Stromal-Epithelial Interactions and the Angiogenic Phenotype of Breast Cancer

Tumor progression is characterized by altered cell-cell interactions, increased invasion and angiogenesis, and upregulation of integrins including alpha5 and av; as well as increased tenascin (TN) and fibronectin (FN) deposition. We asked whether elevated alpha5 integrin could promote malignant progression by compromising tissue polarity and promoting angiogenesis. Using the HMT3522 breast cancer progression cell series and 3D reconstituted basement membrane (rBM) co-culture and xenograft assays we found that malignant transformation correlated with loss of tissue polarity, acquisition of invasiveness, increased alpha5 integrin expression, VEGF and IL-8 upregulation, and a pro-angiogenic phenotype in culture and in vivo. However, only inhibiting alpha5beta1 activity could phenotypically revert these tumors, reduce invasion and impair angiogenesis in culture and in vivo. Moreover, overexpression of alpha5 integrin in S-l nonmalignant cells compromised polarity and induced angiogenesis in vitro and in vivo. Thus, we propose that alpha5beta1 integrin ligation of FN - regulates tissue architecture- mediated (TAM)-dormancy through cooperative interaction and induction or angiogenesis.