Stimulation of VEGF-mediated angiogenesis and tumor growth by low concentrations of anti-angiogenic integrin inhibitors


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Andrew Reynolds7, Ian Hart1, Dylan Jones1, Mishal Salih1, Matt Jones2, Stephen Robinson1, Rita Silva1, Vassiliki Kostourou1, Garry Saunders3, Georges Da Violante4, Françoise Perron-Sierra5, Jim Norman2, Gordon Tucker6, Kairbaan Hodivala-Dilke1

1The Adhesion and Angiogenesis Lab, 2 Centre for Tumour Biology, Cancer Research UK Clinical Centre, Institute of Cancer, Barts and The London School Of Medicine and Dentistry, John Vane Science Centre,, London, UK, 2Integrin Cell Biology Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road,, Glasgow, UK, 3Cancer Research UK London Research Institute, Clare Hall Laboratories,, London, UK, 4Technologie Servier, 5 rue Bel Air, 45000 ,, Orléans, France, 5Institut de Recherches Servier (IdRS), Medicinal Chemistry Division, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France, 6Institut de Recherches Servier (IdRS), Cancer Drug Discovery Division, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France, 7Tumour Angiogenesis Group, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

Abstract

Inhibitors of avb3 and avb5 integrins have entered clinical trials as anti-angiogenic agents for cancer treatment. However, we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic avb3/avb5-inhibitors actually can stimulate tumor growth and tumor angiogenesis, a previously unrecognized effect that could seriously compromise their efficacy. Importantly, low concentrations of avb3/avb5-inhibitors do not appear to act as agonists of integrin adhesive function. Instead, we show that low concentrations of RGD-mimetic avb3/avb5-inhibitors promote VEGF-mediated angiogenesis via a novel mechanism. At low concentrations these inhibitors promote VEGFR2 expression by suppressing its degradation. This occurs because avb3/avb5-inhibitors enhance the Rab4A-mediated recycling of VEGFR2. In support of these findings, we show that Rab4A expression is required for low concentrations of avb3/avb5-inhibitors to promote angiogenesis. This represents a novel mechanism via which putative anti-angiogenic therapy may enhance tumor angiogenesis; findings with major implications for the use of avb3/avb5-inhibitors in humans.

Inhibitors of avb3 and avb5 integrins have entered clinical trials as anti-angiogenic agents for cancer treatment. However, we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic avb3/avb5-inhibitors actually can stimulate tumor growth and tumor angiogenesis, a previously unrecognized effect that could seriously compromise their efficacy. Importantly, low concentrations of avb3/avb5-inhibitors do not appear to act as agonists of integrin adhesive function. Instead, we show that low concentrations of RGD-mimetic avb3/avb5-inhibitors promote VEGF-mediated angiogenesis via a novel mechanism. At low concentrations these inhibitors promote VEGFR2 expression by suppressing its degradation. This occurs because avb3/avb5-inhibitors enhance the Rab4A-mediated recycling of VEGFR2. In support of these findings, we show that Rab4A expression is required for low concentrations of avb3/avb5-inhibitors to promote angiogenesis. This represents a novel mechanism via which putative anti-angiogenic therapy may enhance tumor angiogenesis; findings with major implications for the use of avb3/avb5-inhibitors in humans.