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Genetic ablation of the alpha 6‐integrin subunit in Tie1Cre mice enhances tumour angiogenesis
Author(s) -
Germain Mitchel,
De Arcangelis Adèle,
Robinson Stephen D,
Baker Marianne,
Tavora Bernardo,
D'Amico Gabriela,
Silva Rita,
Kostourou Vassiliki,
Reynolds Louise E,
Watson Alan,
Jones J Louise,
GeorgesLabouesse Elisabeth,
HodivalaDilke Kairbaan
Publication year - 2010
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2654
Subject(s) - angiogenesis , integrin , alpha (finance) , protein subunit , ablation , biology , microbiology and biotechnology , cancer research , immunology , pathology , medicine , genetics , receptor , gene , surgery , construct validity , patient satisfaction
Abstract Laminins are expressed highly in blood vessel basement membranes and have been implicated in angiogenesis. α6β1‐ and α6β4‐integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial α6‐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 α6‐integrin‐subunit when compared with normal breast tissue. These data suggest that a decrease in α6‐integrin‐subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial α6‐integrin subunit affects tumour growth and angiogenesis, we generated α6fl/fl‐Tie1Cre+ mice and showed that endothelial deletion of α6‐integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial α6‐integrin deficiency elevated significantly VEGF‐mediated angiogenesis both in vivo and ex vivo . In particular, α6‐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 α6‐knockout mice, we show that the expression of the α6‐integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo . Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.