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Article
Nature Medicine 15, 392 - 400 (2009)
Published online: 22 March 2009 | doi:10.1038/nm.1941
Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors
Andrew R Reynolds1,2, Ian R Hart3, Alan R Watson2, Jonathan C Welti1, Rita G Silva2, Stephen D Robinson2, Georges Da Violante4, Morgane Gourlaouen1, Mishal Salih2, Matt C Jones5, Dylan T Jones2, Garry Saunders6, Vassiliki Kostourou2, Françoise Perron-Sierra7, Jim C Norman5, Gordon C Tucker8 & Kairbaan M Hodivala-Dilke2
Abstract
Inhibitors of 
v
3 and v5 integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic v3 and v5 inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering v3 integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.
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