**1. Introduction**

The angiogenesis process involves approximately twenty factors, such as basic fibroblast growth factor, placenta growth factor (PIGF-1), epidermal growth factor (EP), as platelet-derived GF (PDGF), and the most important angiogenic factor: vascular endothelial growth factor (VEGF). Studies of restricted expression patterns and functional roles have implicated VEGFs in the generation of new blood vessels from pre-existing vasculature complex genetic pathways. VEGF has since been documented as being a potent stimulator of endothelial cells proliferation and migration and to induce the expression of interstitial collagenases. Specifically, VEGFs regulate physiological angiogenesis, including the vessel and the organ development, the lymphogenesis, and the differentiation during embryogenesis, as well the pathogenesis of a multiplicity of disorders. The hypothesis that VEGF action is required for tumor angiogenesis has been first provided by the findings

of the vascular development of tumor xenografts in mice. These results were confirmed through in situ hybridization studies, showing a correlation between the degree of defective angiogenesis and VEGF mRNA upregulation. These studies uniformly concur that VEGF expression enhances tumor growth. In this chapter, we provide a brief historical overview of the discovery of VEGF, structural characterization of the other members of VEGF family and their receptor, and to summarize the main features of the role of vascular endothelial growth factor in angiogenesis of oral cancer development.

## **2. Discovery of VEGF**

VEGF was first described in 1983 as a factor secreted by hepatocarcinoma cell lines [1] that increased microvascular permeability to plasma proteins in the skin of guinea-pigs. It was highly purified to homogeneity from pituitary folliculostellate cells and characterized in 1989 [2]. Other authors supported evidence that this protein potently stimulated endothelial cell migration [3–5]. It was named "vascular permeability factor" or VPF, potent inducers of vascular hyperpermeability (especially venular endothelium) to fibrinogen and other plasma proteins [6], which upon secretion by tumor cells, promotes vascular leakage [7]. More years later, it was demonstrated that VPF has potent mitogenic activity in a diversity of cell types, and also versus endothelial cells [8]. Vascular endothelial growth factors (VEGFs) are predominantly produced by endothelial, hematopoietic, and stromal cells in response to hypoxia and upon stimulation by growth factors such as transforming growth factor β (TGFβ), interleukins, or platelet-derived growth factors (PDGFs). VEGFs specifically interact with one or several receptor tyrosine kinases (RTKs), VEGF receptor −1, −2, and −3 (VEGFR-1, −2, −3), and with distinct coreceptors such as neuropilins or heparan sulfate glycosaminoglycans. VEGF receptors are classified as type V RTKs whose extracellular domains consist of seven immunoglobulin-like (Ig-like) domains [9, 10]. The intracellular domain consists of seven immunoglobulin-like domains (I–VII), a single transmembrane (TM) region, and a tyrosine kinase consensus sequence (TK) interrupted by a cytoplasmatic kinase domain [11, 12].
