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

被引：32

作者：

Germain, Mitchel ^{[1
]}

De Arcangelis, Adele ^{[2
]}

Robinson, Stephen D. ^{[1
]}

Baker, Marianne ^{[1
]}

Tavora, Bernardo ^{[1
]}

D'Amico, Gabriela ^{[1
]}

Silva, Rita ^{[1
]}

Kostourou, Vassiliki ^{[1
]}

Reynolds, Louise E. ^{[1
]}

Watson, Alan ^{[1
]}

Jones, J. Louise ^{[3
]}

Georges-Labouesse, Elisabeth ^{[2
]}

Hodivala-Dilke, Kairbaan ^{[1
]}

机构：

[1] Univ London, Inst Canc, Adhes & Angiogenesis Lab, London EC1M 6BQ, England

[2] Univ Strasbourg, CNRS, UMR 7104, Inst Genet & Biol Mol & Cellulaire,INSERM,U964, F-67404 Illkirch Graffenstaden, France

[3] Univ London, Inst Canc, Tumor Biol Ctr, London EC1M 6BQ, England

来源：

JOURNAL OF PATHOLOGY | 2010年 / 220卷 / 03期

关键词：

integrins; angiogenesis; knockout mice; ENDOTHELIAL GROWTH-FACTOR; NF-KAPPA-B; ALPHA-6-BETA-4; INTEGRIN; DIFFERENTIAL EXPRESSION; HEMIDESMOSOME FORMATION; EPIDERMOLYSIS-BULLOSA; CELL-ADHESION; IN-VITRO; SURVIVAL; MOUSE;

D O I：

10.1002/path.2654

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：370 / 381

页数：12

共 48 条

[1]

Chung J, 2004, MOL CELLS, V17, P203

[2]

Integrin (α6β4) regulation of eIF-4E activity and VEGF translation:: a survival mechanism for carcinoma cells [J].