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

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

Author information

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

PMID:
28609656
DOI:
10.1016/j.ccell.2017.05.006
[Indexed for MEDLINE]
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