Roles of Bone Marrow Cells in Skeletal Metastases: No Longer Bystanders

Abstract

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.

Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

“…Interestingly, in cancer, the protumorigenic macrophage also known as M2 alternatively activated (or TAM) shares many similarities with the phagocytic macrophage. TAMs have an anti-inflammatory role in the tumor microenvironment, expressing phagocytic markers such as mannose receptors (CD206) and anti-inflammatory cytokines and factors that not only participate in immunosuppression but also promote tumor growth (6). In this study, MFG-E8 was expressed in three different prostate cancer cell lines, and coculture of macrophages with cells undergoing apoptosis increased efferocytosis as well as MFG-E8 production.…”

“…Tumor-associated macrophages (TAMs) 3 have been investigated in the context of cancer (3,4), but their role in bone metastasis remains elusive (3,5,6). Macrophages are activated differentially according to the stimuli provided.…”

Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment

“…Subsequently, the matrices become mineralized, forming hard tissue. The roles of osteoblasts in the tumor microenvironment have been a focus of extensive research efforts thus far, with the vicious cycle hypothesis being the most well investigated by Dr. Gregory Mundy's group [3]. The hypothesis was later clinically and experimentally proven to be legitimate and provided a solid scientific rationale for the development of multiple bone-targeted agents.…”

“…To better understand organ-specific metastases and to ultimately develop more effective therapeutics, the biology of key cellular components in the microenvironment must be clearly determined [23]. Among many types of solid tumors, prostate, breast and lung cancers predominantly develop bone-specific metastases [23]. Bone provides a unique microenvironment for the migrated tumor cells to survive and grow [4].…”

Radium-223 and concomitant therapies: prospects and prudence

“…This pathologic bone remodeling process is further promoted by RANKL produced by osteoblasts (12). Other stromal-derived cells such as tumor associated macrophages and myeloid derived suppressor cells have been shown to promote tumor progression in the bone microenvironment (13). Upon dissemination, prostate cancer tumor cells have also been shown to compete with hematopoietic stem cells via upregulation of CXCR4 by competing with CXCL12 binding partners on bone marrow endothelial cells, stromal cells and osteoblasts (14).…”