TRAIL-R3/R4 and Inhibition of TRAIL Signalling in Cancer
TRAIL-R3/R4 and Inhibition of TRAIL Signalling in Cancer
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DOI：
10.1007/978-3-319-56805-8_2
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发表时间：
2017
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影响因子：
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通讯作者：
Lubna Danish;Daniela Stöhr;P. Scheurich;Nadine Pollak
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文献类型：
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作者：
Lubna Danish;Daniela Stöhr;P. Scheurich;Nadine Pollak
肿瘤坏死因子（TNF）配体家族成员TNF相关凋亡诱导配体（TRAIL）主要在肿瘤细胞中诱导细胞凋亡，而不是在正常组织中，因此代表了一个有吸引力的癌症治疗候选者。人类TRAIL/TRAIL受体系统非常复杂，有四种不同的膜受体结合配体。其中两种受体，TRAIL-R1和TRAIL-R2，传递凋亡信号，也传递非凋亡信号，而另外两种受体，TRAIL-R3和TRAIL-R4，作为抑制剂。大多数肿瘤细胞共表达几种TRAIL受体，允许受体干扰。已经提出了几种分子机制，其中TRAIL- r3和TRAIL- r4可能在质膜水平上抑制促凋亡的TRAIL信号传导，但也可能在细胞内。详细了解单个TRAIL受体的作用及其相互作用将有利于开发用于癌症治疗的新型TRAIL受体激动剂。事实上，由于可溶性TRAIL或受体激动抗体的首次临床研究仅显示有限的成功，因此需要新的TRAIL配方。本文综述了复杂的TRAIL/TRAIL受体系统以及TRAIL- r3和TRAIL- r4可能干扰TRAIL介导的细胞凋亡诱导的机制。此外，我们还讨论了TRAIL受体在患者肿瘤材料中的表达对预后的预测价值。
The tumour necrosis factor (TNF) ligand family member TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis predominantly in tumour cells, but not in normal tissues, representing therefore an attractive candidate for cancer therapy. The human TRAIL/TRAIL receptor system is very complex, four different membrane receptors bind the ligand. Two of these receptors, TRAIL-R1 and TRAIL-R2, transmit apoptotic but also non-apoptotic signals, whereas the other two, TRAIL-R3 and TRAIL-R4, act as inhibitors. Most tumour cells co-express several TRAIL receptors, allowing receptor interference. Several molecular mechanisms have been proposed by which TRAIL-R3 and TRAIL-R4 may counteract pro-apoptotic TRAIL signalling at the plasma membrane level, but possibly also intracellularly. A detailed understanding of the role of the individual TRAIL receptors and their interplay will be advantageous for the development of new TRAIL receptor agonists for cancer therapy. In fact, new TRAIL formulations will be needed since first clinical studies with soluble TRAIL or receptor agonistic antibodies showed only limited success. This review summarizes the complex TRAIL/TRAIL receptor system and the mechanisms by which TRAIL-R3 and TRAIL-R4 may interfere with TRAIL-mediated apoptosis induction. In addition, we discuss the prognostic and predictive value of TRAIL receptor expression in patients’ tumour material.