Tumor Angiogenesis

Abstract

It has long been appreciated that angiogenesis can contribute to the induction or progression of several diseases, including retinopathies, arthritis, psoriasis, and cancer.1,2 Because endothelial cells typically exist in a quiescent state in normal vessels, the molecular changes required for these cells to become proliferative and invasive have long been considered potential targets for the control of both neovascularization and the accompanying pathology. To this end, over the past 3 decades, several novel effectors of angiogenesis have been characterized, ranging from growth factors, such as vascular endothelial cell growth factor (VEGF),3 to signaling effectors, such as RasGAPs,4 to cell adhesion molecules,5,6 including the αv integrins featured in the article by Steri et al.7 Nonetheless, as an aggregate, the efficacy of antiangiogenic agents has only produced a modest impact on disease.8 Article, see p 79 We and others have demonstrated that antagonists of αv integrins target and suppress pathological angiogenesis, resulting in decreased tumor growth,9,10 inflammatory disease,9,11 and retinal disease.5 In glioblastoma patients treated with these agents, some clinical efficacy was noted,12 although overall survival was not significantly impacted in recently announced phase III trials. Studies by Hynes et al showed that mice deficient in either αv or β3 showed robust blood vessel development.13,14 In fact, these animals displayed enhanced endothelial cell VEGF receptor (VEGFR) expression associated with increased tumor angiogenesis. This led the authors to conclude that αvβ3 plays a negative role in angiogenesis. How, then, can one reconcile the fact that αvβ3 antagonists suppress angiogenesis in mice and humans? In an elegant series of …