Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
Curr Pharm Des. 2014;20(17):2799-808. doi: 10.2174/13816128113199990587.
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.
肿瘤坏死因子-α（TNF-α）是一种多功能细胞因子，可调节多种信号通路，这些信号通路与炎症、免疫、细胞死亡（凋亡）、细胞存活（抗凋亡）甚至肿瘤发生有关。TNF-α主要由巨噬细胞（或肝脏中的库普弗细胞）产生，但也由淋巴样细胞、星形胶质细胞、内皮细胞和平滑肌细胞在一定程度上产生。在肝脏中，TNF-α不仅作为导致肝损伤的肝细胞凋亡的关键介质，而且在细胞增殖中发挥重要作用，导致肝再生甚至肝癌发生。TNF-α可能通过各种炎症情况间接促进癌症发生，如酒精性和非酒精性脂肪性肝病和慢性病毒性肝炎。一方面，在炎症中，TNF-α反复诱导细胞凋亡，随后增加了在再生和发育不良过程中形成异常细胞的机会。另一方面，TNF-α作为一种抗血管生成因子取决于其浓度。它通过增加肿瘤中的血管通透性来发挥抗肿瘤作用。当使用隔离肝输注与化疗药物联合灌注时，TNF-α可能会增加肝细胞癌（HCC）或转移性癌症对癌症药物的反应性，就像在不可切除的软组织肉瘤或黑色素瘤中使用隔离肢体灌注方法一样。本文综述了 TNF-α在肝癌发生中的信号通路以及 TNF-α作为 HCC 新治疗策略的新挑战。
