The Osteoblastic Microenvironment Determines the Fate of Breast Cancer Cells Disseminated in the Bone Marrow

ABSTRACT Bone is the most common destination of metastatic breast cancer cells. Upon dissemination to the bone, cancer cells may either colonize aggressively or enter a quiescent state, depending on interactions with the bone microenvironment. This study revealed how the osteoblastic microenvironment determines the fate of cancer cells disseminated in the bone marrow. Cancer cells remain quiescent as disseminated tumor cells (DTCs) or as micrometastases within an inactive osteoblastic microenvironment (homeostasis) but colonize the bone in an active, nonmineralized osteoblastic (osteogenic) microenvironment. In a highly mineralized osteoblastic microenvironment, basal‐like tumor cells remain quiescent, whereas luminal‐like cancer cells survive and invade the bone. These findings provide a comprehensive explanation for the divergent outcomes of disseminated cancer cells in the bone, focusing on whether they colonize, reside in quiescence, or reactivate from dormancy. Moreover, in a supportive osteogenic microenvironment, both cancer cells and well‐differentiated osteoblasts were demonstrated to activate osteoclasts, leading to osteolytic lesions. Cellular (osteoblasts) and matrix (bone matrix) components exhibited distinct roles in bone colonization. Furthermore, the therapeutic potential of disrupting integrin‐mediated interactions between tumor cells and the bone matrix was evaluated in animal experiments to prevent the reactivation of quiescent tumor cells and their colonization of the bone.