The influence of metastatic breast cancer on the bone microenvironment

The bone is a welcoming microenvironment for metastases from many cancers including breast cancer. Cancer cells can easily enter the bone marrow cavity due to its vasculature; there they are exposed to the many growth factors and cytokines that are part of the continuous bone remodeling process. In addition, the cancer cells interact with the resident bone cells, osteoblasts and osteoclasts, to modify the microenvironment resulting in cancer cell colonization and eventually bone degradation. Osteoclasts release numerous molecules such as insulin-like growth factors (IGFs) and transforming growth factor beta (TGF-β) from the matrix. Osteoblasts undergo an inflammatory stress response and produce a set of cytokines that are osteoclastogenic. These cytokines include IL-6, IL-8 (murine homologue MIP-2), VEGF, MCP-1, MIG and LIX. Several of these molecules also are secreted by cancer cells. One notable exception is MCP-1 which is made only in small quantities. During the course of metastasis, osteoblast differentiation is suppressed and the prevalence of osteoblast apopotosis increases. Thus the bone microenvironment is modified by the interaction of cancer cells with both osteoblasts and osteoclasts. Bone loss results from hyperactive osteoclasts and hypoactive osteoblasts. This chapter summarizes the results of studies of osteoblast and breast cancer cell interactions that have been performed in cell culture, in mice and in a novel three dimensional culture bioreactor.