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. alpha 6 beta 1- and alpha 6 beta 4-integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial alpha 6-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 alpha 6-integrin-subunit when compared with normal breast tissue. These data suggest that a decrease in alpha 6-integrin-subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial alpha 6-integrin subunit affects tumour growth and angiogenesis, we generated alpha 6fl/fl-Tie1Cre+ mice and showed that endothelial deletion of alpha 6-integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial alpha 6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. In particular, alpha 6-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 alpha 6-knockout mice, we show that the expression of the alpha 6-integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.