Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications

Angiogenesis, or formation of new blood vessels from pre-existing ones, is essential for normal development and wound healing/reproductive functions in adults. Abnormal regulation of angiogenesis has been implicated in the pathogenesis of several disorders, including cancer. Vascular endothelial growth factor (VEGF)-A is a pivotal stimulator of angiogenesis because its binding to VEGF receptors has been shown to promote endothelial cell migration and proliferation, two key features required for the development of new blood vessels. In addition, VEGF-A increases vascular permeability, which may also contribute to angiogenesis and tumor growth. Recognition of the central role of VEGF-A in angiogenesis has led to the hypothesis that its inhibition may represent a novel and effective approach to the treatment of cancer and other conditions characterized by pathologic angiogenesis. Several lines of evidence support this idea, and early clinical experience with the humanized anti-VEGF-A monoclonal antibody bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA) has been encouraging. Clinical efficacy of antiangiogenic therapy with bevacizumab is being evaluated in several phase 3 trials in various types of cancer, as well as in patients with age-related macular degeneration.