Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling
Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling
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DOI：
10.1172/jci64537
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Chen, Hong
中科院分区：
文献类型：
--
作者：
Pasula, Satish;Cai, Xiaofeng;Chen, Hong
Epsins是一个泛素结合的内吞网格蛋白衔接子家族。缺乏epsin 1和2（Epn 1/2）的小鼠在胚胎第10天死亡，并表现出异常的血管表型。为了研究内皮epsins的血管生成作用，我们产生了血管内皮中Epn 1/2组成性或诱导性缺失的小鼠。这些小鼠在正常条件下没有表现出异常表型，表明缺乏内皮epsin 1和2不会影响正常血管。然而，在肿瘤中，epsins 1和2的缺失导致脉管系统紊乱，血管通透性显著增加，并显著延缓肿瘤生长。从机制上讲，我们发现VEGF促进了epsin与泛素化VEGFR 2的结合。epsins 1和2的缺失特异性地损害VEGFR 2的内吞作用和降解，这导致过度的VEGF信号传导，其通过加剧非生产性渗漏血管生成而损害肿瘤血管功能。这表明肿瘤血管系统需要VEGF信号传导的平衡以提供足够的生产性血管生成用于肿瘤发展，并且内皮epsins 1和2负调节VEGF信号传导的输出。通过阻断epsin 1和2功能促进肿瘤内过度的VEGF信号传导可能代表了一种预防对抗VEGF治疗有抗性的癌症患者中正常血管生成的策略。
Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. To examine the angiogenic role of endothelial epsins, we generated mice with constitutive or inducible deletion of Epn1/2 in vascular endothelium. These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 did not affect normal blood vessels. In tumors, however, loss of epsins 1 and 2 resulted in disorganized vasculature, significantly increased vascular permeability, and markedly retarded tumor growth. Mechanistically, we show that VEGF promoted binding of epsin to ubiquitinated VEGFR2. Loss of epsins 1 and 2 specifically impaired endocytosis and degradation of VEGFR2, which resulted in excessive VEGF signaling that compromised tumor vascular function by exacerbating nonproductive leaky angiogenesis. This suggests that tumor vasculature requires a balance in VEGF signaling to provide sufficient productive angiogenesis for tumor development and that endothelial epsins 1 and 2 negatively regulate the output of VEGF signaling. Promotion of excessive VEGF signaling within tumors via a block of epsin 1 and 2 function may represent a strategy to prevent normal angiogenesis in cancer patients who are resistant to anti-VEGF therapies.