Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Detian Yuan; Shan Huang; Emanuel Berger; Lei Liu; Nina Gross; Florian Heinzmann; Marc Ringelhan; Tracy O Connor; Mira Stadler; Michael Meister; Julia Weber; Rupert Öllinger; Nicole Simonavicius; Florian Reisinger; Daniel Hartmann; Rüdiger Meyer; Maria Reich; Marco Seehawer; Valentina Leone; Bastian Höchst; Dirk Wohlleber; Simone Jörs; Marco Prinz; Duncan Spalding; Ulrike Protzer; Tom Luedde; Luigi Terracciano; Matthias Matter; Thomas Longerich; Percy Knolle; Thomas Ried; Verena Keitel; Fabian Geisler; Kristian Unger; Einat Cinnamon; Eli Pikarsky; Norbert Hüser; Roger J Davis; Darjus F Tschaharganeh; Roland Rad; Achim Weber; Lars Zender; Dirk Haller; Mathias Heikenwalder

doi:10.1016/j.ccell.2017.05.006

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Cancer Cell. 2017 Jun 12;31(6):771-789.e6. doi: 10.1016/j.ccell.2017.05.006.

Authors

Detian Yuan¹, Shan Huang², Emanuel Berger³, Lei Liu⁴, Nina Gross⁵, Florian Heinzmann⁶, Marc Ringelhan⁷, Tracy O Connor¹, Mira Stadler², Michael Meister², Julia Weber⁵, Rupert Öllinger⁵, Nicole Simonavicius⁸, Florian Reisinger⁸, Daniel Hartmann⁴, Rüdiger Meyer⁹, Maria Reich¹⁰, Marco Seehawer⁶, Valentina Leone⁸, Bastian Höchst¹¹, Dirk Wohlleber¹¹, Simone Jörs⁵, Marco Prinz¹², Duncan Spalding¹³, Ulrike Protzer⁸, Tom Luedde¹⁴, Luigi Terracciano¹⁵, Matthias Matter¹⁵, Thomas Longerich¹⁶, Percy Knolle¹¹, Thomas Ried⁹, Verena Keitel¹⁰, Fabian Geisler⁵, Kristian Unger¹⁷, Einat Cinnamon¹⁸, Eli Pikarsky¹⁹, Norbert Hüser⁴, Roger J Davis²⁰, Darjus F Tschaharganeh²¹, Roland Rad⁵, Achim Weber²², Lars Zender²³, Dirk Haller²⁴, Mathias Heikenwalder²⁵

Affiliations

¹ 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.
² Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
³ Chair of Nutrition and Immunology, Technische Universität München, Gregor-Mendel-Straße 2, 85350 Freising-Weihenstephan, Germany.
⁴ Department of Surgery, Technische Universität München, 81675 Munich, Germany.
⁵ 2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
⁶ 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.
⁷ 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.
⁸ Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
⁹ Genome Technology Branch, National Human Genome Research Institute, U.S. National Institutes of Health, Bethesda, MD 20892, USA.
¹⁰ Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, 40204 Düsseldorf, Germany.
¹¹ Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
¹² Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79106 Freiburg, Germany.
¹³ Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
¹⁴ Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.
¹⁵ Institute of Pathology, University Hospital of Basel, 4003 Basel, Switzerland.
¹⁶ Institute of Pathology, University Hospital RWTH, 52074 Aachen, Germany.
¹⁷ Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
¹⁸ The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
¹⁹ 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.
²⁰ Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
²¹ Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ) & Institute of Pathology University Hospital, 69120 Heidelberg, Germany.
²² Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
²³ 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 Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
²⁴ 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.
²⁵ 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.

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.

Keywords: JNK; Kupffer cell; Tnf; cholastasis; intrahepatic cholangiocarcinoma; mitochondrial dysfunction; pro-inflammatory niche; reactive oxygen species; unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Bile Duct Neoplasms / metabolism*
Bile Duct Neoplasms / pathology
Butylated Hydroxyanisole / therapeutic use
Carcinogenesis
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Transformation, Neoplastic / drug effects
Cholangiocarcinoma / metabolism*
Cholangiocarcinoma / pathology
Humans
Kupffer Cells / drug effects
Kupffer Cells / metabolism*
Liver / drug effects
Liver / pathology
MAP Kinase Signaling System*
Mice
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondria / physiology
Oxidative Stress / drug effects
Reactive Oxygen Species / metabolism
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / metabolism
Signal Transduction
Tumor Microenvironment
Tumor Necrosis Factor-alpha / metabolism*

Substances

Reactive Oxygen Species
Receptors, Tumor Necrosis Factor
Tumor Necrosis Factor-alpha
Butylated Hydroxyanisole

Abstract

Publication types

MeSH terms

Substances

Grants and funding