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

doi:10.1038/nm.1941

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 journal › Article › peer-review

406 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 language	English
Pages (from-to)	392-400
Number of pages	9
Journal	Nature Medicine
Volume	15
Issue number	4
DOIs	https://doi.org/10.1038/nm.1941
Publication status	Published - Mar 2009

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Reynolds, A. R., Hart, I. R., Watson, A. R., Welti, J. C., Silva, R. G., Robinson, S. D., Da Violante, G., Gourlaouen, M., Salih, M., Jones, M. C., Jones, D. T., Saunders, G., Kostourou, V., Perron-Sierra, F., Norman, J. C., Tucker, G. C., & Hodivala-Dilke, K. M. (2009). Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nature Medicine, 15(4), 392-400. https://doi.org/10.1038/nm.1941

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title = "Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors",

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.",

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

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doi = "10.1038/nm.1941",

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Reynolds, AR, Hart, IR, Watson, AR, Welti, JC, Silva, RG, Robinson, SD, Da Violante, G, Gourlaouen, M, Salih, M, Jones, MC, Jones, DT, Saunders, G, Kostourou, V, Perron-Sierra, F, Norman, JC, Tucker, GC & Hodivala-Dilke, KM 2009, 'Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors', Nature Medicine, vol. 15, no. 4, pp. 392-400. https://doi.org/10.1038/nm.1941

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AU - Reynolds, Andrew R.

AU - Hart, Ian R.

AU - Watson, Alan R.

AU - Welti, Jonathan C.

AU - Silva, Rita G.

AU - Robinson, Stephen D.

AU - Da Violante, Georges

AU - Gourlaouen, Morgane

AU - Salih, Mishal

AU - Jones, Matt C.

AU - Jones, Dylan T.

AU - Saunders, Garry

AU - Kostourou, Vassiliki

AU - Perron-Sierra, Françoise

AU - Norman, Jim C.

AU - Tucker, Gordon C.

AU - Hodivala-Dilke, Kairbaan M.

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AB - 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.

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