Am. Babic et al., CYR61, A PRODUCT OF A GROWTH FACTOR-INDUCIBLE IMMEDIATE-EARLY GENE, PROMOTES ANGIOGENESIS AND TUMOR-GROWTH, Proceedings of the National Academy of Sciences of the United Statesof America, 95(11), 1998, pp. 6355-6360
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.