Osteoblasts and osteoclasts: an important switch of tumour cell dormancy during bone metastasis

Abstract

Bone metastasis occurs when tumour cells dissociate from primary tumours, enter the circulation (circulating tumour cells, CTCs), and colonize sites in bone (disseminated tumour cells, DTCs). The bone marrow seems to be a particularly dormancy-inducing environment for DTCs, yet the mechanisms of dormancy initiation, reactivation, and interaction within the bone marrow have to be elucidated. Intriguingly, some evidence has suggested that dormancy is a reversible state that is switched ‘on’ or ‘off’ depending on the presence of various bone marrow resident cells, particularly osteoclasts and osteoblasts. It has become clear that these two cells contribute to regulating dormant tumour cells in bone both directly (interaction) and indirectly (secreted factors). The involved mechanisms include TGFβ signalling, the Wnt signalling axis, the Notch2 pathway, etc. There is no detailed review that specifically focuses on ascertaining the dynamic interactions between tumour cell dormancy and bone remodelling. In addition, we highlighted the roles of inflammatory cytokines during this ‘cell-to-cell’ communication. We also discussed the potential clinical relevance of remodelling the bone marrow niche in controlling dormant tumour cells. Understanding the unique role of osteoclasts and osteoblasts in regulating tumour dormancy in bone marrow will provide new insight into preventing and treating tumour bone metastasis.

Dynamic bioinspired coculture model for probing ER + breast cancer dormancy in the bone marrow niche

“…Despite growing knowledge that BM niche cells strongly influence tumor dormancy and activation, many of the specific interactions by which BM niche cells influence BCC function remain unclear, owing in part to in vivo microenvironment complexity (e.g., bone remodeling processes that occur with aging or injury leading to a range of dynamic cell-cell and cell-matrix interactions) ( 6 , 34 ). Reductionist model systems provide an opportunity to control aspects of this complexity and dissect interactions between niche cells and DTCs ( 18 , 19 , 38 ), with a focus to date on examining interactions between mixed populations of BCCs and niche cells in direct coculture (i.e., direct BCC–niche cell contact) ( 29 – 32 , 39 , 40 ).…”

“…BCC switching to proliferation from growth inhibition was observed in these indirect coculture exchange studies and suggested the importance of soluble secreted factors (e.g., cytokines, chemokines, and growth factors) ( 45 , 47 ) in dormancy/reactivation. In vivo, osteoblasts are known to be critical in both bone homeostasis and repair processes, while MSCs are present in the BM and recruited/expanded in bone injury and remodeling processing ( 6 , 34 , 71 ): The 3D indirect coculture model provides future opportunities for further capturing and probing these complex interactions in dormancy/reactivation (e.g., tricultures of BCCs, hFOBs, and hMSCs and triggering/examining matrix remodeling).…”

“…We hypothesized that soluble factors, particularly bioactive proteins, released within the osteoblastic niche regulated the suppression of growth and induced dormancy survival. To probe this within the model system and identify potential targets for regulating dormancy, we selected a range of bioactive proteins known to be pivotal in the metastatic cascade including cell growth, migration, survival, and death [TNFα (tumor necrosis factor-α), MCP1 (monocyte chemoattractant protein 1), FGF2, IL-6, MMP1, and VEGF-A (vascular endothelial growth factor A), and EGF (epidermal growth factor)] (34,(44)(45)(46)(47)(48)(49) and performed a Luminex assay to determine the level of these secreted cytokines, growth factors, enzyme, and chemokines presented within conditioned media from dormancy-promoting hFOB cocultures or growth-promoting hMSC cocultures with BCCs. High levels of TNFα, MCP1, FGF2, and IL-6 were observed in BCC#hFOB coculture-conditioned media in comparison to BCC monoculture and BCC#hMSC-conditioned media, whereas high levels of MMP1 and VEGF-A were observed in BCCs#hMSC-conditioned media in comparison to BCCs monoculture and BCCs#hFOB, assayed at day 10 culture, and normalized to the untreated growth media (Fig.…”

“…For example, in short-term 2D studies, dormant ER + BCCs stimulated stromal cell secretion of inflammatory cytokines, interleukin-6 (IL-6) and IL-8, which in turn stimulated a switch in dormant cell phenotype from epithelial to mesenchymal and reactivated the once dormant cells to proliferate ( 12 ). Moving to indirect 2D cocultures, BCC and niche cells can be cultured in separate wells connected by a membrane or with condition media periodically exchanged: For example, it was observed that ER + BCC growth and proliferation was suppressed when treated with the conditioned media of “educated” osteoblast cells, suggesting the relevance of secreted factor exchange between BCC and BM niche cells in dormancy induction ( 33 , 34 ). While studies to date demonstrate the importance of specific cell-ECM and cell-cell interactions in the BM microenvironment for inducing dormancy/growth, longer-term studies (>2 weeks) remain challenging (e.g., over growth of scaffolds by different cell types) and are needed for examining late recurrence of ER + BCs.…”