CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth

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 α(V)β(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 α(V)β(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.

CYR61是一种分泌型、富含半胱氨酸的肝素结合蛋白，由生长因子诱导的即刻早期基因（immediate–early gene）编码。作为细胞外基质相关的信号分子，CYR61可通过与整合素（integrin）α(V)β(3)结合，促进内皮细胞黏附，并在同一细胞类型中增强生长因子诱导的DNA合成。本研究证实，纯化的CYR61可通过α(V)β(3)依赖通路，刺激培养中人微血管内皮细胞的定向迁移，并可诱导大鼠角膜新生血管形成。CYR61的趋化活性与血管生成活性均可被特异性抗CYR61抗体阻断。尽管多数受试人源肿瘤细胞系均表达CYR61，但胃腺癌细胞系RF-1无此表达。在RF-1细胞中，通过组成型启动子（constitutive promoter）调控CYR61互补DNA（complementary DNA，cDNA）的表达，可显著增强该细胞的致瘤性：在免疫缺陷小鼠体内的成瘤实验显示，其形成的肿瘤体积更大、血管化程度更高，且优于对照RF-1细胞所形成的肿瘤。综上，本研究结果确认CYR61是一种可促进肿瘤生长与血管化的血管生成诱导因子；同时提示CYR61在生理性与病理性新生血管形成过程中均具有潜在作用。