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

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 paracri...

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Bibliographic Details
Published in:Cancer cell 2017-06, Vol.31 (6), p.771-789.e6
Main Authors: Yuan, Detian, Huang, Shan, Berger, Emanuel, Liu, Lei, Gross, Nina, Heinzmann, Florian, Ringelhan, Marc, Connor, Tracy O., Stadler, Mira, Meister, Michael, Weber, Julia, Öllinger, Rupert, Simonavicius, Nicole, Reisinger, Florian, Hartmann, Daniel, Meyer, Rüdiger, Reich, Maria, Seehawer, Marco, Leone, Valentina, Höchst, Bastian, Wohlleber, Dirk, Jörs, Simone, Prinz, Marco, Spalding, Duncan, Protzer, Ulrike, Luedde, Tom, Terracciano, Luigi, Matter, Matthias, Longerich, Thomas, Knolle, Percy, Ried, Thomas, Keitel, Verena, Geisler, Fabian, Unger, Kristian, Cinnamon, Einat, Pikarsky, Eli, Hüser, Norbert, Davis, Roger J., Tschaharganeh, Darjus F., Rad, Roland, Weber, Achim, Zender, Lars, Haller, Dirk, Heikenwalder, Mathias
Format: Article
Language:English
Subjects:
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
cholastasis
Humans
intrahepatic cholangiocarcinoma
JNK
Kupffer cell
Kupffer Cells - drug effects
Kupffer Cells - metabolism
Liver - drug effects
Liver - pathology
MAP Kinase Signaling System
Mice
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - physiology
mitochondrial dysfunction
Oxidative Stress - drug effects
pro-inflammatory niche
reactive oxygen species
Reactive Oxygen Species - metabolism
Receptors, Tumor Necrosis Factor - genetics
Receptors, Tumor Necrosis Factor - metabolism
Signal Transduction
Tnf
Tumor Microenvironment
Tumor Necrosis Factor-alpha - metabolism
unfolded protein response
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Summary: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. [Display omitted] •Hepatic mitochondrial dysfunction induces premalignant cholangiocellular lesions•Hepatocytes under oxidative stress activate Tnf-producing Kupffer cells•Kupffer cell-derived Tnf triggers cholangiocyte overgrowth through JNK•JNK inhibition impairs intrahepatic cholangiocarcinoma development in several models Yuan et al. show that mitochondrial dysfunction and oxidative stress in the liver increase tumor necrosis factor (TNF) expression by Kupffer cells to cause JNK-mediated cholangiocellular proliferation and transformation. The ROS/TNF/JNK axis may be an effective target for intrahepatic cholangiocarcinoma therapy.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2017.05.006