Liver cancer represents a growing health burden worldwide, and treatment options are still limited. Hepatocellular carcinoma (HCC), the most frequent primary hepatic malignancy, arises in most instances in chronically inflamed and fibrotic livers. However, current systemic molecular therapies against HCC are mainly focusing on tyrosine kinases involved in angiogenic and oncogenic signaling pathways, whereas the knowledge on the unique association between inflammation and carcinogenesis in the liver has not yet translated into preventive or therapeutic concepts against HCC. Tumor necrosis factor (TNF) is a cytokine derived from monocytes and various other immunological and parenchymal cells. Upon binding to its receptors, TNF activates different signaling cascades including the pro-apoptotic caspase cascade as well as inflammatory and stress-related pathways such as the NF-ĸB, p38MAPK, and Jun-(N)-terminal kinase (JNK) pathways. The role of TNF in cancer is controversial, since it was attributed both pro- and anti-carcinogenic functions. Its potential function in hepatocarcinogenesis has lately been investigated using genetically modified mouse models. These studies have highlighted that the various TNF-dependent signaling pathways withhold distinct functions in hepatocarcinogenesis, which are in part controversial and strongly depend on the experimental model system. Nevertheless, careful interpretation of findings in mouse models and critical consideration of their limitations might result in a new understanding of this complex pathway in hepatocarcinogenesis and thus might help identify the most promising targets in the TNF pathway and the appropriate clinical settings for future chemo-preventive or therapeutic strategies against HCC.

Keywords:
Tumor necrosis factor, Hepatocellular carcinoma, NF-ĸB, Inflammation, Mouse models, JNK, p38α
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