Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors

Andrew R. Reynolds, Ian R. Hart, Alan R. Watson, Jonathan C. Welti, Rita G. Silva, Stephen D. Robinson, Georges Da Violante, Morgane Gourlaouen, Mishal Salih, Matt C. Jones, Dylan T. Jones, Garry Saunders, Vassiliki Kostourou, Françoise Perron-Sierra, Jim C. Norman, Gordon C. Tucker, Kairbaan M. Hodivala-Dilke

Research output: Contribution to journalArticlepeer-review

365 Citations (Scopus)

Abstract

Inhibitors of alphavbeta3 and alphavbeta5 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 alphavbeta3 and alphavbeta5 inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alphavbeta3 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.
Original languageEnglish
Pages (from-to)392-400
Number of pages9
JournalNature Medicine
Volume15
Issue number4
DOIs
Publication statusPublished - Mar 2009

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