Integrin alpha5beta1 promotes survival of growth-arrested breast cancer cells: an in vitro paradigm for breast cancer dormancy in bone marrow

Abstract

The mechanisms of long-term survival of occult breast cancer cells in the bone marrow microenvironment are not known. Using selected bone marrow stromal components with demonstrated roles in promoting growth arrest and survival of breast cancer cells, we reconstituted an in vitro model for dormancy of breast cancer cells in bone marrow. According to this model, basic fibroblast growth factor, a mammary differentiation factor abundant in the bone marrow stroma, induces growth arrest of relatively well-differentiated breast cancer cells, induces a spread appearance, and restricts their survival to fibronectin by up-regulating integrin alpha5beta1. Most of the basic fibroblast growth factor-arrested cells fail to establish optimal ligation to fibronectin and undergo cell death. Cells that do attach to fibronectin, another major constituent of the bone marrow microenvironment, stay alive and growth-arrested for many weeks. Although capable of adhering to other stromal proteins collagen and laminin, dormant cells do not gain a survival advantage from these interactions. Using function-blocking peptides, we show a specific contribution of alpha5beta1-fibronectin interaction in maintaining survival of growth-arrested cells, potentially by negatively modulating apoptotic response via signaling pathways. Blocking of phosphatidylinositol 3'-kinase and Akt inhibits survival of dormant clones, demonstrating this as one of those pathways. Experiments with human bone marrow stroma cocultures confirm the role of fibronectin ligation in maintaining survival of dormant clones.