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

Germain, Mitchel, De Arcangelis, Adèle, Robinson, Stephen D. ORCID:, Baker, Marianne, Tavora, Bernardo, D'Amico, Gabriela, Silva, Rita, Kostourou, Vassiliki, Reynolds, Louise E., Watson, Alan, Jones, J. Louise, Georges-Labouesse, Elisabeth and Hodivala-Dilke, Kairbaan (2010) Genetic ablation of the alpha 6-integrin subunit in Tie1Cre mice enhances tumour angiogenesis. The Journal of Pathology, 220 (3). pp. 370-381. ISSN 1096-9896

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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.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Science > Research Groups > Cells and Tissues
Depositing User: Users 2731 not found.
Date Deposited: 22 Nov 2011 13:44
Last Modified: 21 Apr 2023 07:32
DOI: 10.1002/path.2654

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