Versican/PG-M is an extracellular matrix proteoglycan, expression of which is elevated in avariety of human tumors. The significance of this change is unclear. Here we show that versicanG3-containing fragments are present at high levels in human astrocytoma. Expression of aversican G3 construct in U87 astrocytoma cells enhances colony growth in soft agarose gel andtumor growth and blood vessel formation in nude mice. The G3-containing medium enhancesendothelial cell adhesion, proliferation, and migration. G3-expressing cells and tumors formedby these cells express increased levels of fibronectin and vascular endothelial growth factor(VEGF). Furthermore, the G3 domain directly binds to fibronectin and forms a complex togetherwith VEGF. In the presence of these three molecules, endothelial cell adhesion, proliferation,and migration were found to be significantly enhanced. Removal of the complex containing thesemolecules reverses these processes. Taken together, these findings implicate G3 as a modifier oftumor growth and angiogenesis and suggest a new avenue for development of anticancer andanti-angiogenic therapies based on targeting versican G3 fragments.