The Adhesion and Angiogenesis Laboratory, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, UK.
J Pathol. 2010 Feb;220(3):370-81. doi: 10.1002/path.2654.
Laminins are expressed highly in blood vessel basement membranes and have been implicated in angiogenesis. alpha6beta1- and alpha6beta4-integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial alpha6-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 alpha6-integrin-subunit when compared with normal breast tissue. These data suggest that a decrease in alpha6-integrin-subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial alpha6-integrin subunit affects tumour growth and angiogenesis, we generated alpha6fl/fl-Tie1Cre+ mice and showed that endothelial deletion of alpha6-integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial alpha6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. In particular, alpha6-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 alpha6-knockout mice, we show that the expression of the alpha6-integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo.
层粘连蛋白在血管基底膜中高度表达，并与血管生成有关。α6β1-和α6β4-整合素是内皮细胞中层粘连蛋白的主要受体，但内皮细胞α6 整合素在肿瘤血管生成中的精确作用尚不清楚。我们发现与正常乳腺组织相比，人浸润性导管乳腺癌中的血管表达的α6 整合素亚基减少。这些数据表明内皮细胞中α6 整合素亚基表达的减少与肿瘤血管生成有关。为了测试内皮细胞α6 整合素亚基的缺失是否影响肿瘤生长和血管生成，我们生成了α6fl/fl-Tie1Cre+ 小鼠，并表明内皮细胞中α6 整合素的缺失足以增强两种小鼠 B16F0 黑色素瘤和 Lewis 细胞肺癌中的肿瘤大小和肿瘤血管生成。从机制上讲，内皮细胞中 α6 整合素的缺失显著增加了体内和体外的 VEGF 介导的血管生成。特别是，α6 整合素缺陷的内皮细胞显示出更高水平的 VEGF 受体 2(VEGFR2)和 VEGF 介导的下游 ERK1/2 激活。通过开发第一种内皮细胞特异性α6 敲除小鼠，我们表明内皮细胞中α6 整合素亚基的表达作为体内和体外血管生成的负调节剂。
