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Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.
Yuan, Detian; Huang, Shan; Berger, Emanuel; Liu, Lei; Gross, Nina; Heinzmann, Florian; Ringelhan, Marc; Connor, Tracy O; Stadler, Mira; Meister, Michael; Weber, Julia; Öllinger, Rupert; Simonavicius, Nicole; Reisinger, Florian; Hartmann, Daniel; Meyer, Rüdiger; Reich, Maria; Seehawer, Marco; Leone, Valentina; Höchst, Bastian; Wohlleber, Dirk; Jörs, Simone; Prinz, Marco; Spalding, Duncan; Protzer, Ulrike; Luedde, Tom; Terracciano, Luigi; Matter, Matthias; Longerich, Thomas; Knolle, Percy; Ried, Thomas; Keitel, Verena; Geisler, Fabian; Unger, Kristian; Cinnamon, Einat; Pikarsky, Eli; Hüser, Norbert; Davis, Roger J; Tschaharganeh, Darjus F; Rad, Roland; Weber, Achim; Zender, Lars; Haller, Dirk; Heikenwalder, Mathias.
Afiliação
  • Yuan D; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Huang S; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Berger E; Chair of Nutrition and Immunology, Technische Universität München, Gregor-Mendel-Straße 2, 85350 Freising-Weihenstephan, Germany.
  • Liu L; Department of Surgery, Technische Universität München, 81675 Munich, Germany.
  • Gross N; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Heinzmann F; Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  • Ringelhan M; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Connor TO; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Stadler M; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Meister M; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Weber J; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Öllinger R; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Simonavicius N; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
  • Reisinger F; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
  • Hartmann D; Department of Surgery, Technische Universität München, 81675 Munich, Germany.
  • Meyer R; Genome Technology Branch, National Human Genome Research Institute, U.S. National Institutes of Health, Bethesda, MD 20892, USA.
  • Reich M; Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, 40204 Düsseldorf, Germany.
  • Seehawer M; Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  • Leone V; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
  • Höchst B; Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Wohlleber D; Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Jörs S; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Prinz M; Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79106 Freiburg, Germany.
  • Spalding D; Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
  • Protzer U; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
  • Luedde T; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.
  • Terracciano L; Institute of Pathology, University Hospital of Basel, 4003 Basel, Switzerland.
  • Matter M; Institute of Pathology, University Hospital of Basel, 4003 Basel, Switzerland.
  • Longerich T; Institute of Pathology, University Hospital RWTH, 52074 Aachen, Germany.
  • Knolle P; Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Ried T; Genome Technology Branch, National Human Genome Research Institute, U.S. National Institutes of Health, Bethesda, MD 20892, USA.
  • Keitel V; Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, 40204 Düsseldorf, Germany.
  • Geisler F; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Unger K; Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Cinnamon E; The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
  • Pikarsky E; The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
  • Hüser N; Department of Surgery, Technische Universität München, 81675 Munich, Germany.
  • Davis RJ; Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Tschaharganeh DF; Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ) & Institute of Pathology University Hospital, 69120 Heidelberg, Germany.
  • Rad R; 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • Weber A; Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
  • Zender L; Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Translational Gastrointestinal Oncology Group within the German Consortium for Translational
  • Haller D; Chair of Nutrition and Immunology, Technische Universität München, Gregor-Mendel-Straße 2, 85350 Freising-Weihenstephan, Germany; ZIEL - Institute for Food & Health, Technische Universität München, 85350 Freising-Weihenstephan, Germany. Electronic address: dirk.haller@tum.de.
  • Heikenwalder M; Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: m.heikenwaelder@dkfz-heidelberg.de.
Cancer Cell ; 31(6): 771-789.e6, 2017 06 12.
Article em En | MEDLINE | ID: mdl-28609656
ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias dos Ductos Biliares / Fator de Necrose Tumoral alfa / Colangiocarcinoma / Sistema de Sinalização das MAP Quinases / Células de Kupffer Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias dos Ductos Biliares / Fator de Necrose Tumoral alfa / Colangiocarcinoma / Sistema de Sinalização das MAP Quinases / Células de Kupffer Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article