期刊
CANCER CELL
卷 31, 期 6, 页码 771-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.05.006
关键词
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资金
- Horizon HEPCAR
- ERC Consolidator grant HepatoMetaboPath''
- DFG [GE 2289/1]
- NIH [DK107220]
- Hartmann Muller Stiftung
- Swiss National Science Foundation (SNF) [SNF 310030_146940]
- [SFB Transregio SFB/TR36]
- [SFB/TR179]
- [SFB/TR209]
- [Graduiertenkolleg (GRK482)]
- Swiss National Science Foundation (SNF) [310030_146940] Funding Source: Swiss National Science Foundation (SNF)
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.
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