%0 Journal Article
%A Yuan, Detian
%A Huang, Shan
%A Berger, Emanuel
%A Liu, Lei
%A Gross, Nina
%A Heinzmann, Florian
%A Ringelhan, Marc
%A Connor, Tracy O
%A Stadler, Mira
%A Meister, Michael
%A Weber, Julia
%A Öllinger, Rupert
%A Simonavicius, Nicole
%A Reisinger, Florian
%A Hartmann, Daniel
%A Meyer, Rüdiger
%A Reich, Maria
%A Seehawer, Marco
%A Leone, Valentina
%A Höchst, Bastian
%A Wohlleber, Dirk
%A Jörs, Simone
%A Prinz, Marco
%A Spalding, Duncan
%A Protzer, Ulrike
%A Luedde, Tom
%A Terracciano, Luigi
%A Matter, Matthias
%A Longerich, Thomas
%A Knolle, Percy
%A Ried, Thomas
%A Keitel, Verena
%A Geisler, Fabian
%A Unger, Kristian
%A Cinnamon, Einat
%A Pikarsky, Eli
%A Hüser, Norbert
%A Davis, Roger J
%A Tschaharganeh, Darjus Felix
%A Rad, Roland
%A Weber, Achim
%A Zender, Lars
%A Haller, Dirk
%A Heikenwälder, Mathias
%T Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.
%J Cancer cell
%V 31
%N 6
%@ 1535-6108
%C Cambridge, Mass.
%I Cell Press
%M DKFZ-2017-01317
%P 771 - 789.e6
%D 2017
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:28609656
%R 10.1016/j.ccell.2017.05.006
%U https://inrepo02.dkfz.de/record/124440