Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer cell, 2017-06, Vol.31 (6), p.771-789.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.