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

• Published in: Nature medicine Vol. 15; no. 4; pp. 392 - 400
• Main Authors: Silva, Rita G, Da Violante, Georges, Reynolds, Andrew R, Jones, Matt C, Robinson, Stephen D, Perron-Sierra, Françoise, Tucker, Gordon C, Gourlaouen, Morgane, Hart, Ian R, Jones, Dylan T, Hodivala-Dilke, Kairbaan M, Norman, Jim C, Watson, Alan R, Saunders, Garry, Kostourou, Vassiliki, Welti, Jonathan C, Salih, Mishal
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2009; Nature Publishing Group
• Subjects: Angiogenesis; Angiogenesis Inhibitors - therapeutic use; Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell adhesion & migration; Chemotherapy; Disease Models, Animal; Growth; Humans; Infectious Diseases; Inhibitor drugs; Inhibitors; Integrin alphaVbeta3 - therapeutic use; Integrins; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical research; Melanoma, Experimental - blood supply; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Metabolic Diseases; Mice; Molecular Medicine; Neoplasms - blood supply; Neoplasms - drug therapy; Neovascularization; Neovascularization, Pathologic - prevention & control; Neurosciences; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Physiological aspects; Receptors, Vitronectin - therapeutic use; Tumors; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1941

Inhibitors of α v β 3 and α v β 5 integrins have previously been shown to inhibit tumor angiogenesis and growth and have entered human clinical trials. Andrew Reynolds and his coworkers now show that low (nanomolar) concentrations of these inhibitors can unexpectedly promote VEGF-dependent tumor angiogenesis and growth in vivo . Such effects could compromise the anticancer efficacy of these agents in humans. Inhibitors of α v β 3 and α v β 5 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 α v β 3 and α v β 5 inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering α v β 3 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.