Vascular endothelial growth factor: Basic biology and clinical implications

The development of a vascular supply is a fundamental requirement for organ development and differentiation in multicellular organisms (Hamilton et al., 1962) and is also necessary for tissue repair and reproductive functions in the adult (Klagsbrun and D’Amore, 1991; Folkman and Shing, 1992). Angiogenesis is also implicated in the pathogenesis of a variety of disorders. These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis (Klagsbrun and D’Amore, 1991; Folkman, 1991). In the case of proliferative retinopathies and age-related macular degeneration, the new blood vessels are directly responsible for many of the destructive events characteristic of these conditions (Garner, 1994). Conversely, in neoplasms the neovascularization provides nourishment to the growing tumor, thus allowing the tumor cells to express their critical growth advantage, and also permits the establishment of continuity with the vasculature of the host (Folkman, 1991). A strong correlation has been noted between density of microvessels in primary breast carcinoma sections, nodal metastases and survival (Weidner et al, 1991, 1992; Horak et al, 1992; Vartanian and Weidner, 1994). Similarly, a correlation has been reported between vascularity and invasive behavior in bladder (Chodak et al., 1980), prostate (Wakui et al., 1992; Bigler et al., 1993), non-small cell lung (Macchiarmi et al., 1992), and uterine cervix (Sillman et al., 1981) carcinomas and in cutaneous melanomas (Srivastava et al., 1988). Furthermore, recent studies have shown a statistically significant increase in microvessel count in severe uterine cervix dysplasia (CIN III) compared to low grade lesions (CIN I) (Smith-McCune et al., 1994).