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

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.

Neuroligin 1 Induces Blood Vessel Maturation by Cooperating with the α6 Integrin

“…ablation of ␣6 integrin leads to perinatal death of mice without evidence of developmental angiogenesis defects (21), whereas endothelial-specific elimination of this integrin increases tumor angiogenesis and growth in a xenograft model (22). Here, we show that in cooperation with NLGN1 ␣6 integrin induces vessel stabilization in one of the most useful models for analyzing the molecular and cellular mechanisms regulating angiogenesis.…”

Chronic Cerebral Hypoxia Promotes Arteriogenic Remodeling Events that can be Identified by Reduced Endoglin (CD105) Expression and a Switch in β1 Integrins

“…An angiogenic role for the a5b1 integrin has been shown both in vivo (Francis et al, 2002) and in vitro (Wang and Milner, 2006). Conversely, the a6b1 integrin mediates endothelial differentiation and stability of blood vessels (Germain et al, 2010). During developmental angiogenesis in the CNS, BECs switch integrins from a5 to a6 dominant (Milner and Campbell, 2002).…”

Integrins in Wound Healing

“…3; Table 2). [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] Integrins can be divided into four subfamilies based on their ligand specificity and/or phylogenetic comparison of the a subunits (Fig. 3).…”