文章：

内皮素1在癌症中的生物学意义和治疗机会

Endothelin 1 in cancer: biological implications and therapeutic opportunities

原文发布日期：2013-07-25

DOI: 10.1038/nrc3546

类型: Review Article

开放获取: 否

要点：

1. Aberrant expression of endothelin 1 (ET1), or overexpression of endothelin receptors or their linked signalling circuits can contribute to tumour initiation and progression through both autocrine and paracrine mechanisms. These alteration mechanisms may arise from genetic and epigenetic changes.
2. An intricate network of crosstalk between ET1 signalling and other growth factor pathways drives tumour progression. This includes crosstalk between the endothelin receptors and epidermal growth factor receptor and vascular endothelial growth factor receptor.
3. ET1 signalling promotes cell proliferation, survival, epithelial-to-mesenchymal transition, neovascularization, response of immune cells and drug resistance in a context-dependent manner. Hence, endothelin receptors have emerged as key targets for cancer therapy.
4. In addition to tumour cells, endothelin receptors are found on tumour-associated host cells, such as blood and lymphatic endothelial cells, fibroblasts and inflammatory cells, thus regulating the contribution of these cell types to cancer progression. Therefore, endothelin receptor antagonists may inhibit tumour progression by blocking crucial signalling events in both the tumour microenvironment and the tumour cells.
5. The activation of ET1 signalling pathways is often negatively correlated with patient outcomes in different types of cancer.
6. Small-molecule antagonists for targeting endothelin receptors have been evaluated in several recent clinical trials. However, the clinical results to date have been disappointing and it is crucial to decipher why the promising preclinical data have not yet been translated to the clinic.
7. Future improved clinical trials might incorporate predictive biomarkers to focus on subsets of patients who are most likely to respond, use other clinical settings or use rational combination therapy with chemotherapeutics or targeted agents.

要点翻译：

1. 内皮素1（ET1）的异常表达，或内皮素受体及其关联信号通路的过度激活，可通过自分泌和旁分泌机制促进肿瘤的发生与发展。这些改变可能源于遗传和表观遗传变异。
2. ET1信号通路与其他生长因子途径之间复杂的交互网络驱动肿瘤进展，包括内皮素受体与表皮生长因子受体、血管内皮生长因子受体之间的相互作用。
3. ET1信号通路以环境依赖性方式促进细胞增殖、存活、上皮-间质转化、新生血管形成、免疫细胞应答及耐药性。因此，内皮素受体已成为癌症治疗的关键靶点。
4. 除肿瘤细胞外，内皮素受体还存在于肿瘤相关宿主细胞（如血液和淋巴管内皮细胞、成纤维细胞及炎症细胞）中，从而调控这些细胞类型对癌症进展的促进作用。因此，内皮素受体拮抗剂可通过同时阻断肿瘤微环境和肿瘤细胞中的关键信号事件来抑制肿瘤进展。
5. 在不同类型癌症中，ET1信号通路的激活常与患者预后呈负相关。
6. 针对内皮素受体的小分子拮抗剂已在多项近期临床试验中进行评估。然而，目前的临床结果令人失望，破译为何有前景的临床前数据尚未能转化为临床疗效至关重要。
7. 未来改进的临床试验可纳入预测性生物标志物以聚焦最可能应答的患者亚群，采用其他临床方案，或与化学治疗药物及靶向药物实施合理联合治疗。

英文摘要：

Activation of autocrine and paracrine signalling by endothelin 1 (ET1) binding to its receptors elicits pleiotropic effects on tumour cells and on the host microenvironment. This activation modulates cell proliferation, apoptosis, migration, epithelial-to-mesenchymal transition, chemoresistance and neovascularization, thus providing a strong rationale for targeting ET1 receptors in cancer. In this Review, we discuss the advances in our understanding of the diverse biological roles of ET1 in cancer and describe the latest preclinical and clinical progress that has been made using small-molecule antagonists of ET1 receptors that inhibit ET1-driven signalling.

摘要翻译： 

内皮素-1（ET1）通过自分泌和旁分泌信号与其受体结合，激活多种效应，对肿瘤细胞和宿主微环境产生多效性作用。该激活可调节细胞增殖、凋亡、迁移、上皮-间质转化、化疗耐药及新生血管形成，从而为靶向ET1受体治疗癌症提供了充分依据。本文综述了ET1在癌症中多样生物学作用的最新研究进展，并介绍了利用小分子拮抗剂阻断ET1驱动的信号传导所取得的最新临床前与临床成果。

原文链接：

Endothelin 1 in cancer: biological implications and therapeutic opportunities