CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth
CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth
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DOI：
10.1073/pnas.95.11.6355
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Lau, LF
中科院分区：
文献类型：
--
作者：
Babic, AM;Kireeva, ML;Lau, LF
CYR 61是一种分泌的、富含半胱氨酸的肝素结合蛋白，由生长因子诱导的立即早期基因编码。作为细胞外基质相关信号分子，CYR 61通过与整合素α（V）β（3）相互作用促进内皮细胞的粘附，并增强相同细胞类型中生长因子诱导的DNA合成。在这项研究中，我们表明，纯化的CYR 61刺激定向迁移的人微血管内皮细胞培养通过α（V）β（3）依赖性途径，并诱导大鼠角膜新生血管形成。CYR 61的趋化活性和血管生成活性均可被特异性抗CYR 61抗体阻断。尽管大多数测试的人肿瘤衍生细胞系表达CYR 61，但胃腺癌细胞系RF-1不表达。CYR 61 cDNA在组成型启动子调控下在RF-1细胞中的表达显著增强了这些细胞的致瘤性，如通过在免疫缺陷小鼠中的生长所测量的，导致比由对照RF-1细胞产生的肿瘤更大且更血管化的肿瘤。总而言之，这些结果确定CYR 61是一种血管生成诱导剂，可以促进肿瘤生长和血管形成;结果还表明CYR 61在生理和病理新血管形成中的潜在作用。
CYR61 is a secreted, cysteine-rich, heparin-binding protein encoded by a growth factor-inducible immediate-early gene. Acting as an extracellular, matrix-associated signaling molecule, CYR61 promotes the adhesion of endothelial cells through interaction with the integrin alpha(V) beta(3) and augments growth factor-induced DNA synthesis in the same cell type. In this study, we show that purified CYR61 stimulates directed migration of human microvascular endothelial cells in culture through an alpha(V) beta(3)-dependent pathway and induces neovascularization in rat corneas. Both the chemotactic and angiogenic activities of CYR61 can be blocked by specific anti-CYR61 antibodies. Whereas most human tumor-derived cell lines tested express CYR61, the gastric adenocarcinoma cell line RF-1 does not. Expression of the CYR61 cDNA under the regulation of a constitutive promoter in RF-1 cells significantly enhances the tumorigenicity of these cells as measured by growth in immunodeficient mice, resulting in tumors that are larger and more vascularized than those produced by control RF-1 cells. Taken together, these results identify CYR61 as an angiogenic inducer that can promote tumor growth and vascularization; the results also suggest potential roles for CYR61 in physiologic and pathologic neovascularization.