The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization
The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization
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DOI：
10.1038/sj.onc.1204004
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发表时间：
2000-12-07
期刊：
影响因子：
8
通讯作者：
Pasquale, EB
中科院分区：
文献类型：
--
作者：
Ogawa, K;Pasqualini, R;Pasquale, EB
Eph受体酪氨酸激酶及其肝配蛋白配体与胚胎血管发育和体内血管生成模型有关。Eph蛋白也可能调节肿瘤新生血管形成，但这种作用以前没有研究过。为了筛选在肿瘤血管中表达的Eph蛋白，我们使用在裸鼠中生长的来自MDA-MB-435人乳腺癌细胞或KS 1767人卡波西肉瘤细胞的肿瘤异种移植物。通过免疫组织化学，在整个肿瘤血管中检测到ephrin-A1配体及其受体之一EphA 2。用抗CD 34抗体双标记表明，ephrin-A1和EphA 2都在异种移植物内皮细胞和肿瘤细胞中表达。此外，EphA 2在异种移植肿瘤中被酪氨酸磷酸化，表明它被激活，推测是通过与肝配蛋白-A1相互作用。Ephrin-A1和EphA 2也在手术切除的人类癌症的脉管系统和肿瘤细胞中检测到。在体外血管生成模型中，EphA 2的显性负性形式抑制人脐静脉内皮细胞（HUVEC）的毛细血管样形成，证明需要EphA受体信号传导。这些数据表明肝配蛋白-Al和EphA 2在人类癌症中起作用，至少部分地通过影响肿瘤新血管形成。Eph蛋白可能代表抗血管生成癌症治疗的有前途的新靶点。
Eph receptor tyrosine kinases and their ephrin ligands have been implicated in embryonic vascular development and in in vivo models of angiogenesis. Eph proteins may also regulate tumor neovascularization, but this role has not been previously investigated. To screen for Eph proteins expressed in tumor blood vessels, we used tumor xenografts grown in nude mice from MDA-MB-435 human breast cancer cells or KS1767 human Kaposi's sarcoma cells, By immunohistochemistry, the ephrin-A1 ligand and one of its receptors, EphA2, were detected throughout tumor vasculature. Double-labeling with anti-CD34 antibodies demonstrated that both ephrin-A1 and EphA2 were expressed in xenograft endothelial cells and also tumor cells. Furthermore, EphA2 was tyrosine-phosphorylated in the xenograft tumors, indicating that it was activated, presumably by interacting with ephrin-A1. Ephrin-A1 and EphA2 were also detected in both the vasculature and tumor cells of surgically removed human cancers. In an in vitro angiogenesis model, a dominant negative form of EphA2 inhibited capillary tube-like formation by human umbilical vein endothelial cells (HUVECs), demonstrating a requirement for EphA receptor signaling, These data suggest that ephrin-A1 and EphA2 play a role in human cancers, at least in part by influencing tumor neovascularization. Eph proteins may represent promising new targets for antiangiogenic cancer treatments.