Tumor angiogenesis: putting a value on plastic GEMMs.

I t 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. We and others have demonstrated that antagonists of αv in-tegrins target and suppress pathological angiogenesis, resulting in decreased tumor growth, 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. 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 angio-genesis. How, then, can one reconcile the fact that αvβ3 antagonists suppress angiogenesis in mice and humans? In an elegant series of studies, Steri et al 7 examined the effects of acute depletion of endothelial cell integrin αvβ3 on neovascu-larization via Cre-mediated inactivation of a floxed β3 gene. Complementary approaches were used in this multicenter tour de force of mouse genetics, including Tie2-driven expression of Cre and hydroxytamoxifen-inducible expression of Cre driven by platelet-derived growth factor b promoters. The finding by Steri et al 7 that αvβ3 is required for angio-genesis is consistent with previous studies by Byzoya and et al, 15 who showed that mice expressing a signaling mutant of the β3 integrin subunit in which both cytosolic tyrosine residues were mutated to phenylalanine were deficient in angiogen-esis. This was associated with decreased interactions between VEGFR2 and integrin αvβ3, which were in turn associated with decreased VEGFR2 activation. The deficiency may have resulted from the absence of an active integrin signaling complex , because …