Clinical Aspects of Tumor Necrosis Factor-α Signaling in Hepatocellular Carcinoma

Tumor necrosis factor alpha (TNF-alpha) is a multi-functional cytokine that regulates a variety of signaling pathways implicated in inflammation, immunity, cell death (apoptosis), cell survival (anti-apoptosis), and even tumorigenesis. TNF-alpha is predominantly produced by macrophages (or Kupffer cells within the liver), but generated by lymphoid cells, astrocytes, endothelial cells, and smooth muscle cells to some degree. In the liver, TNF-alpha not only serves as a key mediator of hepatocyte apoptosis resulting in the liver damage, but also plays an important role in cellular proliferation leading to liver regeneration or even hepatocarcinogenesis. TNF-alpha may indirectly contribute to carcinogenesis via various inflammatory conditions such as alcoholic and non-alcoholic fatty liver diseases and chronic viral hepatitis. On the one hand, in inflammation, TNF-alpha induces apoptosis repeatedly and subsequently enhances the chance of formation of anomalous cells during the process of regeneration and dysplasia. On the other hand, TNF-alpha exerts as an anti-angiogenic factor depending on its concentration. It shows an anti- tumorous effect by increasing vascular permeability in the tumors. When it is perfused in combination with chemotherapeutic drugs using isolated hepatic infusion, TNF-alpha may increase the responsiveness of hepatocellular carcinoma (HCC) or metastatic cancers to anti-cancer agents as isolated limb perfusion methods in an unresectable soft tissue sarcoma or melanoma. This article reviews the TNF-alpha signaling pathway in hepatocarcinogenesis and the new challenge of TNF-alpha as a new therapeutic strategy in HCC.