Vascular integrins:: Mediators and therapeutic targets in angiogenesis

Vascular integrins are essential regulators and mediators of physiological and pathological angiogenesis, including tumor angiogenesis. Integrins provide the physical interaction with the extracellular matrix necessary for cell adhesion, migration and positioning, and induce signaling events essential for cell survival, proliferation and differentiation. Integrins preferentially expressed on neovascular endothelial cells, such as alpha V beta 3 and alpha 5 beta 1, are considered as relevant targets for anti-angiogenic therapies. While traditionally integrins have been inhibited by using small molecular extracelluar inhibitors and function blocking antibodies, we have been investigating alternative approaches to suppress angiogenesis by targeting integrin-dependent intracellular events. These include use of TNF and IFN gamma to disrupt angiogenic vessels by inhibiting integrin signaling function, the expression of mutated integrins with dominant-negative effects, and the inhibition of COX-2 to block integrin-mediated Rac activation. We are currently exploring the possibility of using these recent advances to improve disruption of angiogenic vessels in cancer patients.