EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival
EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival
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DOI：
10.1038/sj.onc.1209694
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发表时间：
2006-11-09
期刊：
影响因子：
8
通讯作者：
Lin, P. C.
中科院分区：
文献类型：
--
作者：
Kamiyama, M.;Pozzi, A.;Lin, P. C.
前列腺素E2（PGE（2））是环氧合酶（考克斯）的主要代谢产物，在肿瘤生物学中起重要作用。我们使用EP 2基因敲除小鼠研究了EP 2（PGE 2受体）在肿瘤血管生成中的作用。我们发现，EP 2受体的缺失损害肿瘤血管生成，这一发现证实了在体内角膜血管生成模型和离体主动脉环测定。为了进一步表征EP 2受体在血管生成中的细胞机制，我们从野生型（wt）和EP 2（-/）-小鼠分离原代肺内皮细胞（EC），并观察到EP 2（-/）-EC与wt EC相比在血管分支形成方面表现出缺陷。此外，EP 2（-/）-EC在胶原包被的表面上显示出受损的细胞运动性，并且与对照细胞相比，它们对PGE（2）诱导的细胞迁移的反应较差。然而，在EP 2（-/）-和wt Ec之间没有观察到细胞增殖的差异。此外，在生长因子耗尽条件下，EP 2（-/）-EC比wt细胞更容易凋亡。总的来说，我们的数据表明，内皮细胞中的EP 2信号通过促进细胞存活和内皮细胞运动直接调节肿瘤血管生成。此外，我们的研究结果表明，EP 2是一个主要的受体在PGE（2）介导的细胞运动的EC。
Prostaglandin E2 (PGE(2)), a major cyclooxygenase (COX) metabolite, plays important roles in tumor biology. We studied the role of EP2, a receptor for PGE2, in tumor angiogenesis using EP2 knockout mice. We found that deletion of the EP2 receptor impaired tumor angiogenesis and this finding was confirmed by an in vivo corneal angiogenesis model and an ex vivo aortic ring assay. To further characterize the cellular mechanisms of the EP2 receptor in angiogenesis, we isolated primary pulmonary endothelial cells (ECs) from wild-type (wt) and EP2(-/)-mice and observed that EP2(-/)-ECs exhibited defects in vascular branch formation when compared to wt ECs. In addition, EP2(-/)-ECs showed impaired cell motility on collagen-coated surface and they responded poorly to PGE(2)-induced cell migration compared to control cells. However, no difference in cell proliferation was observed between the EP2(-/)-and wt Ecs. In addition, EP2(-/)-ECs were more susceptible to apoptosis than wt cells under growth factor depletion conditions. Collectively, our data demonstrate that EP2 signaling in endothelium directly regulates tumor angiogenesis by contributing to cell survival and endothelial cell motility. Moreover, our finding suggests that EP2 is a major receptor in PGE(2)-mediated cell motility in ECs.