Tumor Angiogenesis and Novel Vascular Endothelial Receptor (VEGFR)-Specific Small Molecule Inhibitors

Abstract

The knowledge related to angiogenesis has grown exponentially over the past few decades with the recognition that angiogenesis is essential for numerous normal and pathological processes. Very importantly, angiogenesis is required for the growth and metastasis of solid tumors in human beyond the size of 1–2 mm³ (Arap et al. 1998; Folkman 1990, 1995). Angiogenesis is the process of developing buds and outgrowth of capillaries from existing blood vessels that are derived as extensions due to hypoxia or other forms of signaling that occurs in the microenvironment that surrounds a tissue or tumors. On the other hand neovascularization is defined as the formation of functional microvascular network with red blood cell perfusion. Angiogenesis is required for invasive tumor growth and metastasis and therefore constitutes an important step in the control of cancer progression. In general vascular tumors are severely restricted in their growth potential because of the lack of a blood supply. To achieve the new blood vessel formation, endothelial cells must first escape from their stable location by breaking through the basement membrane, and this degradation is associated with migration of endothelial cells out of the vascular channel toward the angiogenic stimulus. During this process, the subendothelial basement membrane, a dense meshwork of collagen, glycoproteins, and proteoglycans are proteolytically disrupted to allow formation of new capillaries. Though it is an integral component of normal processes such as reproduction and wound healing, angiogenesis is known to play an important role in other pathological processes ranging from tumor growth and metastasis to inflammation and ocular diseases. During angiogenesis tumor cells exploit their microenvironment by releasing cytokines and growth factors to activate normal, quiescent cells around them and initiate a cascade of events that quickly becomes dysregulated. For example, tumor cell-released vascular endothelial growth factor (VEGF) stimulates the sprouting and proliferation of endothelial cells and thereby play a crucial role in neovascularization of solid tumors (Leung et al. 1989). The expression of VEGF has been shown to correlate with the density of microvessels in various tumors and exhibit higher metastatic ability (Folkman 1995; Leung et al. 1989; Toi et al. 1994). Therefore, inhibition of angiogenesis triggered by VEGF or other factors is accepted as a valuable approach to cancer therapy.