Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

Angiogenesis is the sprouting of new capillaries from pre-existing blood vessels that involves endothelial cell (EC) differentiation, proliferation, migration, cord formation and tubulogenesis (Risau 1997). This process was earlier recognized by the studies of Judah Folkman as a crucial step for tumor formation (Folkman 1971). Many endothelium-specific molecules can influence angiogenesis including members of the VEGF, angiopoietin and ephrin families. In addition, non vascular endothelium-specific factors contribute to blood vessel formation, i.e., platelet-derived growth factor, PDGF and transforming growth factor┚, TGF-┚ families (Yancopoulos et al. 2000). VEGF family members interact through some degree of specificity with receptor tyrosine kinases (RTK; VEGFR-1 to 3). VEGFR-1 (fms-like tyrosine kinase, Flt-1) (Shibuya et al. 1990), VEGFR-2 (fetal liver kinase, Flk-1 in mice or KDR in humans) (Matthews et al. 1991; Millauer et al. 1993; Terman et al. 1991), VEGFR-3 (Flt-4)(Pajusola et al. 1992) and a fourth receptor, Flt-3/Flk-2, belongs to the RTK family. The last receptor was identified but it does not bind to VEGF (Hannum et al. 1994). VEGF can also bind to a distinct type of high-affinity non-tyrosine kinase receptors: Neuropilin-1 and2 (NRP-1/-2). These molecules are found in endothelial and neuronal cell surfaces (Jussila and Alitalo 2002), as well as in tumor cells (Bagri et al. 2009; Pellet-Many et al. 2008). VEGFR-2 was discovered before the identification of its ligand, VEGF (Risau 1997; Yancopoulos et al. 2000). VEGFR-2 is a receptor-tyrosine kinase named KDR in human (Terman et al. 1992; Yancopoulos et al. 2000), Flk-1 (Matthews et al. 1991) or NYW/FLK-1 in mice (Oelrichs et al. 1993) and TKr-11 in rat (Sarzani et al. 1992) was earlier identified as a transducer of VEGF in EC (Waltenberger et al. 1994). VEGF-A is the major form that binds and signals through VEGFR-2 to develop blood vessels and to maintain the vascular network (Ferrara 1999). VEGFR-2 is thought to mediate the key effects of the endothelial-specific mitogen VEGF on cell proliferation and permeability. Therefore, the majority of VEGFR-2 actions are related to angiogenesis (Ferrara et al. 2003; Shibuya and Claesson-Welsh 2006). Homozygous deficient VEGFR-2 mice die in the second week of gestation as a consequence of insufficient development of hematopoietic and EC (Matthews et al. 1991), indicating that