What Is the Role of Vascular Endothelial Growth Factor-Related Molecules in Tumor Angiogenesis?

Abstract

Growth of solid tumors depends on angiogenesis, the process by which new blood vessels develop from the endothelium of a pre-existing vasculature. 1 Tumors promote angiogenesis by secreting growth factors that stimulate endothelial migration, proliferation, proteolytic activity, and capillary morphogenesis. 2 Newly formed blood vessels supply the tumor with nutrients and oxygen, dispose of its metabolic waste products, and generate paracrine stimuli, which further promote tumor cell proliferation and invasiveness. 1,3 Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a central regulator of the angiogenic process in physiological and pathological conditions. 4 This molecule was first named vascular permeability factor by Dvorak and co-workers because of its potent stimulatory effect on the permeability of the tumor microvasculature. 5 Ferrara et al 6 coined the term VEGF to describe a mitogenic factor that selectively stimulated endothelial cell proliferation and angiogenesis. The same molecule was independently discovered by others. 7,8 Connolly et al 9 reported that vascular permeability factor was mitogenic for endothelial cells and had the capacity to stimulate vascular proliferation. Sequence analysis of cDNAs demonstrated that vascular permeability factor and VEGF were the same molecule. 4 Recently, the VEGF family of growth factors has expanded with the addition of four new molecules: placenta growth factor (PlGF), VEGF-B, VEGF-C, and VEGF-D (Table 1) ▶ . 10-13 VEGF and VEGF-related molecules have homologous amino acid sequences including eight cysteine residues, which are also found in platelet-derived growth factors A and B, and bind to the same class of tyrosine kinase receptors. 4,8 In this issue of the American Journal of Pathology, Salven et al 14 report that VEGF-B and VEGF-C are expressed in a variety of human tumors. This commentary briefly reviews our knowledge of this field and critically evaluates the potential role of VEGF-related molecules in tumor angiogenesis and neoplastic progression. Table 1. VEGF and VEGF-Related Molecules