Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.
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.
Reynolds
Andrew R
AR
Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. andrew.reynolds@icr.ac.uk
Hart
Ian R
IR
Watson
Alan R
AR
Welti
Jonathan C
JC
Silva
Rita G
RG
Robinson
Stephen D
SD
Da Violante
Georges
G
Gourlaouen
Morgane
M
Salih
Mishal
M
Jones
Matt C
MC
Jones
Dylan T
DT
Saunders
Garry
G
Kostourou
Vassiliki
V
Perron-Sierra
Françoise
F
Norman
Jim C
JC
Tucker
Gordon C
GC
Hodivala-Dilke
Kairbaan M
KM
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
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