Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo
Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo
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DOI：
10.1038/sj.onc.1205679
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发表时间：
2002-10-10
期刊：
影响因子：
8
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Brantley, DM;Cheng, N;Chen, J
Eph家族的受体酪氨酸激酶及其配体，称为ephrin，在胚胎发生过程中的血管发育中起着至关重要的作用。这些分子在成人血管生成中的功能尚未得到很好的表征。在这里，我们报告说，阻断Eph A类受体激活可以抑制两种独立肿瘤类型的血管生成，即血管生成依赖性胰岛细胞癌的RIP-Tag转基因模型和转移性乳腺癌的4 T1模型。Ephrin-A1配体在肿瘤和内皮细胞中表达，EphA 2受体主要定位于肿瘤相关的血管内皮细胞。可溶性EphA 2-Fc或EphA 3-Fc受体在皮肤窗测定中抑制肿瘤血管生成，并在体内抑制肿瘤生长。EphA 2-Fc或EphA 3-Fc处理导致肿瘤血管密度、肿瘤体积和细胞增殖降低，但细胞凋亡增加。然而，EphA 2-Fc对培养物中的肿瘤细胞生长或凋亡没有直接影响，但抑制了内皮细胞响应肿瘤细胞的迁移，表明可溶性受体抑制了肿瘤的血管募集。这些数据为Eph A类受体调节肿瘤诱导的致病性血管生成提供了第一个功能证据，并支持A类Eph受体在肿瘤进展中的功能。
The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.