Genetic ablation of the alpha 6-integrin subunit in Tie1Cre mice enhances tumour angiogenesis.
Laminins are expressed highly in blood vessel basement membranes and have been implicated in angiogenesis. alpha6beta1- and alpha6beta4-integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial alpha6-integrin in tumour angiogenesis is not clear. We show that blood vessels in human invasive ductal carcinoma of the breast have decreased expression of the alpha6-integrin-subunit when compared with normal breast tissue. These data suggest that a decrease in alpha6-integrin-subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial alpha6-integrin subunit affects tumour growth and angiogenesis, we generated alpha6fl/fl-Tie1Cre+ mice and showed that endothelial deletion of alpha6-integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial alpha6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. In particular, alpha6-integrin-deficient endothelial cells displayed increased levels of VEGF-receptor 2 (VEGFR2) and VEGF-mediated downstream ERK1/2 activation. By developing the first endothelial-specific alpha6-knockout mice, we show that the expression of the alpha6-integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo.
Germain
Mitchel
M
The Adhesion and Angiogenesis Laboratory, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, UK.
De Arcangelis
Adèle
A
Robinson
Stephen D
SD
Baker
Marianne
M
Tavora
Bernardo
B
D'Amico
Gabriela
G
Silva
Rita
R
Kostourou
Vassiliki
V
Reynolds
Louise E
LE
Watson
Alan
A
Jones
J Louise
JL
Georges-Labouesse
Elisabeth
E
Hodivala-Dilke
Kairbaan
K
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000098:blood supply; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000633:toxicity; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D039503:Integrin alpha6; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases