Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins.
Inhibition of alphavbeta3 or alphavbeta5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking beta3 integrins or both beta3 and beta5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither beta3 nor beta5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of beta3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the beta3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in beta3-null endothelial cells. These data indicate that alphavbeta3 and alphavbeta5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of alphav-integrin antagonists in anti-angiogenic therapeutics.
Reynolds
Louise E
LE
Cell Adhesion and Disease Laboratory, Richard Dimbleby Department, Imperial Cancer Research Fund, St. Thomas' Hospital, London, UK.
Wyder
Lorenza
L
Lively
Julie C
JC
Taverna
Daniela
D
Robinson
Stephen D
SD
Huang
Xiaozhu
X
Sheppard
Dean
D
Hynes
Richard O
RO
Hodivala-Dilke
Kairbaan M
KM
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D039641:Integrin beta Chains; D039661:Integrin beta3; D016023:Integrins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D019030:Receptors, Vitronectin / Q000378:metabolism; D015861:Retinal Neovascularization; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015703:Antigens, CD; D016228:Endothelial Growth Factors; D039641:Integrin beta Chains; D039661:Integrin beta3; D016023:Integrins; D008222:Lymphokines; D010980:Platelet Membrane Glycoproteins; D017978:Receptors, Growth Factor; D019030:Receptors, Vitronectin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C064660:integrin alphaVbeta5; C084344:integrin beta5; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor