Roles of bone marrow cells in skeletal metastases: no longer bystanders.

Bone serves one of the most congenial metastatic microenvironments for multiple types of solid tumors, but its role in this process remains under-explored. Among many cell populations constituting the bone and bone marrow microenvironment, osteoblasts (originated from mesenchymal stem cells) and osteoclasts (originated from hematopoietic stem cells) have been the main research focus for pro-tumorigenic roles. Recently, increasing evidence further elucidates that hematopoietic lineage cells as well as stromal cells in the bone marrow mediate distinct but critical functions in tumor growth, metastasis, angiogenesis and apoptosis in the bone microenvironment. This review article summarizes the key evidence describing differential roles of bone marrow cells, including hematopoietic stem cells (HSCs), megakaryocytes, macrophages and myeloid-derived suppressor cells in the development of metastatic bone lesions. HSCs promote tumor growth by switching on angiogenesis, but at the same time compete with metastatic tumor cells for occupancy of osteoblastic niche. Megakaryocytes negatively regulate the extravasating tumor cells by inducing apoptosis and suppressing proliferation. Macrophages and myeloid cells have pro-tumorigenic roles in general, suggesting a similar effect in the bone marrow. Hematopoietic and stromal cell populations in the bone marrow, previously considered as simple by-standers in the context of tumor metastasis, have distinct and active roles in promoting or suppressing tumor growth and metastasis in bone. Further investigation on the extended roles of bone marrow cells will help formulate better approaches to treatment through improved understanding of the metastatic bone microenvironment.