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.
Authors and Affiliations
Cancer Research UK Clinical Centre, Cancer Research UK, Bart's & The London Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, London, UK
M Germain, R Silva, L Reynolds, S Robinson & K Hodivala-Dilke
Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York, USA
Urology Department, Children's Hospital, Boston, Massachusetts, USA
DR2 CNRS, Institut de génétique et de biologie moléculaire et cellulaire, Illkirch Cedex, CU de Strasbourg, France