文章：

TRAIL凋亡通路在癌症发生、进展和治疗中的作用

The TRAIL apoptotic pathway in cancer onset, progression and therapy

原文发布日期：2008-10-01

DOI: 10.1038/nrc2465

类型: Review Article

开放获取: 否

要点：

1. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent stimulator of apoptosis, and tumour cells are significantly more sensitive to TRAIL-induced apoptosis than normal cells. Although the molecular basis for the tumour-selective activity of TRAIL remains to be fully defined, the TRAIL pathway is an attractive therapeutic target for the treatment of cancer.
2. In addition to triggering a pro-apoptotic signal through activation of caspases, TRAIL can activate diverse intracellular signalling pathways involving NFκB, phosphoinositoide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) family proteins that can stimulate cell survival and proliferation.
3. TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumours. Moreover, genetic lesions in various components of the TRAIL pathway have been found in human tumour samples, suggesting that inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumour onset and progression.
4. In preclinical trials, recombinant forms of TRAIL and agonistic anti-TRAIL receptor antibodies can have single-agent activity against TRAIL-sensitive tumour cells in vitro and in vivo. These agents can synergize with chemotherapeutic drugs and novel molecular therapeutic agents to more effectively kill TRAIL-sensitive tumour cells and TRAIL-resistant tumours.
5. Early-phase clinical trials using recombinant TRAIL and agonistic anti-TRAIL receptor antibodies indicate that these agents can be delivered safely and are generally well-tolerated. Although some objective anti-tumour responses have been reported with these agents as monotherapies, they probably hold greater promise for further clinical development when used in combination with other cancer treatments.

要点翻译：

1. 肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是一种有效的凋亡刺激因子，其对肿瘤细胞诱导凋亡的敏感性显著高于正常细胞。尽管TRAIL肿瘤选择性活性的分子机制尚未完全阐明，但TRAIL通路已成为极具吸引力的癌症治疗靶点。
2. 除通过激活caspases蛋白触发促凋亡信号外，TRAIL还能激活多种细胞内信号通路，包括NFκB、磷酸肌醇3-激酶（PI3K）及丝裂原活化蛋白激酶（MAPK）家族蛋白，这些通路可刺激细胞存活与增殖。
3. TRAIL在肿瘤发生发展的监视与清除过程中是重要的免疫效应分子。此外，在人类肿瘤样本中发现TRAIL通路多个组分存在遗传损伤，这表明TRAIL通路失活和/或逃逸TRAIL介导的免疫监视可能在肿瘤发生与进展中起重要作用。
4. 临床前试验表明，重组TRAIL及激动性抗TRAIL受体抗体在体外和体内对TRAIL敏感肿瘤细胞均具有单药活性。这些制剂与化疗药物及新型分子靶向药物联用时可产生协同效应，更有效地杀伤TRAIL敏感肿瘤细胞及TRAIL耐药肿瘤。
5. 使用重组TRAIL和激动性抗TRAIL受体抗体的早期临床试验表明，这些药物可安全给药且普遍耐受良好。虽然已有这些单药治疗获得客观抗肿瘤反应的报道，但与其他癌症疗法联合应用时可能具有更大的临床开发价值。

英文摘要：

Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.

摘要翻译： 

触发肿瘤细胞凋亡是许多癌症治疗的基础。肿瘤坏死因子（TNF）超家族的死亡受体已被广泛研究，这些受体激活时产生的信号也得到了深入分析。TNF相关凋亡诱导配体（TRAIL）受体（TRAILR1和TRAILR2）是癌症治疗中有前景的靶点。本文综述了TRAIL介导的凋亡在分子水平上的调控机制、TRAIL在癌症发生中的作用，以及重组TRAIL和针对TRAILR1与TRAILR2的激动性抗体的潜在治疗应用价值。

原文链接：

The TRAIL apoptotic pathway in cancer onset, progression and therapy