Novel roles for integrins in tumour angiogenesis

The laminin receptors α₃β₁ and α₆β₁ are expressed by endothelial cells, but their direct roles in tumour angiogenesis and especially breast cancer angiogenesis remains unexplored. We show that α₆β₁-integrin is expressed in 80–90% of blood vessels associated with normal breast or ductal carcinoma in situ. However, the proportion of vessels that express α₆β₁ drops to less than 30% in invasive ductal carcinoma samples, suggesting that loss of this laminin receptor can enhance invasive carcinoma angiogenic events. Furthermore, the deletion of α₆-integrin or α₃-integrin in ex vivo angiogenic assays can promote VEGF-mediated microvessel sprouting. Taken together these results implicate these integrins in the negative control of angiogenesis. Since global deletion of the α₃-integrin or α₆-integrin genes in mice is lethal, we have generated mice where these genes are deleted on endothelial cells only.

Our data indicate that mice deficient in individual laminin receptors on endothelial cells in vivo not only support tumour growth but have enhanced tumourigenesis. Moreover, tumour angiogenesis is elevated in these mice, suggesting strongly that laminin receptors are not required for tumour angiogenesis. We also observed that angiogenic responses to hypoxia are enhanced in mice deficient for laminin receptors on endothelial cells and have evidence that, at least in α₃-null endothelial cells, VEGF-receptor 2 (FLK1) levels are elevated when compared with controls. We provide the first evidence that α₃-integrin and α₆-integrin can be differentially expressed in the angiogenic vessels associated with invasive carcinoma of the breast and suggest that these laminin receptors can negatively regulate angiogenesis in vivo and ex vivo.