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 extracel lular, matrix-associated signaling molecule, CYR61 promotes the adhesi on 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 direc ted migration of human microvascular endothelial cells in culture thro ugh an alpha(V) beta(3)-dependent pathway and induces neovascularizati on in rat corneas. Both the chemotactic and angiogenic activities of C YR61 can be blocked by specific anti-CYR61 antibodies. Whereas most hu man tumor-derived cell lines tested express CYR61, the gastric adenoca rcinoma cell line RF-1 does not. Expression of the CYR61 cDNA under th e regulation of a constitutive promoter in RF-1 cells significantly en hances the tumorigenicity of these cells as measured by growth in immu nodeficient mice, resulting in tumors that are larger and more vascula rized than those produced by control RF-1 cells. Taken together, these results identify CYR61 as an angiogenic inducer that can promote tumo r growth and vascularization; the results also suggest potential roles for CYR61 in physiologic and pathologic neovascularization.