title: Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.
abstract: Inhibitors of alpha(v)beta(3) and alpha(v)beta(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 alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(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.
authors.affiliation: Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. andrew.reynolds@icr.ac.uk
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: Alan R
authors.initials: AR
authors.lastname: Watson
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Welti
authors.forename: Rita G
authors.initials: RG
authors.lastname: Silva
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Robinson
authors.forename: Georges
authors.initials: G
authors.lastname: Da Violante
authors.forename: Morgane
authors.initials: M
authors.lastname: Gourlaouen
authors.forename: Mishal
authors.initials: M
authors.lastname: Salih
authors.forename: Matt C
authors.initials: MC
authors.lastname: Jones
authors.forename: Dylan T
authors.initials: DT
authors.lastname: Jones
authors.forename: Garry
authors.initials: G
authors.lastname: Saunders
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kostourou
authors.forename: Françoise
authors.initials: F
authors.lastname: Perron-Sierra
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Tucker
authors.forename: Kairbaan M
authors.initials: KM
authors.lastname: Hodivala-Dilke
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D019030:Receptors, Vitronectin / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019030:Receptors, Vitronectin; D042461:Vascular Endothelial Growth Factor A; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid