Molecular Pathways: Endothelial Cell FAK-A Target for Cancer Treatment.
Molecular Pathways: Endothelial Cell FAK-A Target for Cancer Treatment.
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DOI：
10.1158/1078-0432.ccr-14-2021
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发表时间：
2016-08-01
期刊：
影响因子：
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通讯作者：
Hodivala-Dilke K
中科院分区：
文献类型：
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作者：
Roy-Luzarraga M;Hodivala-Dilke K
非受体蛋白酪氨酸激酶，粘着斑激酶（FAK，也称为PTK 2），是多种细胞（包括内皮细胞）中整合素和生长因子受体下游信号转导的关键介质。FAK在几种晚期实体瘤中上调，并且已被描述为通过对肿瘤细胞和基质细胞的作用促进肿瘤进展和转移。这一观察结果导致了几种FAK抑制剂的开发，其中一些已经进入临床试验（GSK 2256098、VS-4718、VS-6062、VS-6063和BI 853520）。对化疗的耐药性是癌症治疗的严重限制，直到最近，大多数研究仅限于肿瘤细胞，排除了肿瘤微环境可能发挥的作用。最近的一份报告确定了内皮细胞FAK（EC-FAK）作为化疗敏感性的主要调节因子。通过调节内皮细胞源性旁分泌（也称为血管分泌）信号，仅内皮细胞隔室中FAK的丧失能够诱导恶性细胞隔室中对DNA损伤疗法的化学敏感性，从而减少肿瘤生长。本文就EC-FAK在肿瘤发生、发展中的作用及FAK靶向抗癌策略的研究进展作一综述。
The nonreceptor protein tyrosine kinase, focal adhesion kinase (FAK, also known as PTK2), is a key mediator of signal transduction downstream of integrins and growth factor receptors in a variety of cells, including endothelial cells. FAK is upregulated in several advanced-stage solid tumors and has been described to promote tumor progression and metastasis through effects on both tumor cells and stromal cells. This observation has led to the development of several FAK inhibitors, some of which have entered clinical trials (GSK2256098, VS-4718, VS-6062, VS-6063, and BI853520). Resistance to chemotherapy is a serious limitation of cancer treatment and, until recently, most studies were restricted to tumor cells, excluding the possible roles performed by the tumor microenvironment. A recent report identified endothelial cell FAK (EC-FAK) as a major regulator of chemosensitivity. By dysregulating endothelial cell–derived paracrine (also known as angiocrine) signals, loss of FAK solely in the endothelial cell compartment is able to induce chemosensitization to DNA-damaging therapies in the malignant cell compartment and thereby reduce tumor growth. Herein, we summarize the roles of EC-FAK in cancer and development and review the status of FAK-targeting anticancer strategies.