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 HöchstDirk 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

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.

Original languageAmerican English
Pages (from-to)771-789.e6
JournalCancer Cell
Volume31
Issue number6
DOIs
StatePublished - 12 Jun 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • JNK
  • Kupffer cell
  • Tnf
  • cholastasis
  • intrahepatic cholangiocarcinoma
  • mitochondrial dysfunction
  • pro-inflammatory niche
  • reactive oxygen species
  • unfolded protein response

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