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

Nature Medicine volume 15, pages 392–400 (2009)Cite this article

Abstract

Inhibitors of αvβ3 and αvβ5 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 αvβ3 and αvβ5 inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering αvβ3 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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Figure 2: Low concentrations of αvβ3/αvβ5 inhibitors promote VEGF-mediated angiogenesis and compromise antiangiogenic effects.
Figure 1: Nanomolar concentrations of αvβ3/αvβ5 inhibitors enhance tumor growth and angiogenesis.
Figure 3: VEGFR2 is required for the effects of low dose αvβ3/αvβ5 inhibitors.
Figure 4: Low concentrations of an αvβ3/αvβ5 inhibitor suppress VEGFR2 degradation and alter the subcellular localization of VEGFR2 and αvβ3 integrin.
Figure 5: Low concentrations of an αvβ3/αvβ5 inhibitor promote Rab4A-mediated recycling of VEGFR2 and αvβ3 integrin.
Figure 6: Low concentrations of αvβ3/αvβ5 inhibitors promote endothelial cell migration but not proliferation.

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Acknowledgements

We would like to thank S. Goodman (Merck KGaA) for the gift of the cilengitide; P. Casara (Institut de Recherches Servier) for the synthesis of S 36578; D. Hicklin (Imclone Systems Incorporated) for the gift of the DC101 antibody; M. Marsh (University College London) for the gift of the CD63-specific antibody; P. Newman (Medical College of Wisconsin) for the gift of the AP5 antibody; A. Mustafa and the staff of the Biological Services Units at Queen Mary University of London and Cancer Research UK for their assistance with animal experiments; G. Elia and the staff of the Histopathology Unit at Cancer Research UK for the preparation of tissue sections; G. D'Amico Lago, P. Caswell, C. Junges and M. Bertrand for assistance with experiments; and B. Imhof, J. Hickman and S. Kermorgant for useful discussions and critical comments on the manuscript. A.R.R. was funded by a Post-Doctoral Fellowship from Cancer Research UK, a Post-Doctoral Fellowship from the Barts and the Royal London Charitable Foundation (RAB04/F2) and a Senior Fellowship from Breakthrough Breast Cancer. J.C.W. and M.G. were supported by Breakthrough Breast Cancer, R.G.S. was a student of the Third Gulbenkian PhD Programme in Biomedicine and was sponsored by the Portuguese Foundation for Science and Technology (SFRH/BD/1/) 2003. I.R.H., A.R.W., D.T.J., M.C.J., S.D.R., V.K., G.S., J.C.N. and K.M.H.-D. are funded by Cancer Research UK.

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Authors and Affiliations

  1. Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

    Andrew R Reynolds, Jonathan C Welti & Morgane Gourlaouen

  2. The Adhesion and Angiogenesis Laboratory, Queen Mary University of London, Barts & The London School of Medicine & Dentistry, Institute of Cancer, John Vane Science Centre, London, UK

    Andrew R Reynolds, Alan R Watson, Rita G Silva, Stephen D Robinson, Mishal Salih, Dylan T Jones, Vassiliki Kostourou & Kairbaan M Hodivala-Dilke

  3. Centre for Tumour Biology, Queen Mary University of London, Barts & The London School of Medicine & Dentistry, Institute of Cancer, John Vane Science Centre, London, UK

    Ian R Hart

  4. Technologie Servier, Orléans, France

    Georges Da Violante

  5. Integrin Cell Biology Laboratory, Beatson Institute for Cancer Research, Glasgow, UK

    Matt C Jones & Jim C Norman

  6. Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, UK

    Garry Saunders

  7. Institut de Recherches Servier Medicinal Chemistry Division, Croissy-sur-Seine, France

    Françoise Perron-Sierra

  8. Institut de Recherches Servier Cancer Research & Drug Discovery Division, Croissy-sur-Seine, France

    Gordon C Tucker

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Contributions

A.R.R. conceived of and designed the study, performed the majority of the experiments and co-wrote the manuscript; I.R.H. assisted with in vivo experiments and provided comments on the manuscript; A.R.W., R.G.S., V.K. and G.S. assisted with in vivo experiments; J.C.W., S.D.R. and D.T.J. assisted with quantitative PCR and angiogenesis assays; G.D.V. made measurements on plasma samples; M.G. and M.C.J. assisted with in vitro biochemical assays; M.S. performed the analysis of VEGFR2 staining, F.P.-S. synthesized S 36578; J.C.N. designed and performed some of the receptor trafficking experiments and helped with data interpretation; G.C.T. assisted with the study design and provided vital research reagents; and K.M.H.-D. supervised the research and co-wrote the manuscript.

Corresponding authors

Correspondence to Andrew R Reynolds or Kairbaan M Hodivala-Dilke.

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Reynolds, A., Hart, I., Watson, A. et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med 15, 392–400 (2009). https://doi.org/10.1038/nm.1941

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