van Horssen Remco, Ten Hagen Timo L M, Eggermont Alexander M M
Department of Surgical Oncology, Erasmus MC--Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Oncologist. 2006 Apr;11(4):397-408. doi: 10.1634/theoncologist.11-4-397.
Tumor necrosis factor alpha (TNF-alpha), isolated 30 years ago, is a multifunctional cytokine playing a key role in apoptosis and cell survival as well as in inflammation and immunity. Although named for its antitumor properties, TNF has been implicated in a wide spectrum of other diseases. The current use of TNF in cancer is in the regional treatment of locally advanced soft tissue sarcomas and metastatic melanomas and other irresectable tumors of any histology to avoid amputation of the limb. It has been demonstrated in the isolated limb perfusion setting that TNF-alpha acts synergistically with cytostatic drugs. The interaction of TNF-alpha with TNF receptor 1 and receptor 2 (TNFR-1, TNFR-2) activates several signal transduction pathways, leading to the diverse functions of TNF-alpha. The signaling molecules of TNFR-1 have been elucidated quite well, but regulation of the signaling remains unclear. Besides these molecular insights, laboratory experiments in the past decade have shed light upon TNF-alpha action during tumor treatment. Besides extravasation of erythrocytes and lymphocytes, leading to hemorrhagic necrosis, TNF-alpha targets the tumor-associated vasculature (TAV) by inducing hyperpermeability and destruction of the vascular lining. This results in an immediate effect of selective accumulation of cytostatic drugs inside the tumor and a late effect of destruction of the tumor vasculature. In this review, covering TNF-alpha from the molecule to the clinic, we provide an overview of the use of TNF-alpha in cancer starting with molecular insights into TNFR-1 signaling and cellular mechanisms of the antitumor activities of TNF-alpha and ending with clinical response. In addition, possible factors modulating TNF-alpha actions are discussed.
肿瘤坏死因子α（TNF-α）于30年前被分离出来，是一种多功能细胞因子，在细胞凋亡、细胞存活以及炎症和免疫过程中发挥关键作用。尽管因其抗肿瘤特性而得名，但TNF已被发现与多种其他疾病有关。目前TNF在癌症治疗中的应用是用于局部晚期软组织肉瘤和转移性黑色素瘤以及其他任何组织学类型的不可切除肿瘤的区域治疗，以避免肢体截肢。在离体肢体灌注实验中已证实，TNF-α与细胞抑制药物具有协同作用。TNF-α与肿瘤坏死因子受体1和受体2（TNFR-1、TNFR-2）的相互作用激活了多种信号转导途径，从而导致TNF-α发挥多种功能。TNFR-1的信号分子已得到较为充分的阐明，但信号转导的调控仍不清楚。除了这些分子层面的认识，过去十年的实验室实验也揭示了TNF-α在肿瘤治疗过程中的作用机制。除了导致红细胞和淋巴细胞外渗，进而引起出血性坏死外，TNF-α还通过诱导血管通透性增加和破坏血管内皮来靶向肿瘤相关血管系统（TAV）。这导致了细胞抑制药物在肿瘤内选择性蓄积的即时效应以及肿瘤血管破坏的延迟效应。在这篇从分子到临床全面介绍TNF-α的综述中，我们首先从TNFR-1信号转导的分子层面见解以及TNF-α抗肿瘤活性的细胞机制入手，到临床反应，概述了TNF-α在癌症治疗中的应用。此外，还讨论了可能调节TNF-α作用的因素。
