OVEREXPRESSION OF VASCULAR-ENDOTHELIAL-GROWTH-FACTOR INDUCES CELL-TRANSFORMATION IN COOPERATION WITH FIBROBLAST-GROWTH-FACTOR-2

Vascular endothelial growth factor (VEGF) is a family of homodimeric p roteins produced from a single gene by alternative splicing of the VEG F transcript. VEGF induces irt vivo angiogenesis and vascular permeabi lity. We have recently demonstrated that VEGF is an autocrine growth f actor for retinal pigment epithelial (RPE) cells. To further understan d the role of VEGF, we overexpressed VEGF in rat RPE cells. The transf ected cells exhibited a growth advantage in vitro and an increased res ponse to the mitogenic effect of fibroblasts growth factor-2 (FGF-2), and formed colonies in soft agar upon FGF-2 addition. Moreover, analys is of FGF-receptors evidenced a dramatic increase in FGFR-1 mRNA and p rotein level, supporting the hypothesis that this receptor mediates th e transforming effect of FGF-2. These results reveal that the oncogeni c role of VEGF is exerted through a cross regulation between VEGF and FGF signal transduction pathways.