Genetic ablation of the alpha 6-integrin subunit in Tie1Cre mice enhances tumour angiogenesis

Mitchel Germain, Adèle De Arcangelis, Stephen D. Robinson, Marianne Baker, Bernardo Tavora, Gabriela D'Amico, Rita Silva, Vassiliki Kostourou, Louise E. Reynolds, Alan Watson, J. Louise Jones, Elisabeth Georges-Labouesse, Kairbaan Hodivala-Dilke

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Laminins are expressed highly in blood vessel basement membranes and have been implicated in angiogenesis. a6ß1- and a6ß4-integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial a6-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 a6-integrin-subunit when compared with normal breast tissue. These data suggest that a decrease in a6-integrin-subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial a6-integrin subunit affects tumour growth and angiogenesis, we generated a6fl/fl-Tie1Cre+ mice and showed that endothelial deletion of a6-integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial a6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. In particular, a6-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 a6-knockout mice, we show that the expression of the a6-integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo.
Original languageEnglish
Pages (from-to)370-381
Number of pages12
JournalThe Journal of Pathology
Volume220
Issue number3
DOIs
Publication statusPublished - Feb 2010

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