Elucidating the role of endothelial αvβ3-integrin in tumour growth and angiogenesis

Angiogenesis, the formation of new vessels from pre-existing ones, is essential for primary tumour growth as well as for metastasis, and endothelial cells play a central role in this process: they drive blood vessel formation in response to signals from the local environment by a mechanism that is integrin-dependent. αvβ3-integrin seemingly poses an ideal anti-angiogenic target. Its expression is vastly up-regulated in neo-angiogenic vessels, while its expression in quiescent vasculature is minimal. However, anti-angiogenic therapy targeting αvβ3-integrin has proven somewhat disappointing. In part, this may relate to the fact that αvβ3-integrin is not expressed solely by endothelial cells, but across a wide range of cell types that each contribute to angiogenesis. In this thesis, I describe my studies on understanding the role of αvβ3-integrin as expressed specifically by endothelial cells in tumour growth and angiogenesis using endothelial specific β3-integrin deficient mice. I have shown that inducible deletion of endothelial β3-integrin inhibits tumour growth and angiogenesis preventatively, while its constitutive deletion is ineffective; furthermore, I have found that even the inducible deletion does not alter angiogenesis in already established tumours. The findings described in this thesis re-establish αvβ3-integrin as good antiangiogenic target, but imply that timing and length of inhibition are critical factors to be considered when targeting endothelial β3-integrin-expression