-AMERICA, Middle Aged, ETHNIC-GROUPS, Neoplasm Proteins, 3. Good health, Gene Expression Regulation, Neoplastic, Infectious Diseases, Oncology, Hepatocellular carcinoma, Female, Liver cancer, Research Article, Signal Transduction, Adult, medicine.medical_specialty, Carcinoma, Hepatocellular, Tumor suppressor gene, BETA-CATENIN MUTATIONS, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology and Hepatology, Biology, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, medicine, Humans, Molecular Biology, Aged, FREQUENT SOMATIC MUTATIONS, Hippo signaling pathway, lcsh:R, Biology and Life Sciences, AFLATOXIN EXPOSURE, ALPHA-FETOPROTEIN GENE, medicine.disease, Human genetics, digestive system diseases, People and Places, Mutation, Cancer research, lcsh:Q, Carcinogenesis
Abstract

Hepatocellular carcinoma usually afflicts individuals in their later years following longstanding liver disease. In Peru, hepatocellular carcinoma exists in a unique clinical presentation, which affects patients around age 25 with a normal, healthy liver. In order to deepen our understanding of the molecular processes ongoing in Peruvian liver tumors, mutation spectrum analysis was carried out on hepatocellular carcinomas from 80 Peruvian patients. Sequencing analysis focused on nine genes typically altered during liver carcinogenesis, i.e. ARID2, AXIN1, BRAF, CTNNB1, NFE2L2, H/K/N-RAS, and TP53. We also assessed the transcription level of factors involved in the control of the alpha-fetoprotein expression and the Hippo signaling pathway that controls contact inhibition in metazoans. The mutation spectrum of Peruvian patients was unique with a major class of alterations represented by Insertions/Deletions. There were no changes at hepatocellular carcinoma-associated mutation hotspots in more than half of the specimens analyzed. Furthermore, our findings support the theory of a consistent collapse in the Hippo axis, as well as an expression of the stemness factor NANOG in high alpha-fetoprotein-expressing hepatocellular carcinomas. These results confirm the specificity of Peruvian hepatocellular carcinoma at the molecular genetic level. The present study emphasizes the necessity to widen cancer research to include historically neglected patients from South America, and more broadly the Global South, where cancer genetics and tumor presentation are divergent from canonical neoplasms.

Published
2014
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6. Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion

Author

Francesca De Giorgi, Naoual L Benali-Furet, François Ichas, Patrizia Paterlini-Bréchot, Rosario Rizzuto, Ludivine Houel, David Lagorce, Mounia Chami, Ralf Bartenschlager, Fabienne Vernejoul, Louis Buscail, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Ferrara (UniFE), Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Department of Molecular Virology, and Universität Heidelberg [Heidelberg]

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], aequorin, Hepacivirus, Endoplasmic Reticulum, Membrane Potentials, Mice, 0302 clinical medicine, LIVER-CANCER, Promoter Regions, Genetic, Endoplasmic Reticulum Chaperone BiP, Calcium signaling, 0303 health sciences, 3. Good health, Cell biology, Mitochondria, APOPTOSIS, cell death, Liver, 030220 oncology & carcinogenesis, HCV, ER stress, Liver cancer, Programmed cell death, HVC Core, chemistry.chemical_element, Mice, Transgenic, Calcium, Biology, Transfection, Models, Biological, 03 medical and health sciences, HCV core, Cell Line, Tumor, Genetics, In Situ Nick-End Labeling, Animals, Humans, Molecular Biology, 030304 developmental biology, Calcium metabolism, Apoptosis, Calcium signalling, Endoplasmic reticulum, Intracellular Membranes, Virology, CALCIUM SIGNALLING, Calcium ATPase, Mice, Inbred C57BL, chemistry, Unfolded protein response, endoplasmic reticulum, mitochondria
Abstract

International audience; Hepatitis C virus (HCV) core, known to be involved in liver carcinogenesis, is processed in the endoplasmic reticulum (ER). We thus investigated the impact of three HCV core isolates on ER stress, ER calcium signalling and apoptosis. We show that HCV core constructs trigger hyperexpression of Grp78/BiP, Grp 94, calreticulin and sarco/endoplasmic reticulum calcium ATPase, inducing ER stress. By using the ER-targeted aequorin calcium probe, we found that ER calcium depletion follows ER stress in core-expressing cells. HCV core induces apoptosis through overexpression of the CHOP/GADD153 proapoptotic factor, Bax translocation to mitochondria, mitochondrial membrane depolarization, cytochrome c release, caspase-3 and PARP cleavage. Furthermore, reversion of HCV core-induced ER calcium depletion (by transfection of SERCA2) completely abolished mitochondrial membrane depolarization, suggesting that both ER stress (through CHOP overexpression) and calcium signalling play a major role in the HCV core-mediated control of apoptosis. ER stress and apoptosis were also found in a proportion of HCV-full-length replicon-expressing cells and in the liver of HCV core transgenic mice. In conclusion, our data demonstrate that HCV core deregulates the control of apoptosis by inducing ER stress and ER calcium depletion providing new elements to understand the mechanisms involved in HCV-related liver chronic diseases.

Published
2005

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