Involvement of G Proteins in Vascular Permeability Factor/ Vascular Endothelial Growth Factor Signaling

Excerpt

In order to grow beyond minimal size, tumors mustgenerate a new vascular supply for purposes of gas exchange, cell nutrition, and waste disposal (Folkman 1971,1996; Folkman and Klagsbrun 1987; Folkman et al.1989). They do so by secreting angiogenic cytokines thatinduce the formation of new blood vessels (Folkman andKlagsbrun 1987; Folkman et al. 1989; Risau 1997; Dvorak et al. 1999). Tumor-secreted angiogenic cytokines include fibroblast growth factor, platelet-derived growthfactor B, and vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) (Senger et al. 1986;Vlodavsky et al. 1991; Benezra et al. 1993; Risau 1997).VPF/VEGF is likely the most important of these becauseit is expressed abundantly by a wide variety of human andanimal tumors and because of its potency, selectivity forendothelial cells, and ability to regulate most and perhapsall of the steps in the angiogenic cascade (Dvorak et al.1979,1984,1999; Dvorak 1990; Risau 1997; Ferrara1999). Moreover, a number of other angiogenic cytokinesact, at least in part, by up-regulating VPF/VEGF expression (Seghezzi et al. 1998; Dvorak et al. 1999).VPF/VEGF extensively reprograms endothelial cell expression of proteases, integrins, and glucose transporters;stimulates endothelial cell migration and division;protects endothelial cells from apoptosis and senescence;and induces angiogenesis in both in vitro and in vivomodels (for review, see Leung et al. 1989; Risau 1997;Dvorak et al. 1999; Ferrara 1999). In addition,VPF/VEGF is the only angiogenic cytokine identifiedthus far that renders microvessels hyperpermeable to circulating macromolecules, a characteristic feature of angiogenic blood vessels (Dvorak et al. 1979, 1984; Sengeret al. 1983, 1986; Dvorak 1990)...