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IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice
Author(s) -
Bergmann Juri,
Müller Miryam,
Baumann Niklas,
Reichert Manuel,
Heneweer Carola,
Bolik Julia,
Lücke Karsten,
Gruber Sabine,
Carambia Antonella,
Boretius Susanne,
Leuschner Ivo,
Becker Thomas,
Rabe Björn,
Herkel Johannes,
Wunderlich F. Thomas,
Mittrücker HansWilli,
RoseJohn Stefan,
SchmidtArras Dirk
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28874
Subject(s) - cancer research , carcinogenesis , signal transduction , hepatocellular carcinoma , angiogenesis , tumor progression , biology , cytokine , immunology , medicine , microbiology and biotechnology , cancer
Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin‐6 (IL‐6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL‐6 classic and the IL‐6 trans‐signaling pathway. Whereas IL‐6 classic signaling is important for innate and acquired immunity, IL‐6 trans‐signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL‐6 trans‐signaling, but not IL‐6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA‐damage‐induced hepatocyte apoptosis through suppression of p53 and enhances β‐catenin activation and tumor proliferation. Second, IL‐6 trans‐signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL‐6 trans‐signaling are largely protected from tumor formation in a diethylnitrosamine/3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene model of HCC. Conclusion : IL‐6 trans‐signaling, and not IL‐6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL‐6 trans‐signaling, rather than total inhibition of IL‐6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL‐6 classic signaling‐driven protective immune responses. (H epatology 2017;65:89‐103).