文章：

探索少有人涉足的领域：癌症生物学和治疗领域的研究

Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy

原文发布日期：2017-05-24

DOI: 10.1038/nrc.2017.28

类型: Review Article

开放获取: 否

要点：

1. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a molecule belonging to the tumour necrosis factor (TNF) superfamily. In humans, two TRAIL receptors (TRAIL-R1 and TRAIL-R2) and in mice one receptor (mTRAIL-R) can signal apoptosis upon binding of TRAIL.
2. Induction of apoptosis is enabled through recruitment of the death-inducing signalling complex (DISC). This complex leads to activation of a caspase cascade.
3. TRAIL–TRAIL-R binding can also induce non-apoptotic signalling including via activation of nuclear factor-κB (NF-κB), p38, ERK, SRC and RAC1.
4. Mice deficient in TRAIL or mTRAIL-R are more susceptible to various cancers whereas conditional deletion of mTRAIL-R in Kras- driven cancers ameliorates disease progression. TRAIL–TRAIL-R blockade might therefore be a therapeutic option for patients with KRAS-mutated cancers.
5. TRAIL–TRAIL-R interaction on myeloid-derived suppressor cells in the tumour microenvironment can limit their lifespan and thereby tip the balance towards an antitumour immune environment. Hence, patients with an immunosuppressive cancer microenvironment might benefit from TRAIL-R agonistic therapy.
6. Clinical trials testing an untagged form of recombinant TRAIL, agonistic TRAIL-R1 or TRAIL-R2-specific antibodies or antibody derivatives with higher crosslinking capacity have not led to anticipated therapeutic benefit.
7. Preclinical approaches using therapeutic combinations comprising optimized TRAIL-R agonists and recently discovered powerful apoptosis sensitizers are, however, promising. Therefore, such novel pro-apoptotic combination therapies should be tested in clinical trials.
8. Several drugs, some of which have been approved by the US Food and Drug Administration, induce extrinsic apoptosis through autocrine engagement of the TRAIL–TRAIL-R pathway. Therefore, expression of TRAIL apoptosis pathway components, as well as lack of expression of inhibitors thereof, might be useful for patient selection in clinical trials testing the efficacy of such drugs.

要点翻译：

1. 肿瘤坏死因子相关凋亡诱导配体（TRAIL）是属于肿瘤坏死因子超家族的分子。在人体中，两种TRAIL受体（TRAIL-R1和TRAIL-R2）及小鼠中的一种受体（mTRAIL-R）可在与TRAIL结合时传递凋亡信号。
2. 通过募集死亡诱导信号复合物（DISC）实现凋亡诱导。该复合物可激活半胱天冬酶级联反应。
3. TRAIL与TRAIL-R的结合还可诱导非凋亡信号传导，包括通过激活核因子κB（NF-κB）、p38、ERK、SRC和RAC1实现的信号传导。
4. 缺乏TRAIL或mTRAIL-R的小鼠更易罹患多种癌症，而在Kras驱动的癌症中条件性敲除mTRAIL-R可改善疾病进展。因此，对于KRAS突变癌症患者，TRAIL–TRAIL-R阻断可能成为一种治疗选择。
5. 肿瘤微环境中髓源性抑制细胞上的TRAIL–TRAIL-R相互作用可限制其寿命，从而使平衡向抗肿瘤免疫环境倾斜。因此，具有免疫抑制性癌症微环境的患者可能从TRAIL-R激动疗法中获益。
6. 针对未标记形式重组TRAIL、激动性TRAIL-R1或TRAIL-R2特异性抗体以及具有更高交联能力的抗体衍生物的临床试验尚未取得预期疗效。
7. 然而，采用优化TRAIL-R激动剂与近期发现的强效凋亡增敏剂联合治疗的临床前策略展现出良好前景。因此，此类新型促凋亡联合疗法应在临床试验中进行验证。
8. 若干药物（其中部分已获美国食品药品监督管理局批准）可通过TRAIL–TRAIL-R通路的自分泌作用诱导外源性凋亡。因此，TRAIL凋亡通路组分的表达水平及其抑制剂的缺失情况，可能有助于此类药物临床试验中的患者筛选。

英文摘要：

The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL–TRAIL-R system to their own advantage. However, novel insight on two fronts — how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered — gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL–TRAIL-R system — as well as the gaps therein — and discuss the opportunities and challenges in effectively targeting this pathway.

摘要翻译： 

肿瘤坏死因子相关凋亡诱导配体（TRAIL）能在小鼠体内诱导癌细胞凋亡而不产生毒性的发现，促使人们对促凋亡TRAIL受体（TRAIL-R）信号通路进行深入研究，并开发出激活TRAIL-R的生物治疗候选药物。然而，这些TRAIL-R激动剂的临床试验结果迄今令人失望。最新证据表明，许多癌症不仅对抗TRAIL，还利用内源性TRAIL–TRAIL-R系统为自身谋利。不过，两方面的新见解——如何克服癌细胞对基于TRAIL的促凋亡治疗的耐药性，以及如何抵消内源性TRAIL的促肿瘤效应——为利用TRAIL系统治疗癌症带来了合理希望。在本综述中，我们评估当前对TRAIL–TRAIL-R系统生物学的理解现状及其空白，并讨论有效靶向该通路所面临的机遇与挑战。

原文链接：

Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy