ONCOGENIC H-RAS STIMULATES TUMOR ANGIOGENESIS BY 2 DISTINCT PATHWAYS

The switch from a quiescent tumor to an invasive tumor is accompanied by the acquisition of angiogenic properties. This phenotypic change li kely requires a change in the balance of angiogenic stimulators and an giogenic inhibitors. The nature of the angiogenic switch is not known. Here, we show that introduction of activated H-ras into immortalized endothelial cells is capable of activating the angiogenic switch. Angi ogenic switching is accompanied by up-regulation of vascular endotheli al growth factor and matrix metalloproteinase (MMP) bioactivity and do wnregulation of tissue inhibitor of MMP. Furthermore, we show that inh ibition of phosphatidylinositol-3-kinase leads to partial inhibition o f tumor angiogenesis, thus demonstrating that activated H-ras activate s tumor angiogenesis through two distinct pathways. Finally, we show e vidence for two forms of tumor dormancy.