Clinical aspects of tumor necrosis factor-α signaling in hepatocellular carcinoma.
Tumor necrosis factor alpha (TNF-α) 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-α 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-α 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-α 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-α 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-α 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-α 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-α signaling pathway in hepatocarcinogenesis and the new challenge of TNF-α as a new therapeutic strategy in HCC.
Myoung-Kuk
MK
Jang
Hyoung Su
HS
Kim
Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. yhchung@amc.seoul.kr.
Young-Hwa
YH
Chung
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008954:Models, Biological; D011230:Precancerous Conditions / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha