ArticleCancer cell2017
Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.
Erratum issuedOpen access · greenAbstract read
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Article in Cancer cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 126 papers, 1 of them a synthesis that pooled it.
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126citing papers in PubMed, 1 pooled it
16.6field-weighted citation impact, top 1% of its field
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Who cites it
126 citing papers in PubMed, 1 synthesis or guideline pooled it, 190 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
- Irradiated Liver Cancer Cell Vaccine Transfected With GM-CSF Induces Specific and Long-Lasting Anti-tumour Immunity Through the Synergistic Effect of Oxidised mtDNA and GM-CSF.Cell proliferation · 2026Article
- Radiotherapy and cytokines: A systems view of immunotherapy and toxicity (Review).International journal of molecular medicine · 2026Review
- Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.Nature communications · 2026Article
- Preclinical mouse models for studying cholangiocarcinoma.Liver research (Beijing, China) · 2026Review
- Preoperative exercise induces anti-tumor Kupffer cells to prevent surgical stress-promoted colorectal cancer liver metastasis.Cell reports. Medicine · 2026Article
- The Role of Kupffer Cells and Liver Macrophages in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.Biomedicines · 2026Review
- Stratifying cholangiocarcinoma: tumor microenvironment, molecular drivers, and novel immunotherapeutic approaches.Clinical and molecular hepatology · 2026Review
- MEF2D-expressing cancer precursors reprogram tissue-resident macrophages to support liver tumorigenesis.Nature cancer · 2025Article
- Research progress on programmed cell death of cardiomyocytes in pressure-overload hypertrophic cardiomyopathy.Apoptosis : an international journal on programmed cell death · 2025Review
- Lymphocyte-C-Reactive Protein Ratio: Impact on Prognosis of Patients Following Resection of Primary Liver Cancer.World journal of surgery · 2025Article
- Valproic Acid Reduces Invasiveness and Cellular Growth in 2D and 3D Glioblastoma Cell Lines.International journal of molecular sciences · 2025Article
- High metastatic tumor-derived CXCL16 mediates liver colonization metastasis by inducing Kupffer cell polarization via the PI3K/AKT/FOXO3a pathway.Neoplasia (New York, N.Y.) · 2025Article
- PPDPF-mediated regulation of BCAA metabolism enhances mTORC1 activity and drives cholangiocarcinoma progression.Oncogene · 2025Article
- Review
- Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma.The American journal of pathology · 2025Review
- The promise of mitochondria in the treatment of glioblastoma: a brief review.Discover oncology · 2025Review
- Immunomodulatory role of vitamin D and emerging immunotherapies in hepatocellular carcinoma.Frontiers in nutrition · 2025Review
- Significance and mechanisms of perineural invasion in malignant tumors.Frontiers in oncology · 2025Review
- The role of reactive oxygen species in the transformation from prostatitis to prostate cancer: a review.Frontiers in immunology · 2025Review
66 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
44 authors at 17 institutions in 5 countries.
Detian YuanInstitute 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.
Shan HuangDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Emanuel BergerChair of Nutrition and Immunology, Technische Universität München, Gregor-Mendel-Straße 2, 85350 Freising-Weihenstephan, Germany.
Lei LiuDepartment of Surgery, Technische Universität München, 81675 Munich, Germany.
Nina Gross2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Florian HeinzmannDepartment of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Marc RingelhanInstitute 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.
Tracy O ConnorInstitute 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.
Mira StadlerDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Michael MeisterDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Julia Weber2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Rupert Öllinger2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Nicole SimonaviciusInstitute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
Florian ReisingerInstitute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
Daniel HartmannDepartment of Surgery, Technische Universität München, 81675 Munich, Germany.
Rüdiger MeyerGenome Technology Branch, National Human Genome Research Institute, U.S. National Institutes of Health, Bethesda, MD 20892, USA.
Maria ReichClinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, 40204 Düsseldorf, Germany.
Marco SeehawerDepartment of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Valentina LeoneInstitute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
Bastian HöchstInstitute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Dirk WohlleberInstitute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Simone Jörs2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Marco PrinzInstitute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79106 Freiburg, Germany.
Duncan SpaldingDepartment of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Ulrike ProtzerInstitute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany.
Tom LueddeDivision of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.
Luigi TerraccianoInstitute of Pathology, University Hospital of Basel, 4003 Basel, Switzerland.
Matthias MatterInstitute of Pathology, University Hospital of Basel, 4003 Basel, Switzerland.
Thomas LongerichInstitute of Pathology, University Hospital RWTH, 52074 Aachen, Germany.
Percy KnolleInstitute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Thomas RiedGenome Technology Branch, National Human Genome Research Institute, U.S. National Institutes of Health, Bethesda, MD 20892, USA.
Verena KeitelClinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, 40204 Düsseldorf, Germany.
Fabian Geisler2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Kristian UngerResearch Unit of Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Einat CinnamonThe Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Eli PikarskyThe 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.
Norbert HüserDepartment of Surgery, Technische Universität München, 81675 Munich, Germany.
Roger J DavisHoward Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Darjus F TschaharganehHelmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ) & Institute of Pathology University Hospital, 69120 Heidelberg, Germany.
Roland Rad2nd Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Achim WeberDepartment of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
Lars ZenderDepartment 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.
Dirk HallerChair 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.
Mathias HeikenwalderInstitute 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.
Technical University of Munich · DEKlinikum rechts der Isar · DEHeidelberg University · DEHelmholtz Zentrum München · DEHebrew University of Jerusalem · ILHeinrich Heine University Düsseldorf · DERWTH Aachen University · DEUniversity Hospital of Basel · CHUniversity of Tübingen · DEGerman Cancer Research Center · DEImperial College London · GBNational Human Genome Research Institute · USNational Institutes of Health · USUniversity Children's Hospital Tübingen · DEUniversity Hospital of Zurich · CHUniversity of Freiburg · DEUniversity of Massachusetts Chan Medical School · US
Funding
Intratumor heterogeneity and tumor evolutionZIABC010834 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI RIED, THOMAS · 2009 to 2023
$12.2MPrediction of Therapy Response in Colorectal CancerZIABC010837 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI RIED, THOMAS · 2009 to 2022
$8.9MMetabolic Stress SignalingR01DK107220 · NIDDK · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI DAVIS, ROGER J. · 2016 to 2023
$3.6MIntramural NIH HHS ZIA BC010834NIDDK NIH HHS R01 DK107220
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.
Indexed as
MAP Kinase Signaling SystemAnimalsBile Duct NeoplasmsButylated HydroxyanisoleCarcinogenesisCell Line, TumorCell ProliferationCell Transformation, NeoplasticCholangiocarcinomaHumansKupffer CellsLiverMiceMitochondriaOxidative StressReactive Oxygen SpeciesButylated HydroxyanisoleReactive Oxygen SpeciesReceptors, Tumor Necrosis FactorTumor Necrosis Factor-alphacholastasisintrahepatic cholangiocarcinomaJNKKupffer cellmitochondrial dysfunctionpro-inflammatory nichereactive oxygen speciesTnfunfolded protein response
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