O'Kane Hugh F, Watson Chris J, Johnston Samuel R, Petak Istvan, Watson R William G, Williamson Kate E
Uro-oncology Group, Queen's University Belfast, Belfast, United Kingdom.
J Urol. 2006 Feb;175(2):432-8. doi: 10.1016/S0022-5347(05)00160-6.
We describe key components of normal and aberrant death receptor pathways, the association of these abnormalities with tumorigenesis in bladder, prostate and renal cancer, and their potential application in novel therapeutic strategies targeted toward patients with cancer.
A MEDLINE literature search of the key words death receptors, TRAIL (tumor necrosis factor related apoptosis inducing ligand), FAS, bladder, prostate, renal and cancer was done to obtain information for review. A brief overview of the TRAIL and FAS death receptor pathways, and their relationship to apoptosis is described. Mechanisms that lead to nonfunction of these pathways and how they may contribute to tumorigenesis are linked. Current efforts to target death receptor pathways as a therapeutic strategy are highlighted.
Activation of tumor cell expressing death receptors by cytotoxic immune cells is the main mechanism by which the immune system eliminates malignant cells. Death receptor triggering induces a caspase cascade, leading to tumor cell apoptosis. Receptor gene mutation or hypermethylation, decoy receptor or splice variant over expression, and downstream inhibitor interference are examples of the ways that normal pathway functioning is lost in cancers of the bladder and prostate. Targeting death receptors directly through synthetic ligand administration and blocking downstream inhibitor molecules with siRNA or antisense oligonucleotides represent novel therapeutic strategies under development.
Research into the death receptor pathways has demonstrated the key role that pathway aberrations have in the initiation and progression of malignancies of the bladder, prostate and kidney. This new understanding has resulted in exciting approaches to restore the functionality of these pathways as a novel therapeutic strategy.
我们描述正常和异常死亡受体途径的关键组成部分，这些异常与膀胱癌、前列腺癌和肾癌肿瘤发生的关联，以及它们在针对癌症患者的新型治疗策略中的潜在应用。
通过对关键词“死亡受体”“TRAIL（肿瘤坏死因子相关凋亡诱导配体）”“FAS”“膀胱”“前列腺”“肾”和“癌症”进行医学文献数据库检索，以获取用于综述的信息。简要概述了TRAIL和FAS死亡受体途径及其与细胞凋亡的关系。阐述了导致这些途径功能丧失的机制以及它们如何促进肿瘤发生。重点介绍了目前将死亡受体途径作为治疗策略的研究进展。
细胞毒性免疫细胞激活表达死亡受体的肿瘤细胞是免疫系统清除恶性细胞的主要机制。死亡受体触发诱导半胱天冬酶级联反应，导致肿瘤细胞凋亡。受体基因突变或高甲基化、诱饵受体或剪接变体过表达以及下游抑制剂干扰是膀胱癌和前列腺癌中正常途径功能丧失的一些方式。通过给予合成配体直接靶向死亡受体以及用小干扰RNA或反义寡核苷酸阻断下游抑制剂分子代表了正在开发的新型治疗策略。
对死亡受体途径的研究表明，途径异常在膀胱癌、前列腺癌和肾癌的发生和发展中起关键作用。这种新认识带来了令人兴奋的方法，即将恢复这些途径的功能作为一种新型治疗策略。
