Bone niches in the regulation of tumour cell dormancy

Abstract

Secondary metastases, accounting for 90 % of cancer-related deaths, pose a formidable challenge in cancer treatment, with bone being a prevalent site. Importantly, tumours may relapse, often in the skeleton even after successful eradication of the primary tumour, indicating that tumour cells may lay dormant within bone for extended periods of time. This review summarises recent findings in the mechanisms underlying tumour cell dormancy and the role of bone cells in this process. Hematopoietic stem cell (HSC) niches in bone provide a model for understanding regulatory microenvironments. Dormant tumour cells have been shown to exploit similar niches, with evidence suggesting interactions with osteoblast-lineage cells and other stromal cells via CXCL12-CXCR4, integrins, and TAM receptor signalling, especially through GAS6-AXL, led to dormancy, with exit of dormancy potentially regulated by osteoclastic bone resorption and neuronal signalling. A comprehensive understanding of dormant tumour cell niches and their regulatory mechanisms is essential for developing targeted therapies, a critical step towards eradicating metastatic tumours and stopping disease relapse.

Keywords: Bone metastasis; Bone niches; Bone stromal cells; Osteoblasts; Osteoclasts; Tumour cell dormancy.

Fig. 1

Recently, Phan and Croucher described 6 defining features of dormant tumour cells. 1) The transition of tumour cells into the dormant state is dependent upon cell-extrinsic factors within the niche. 2) Upon engagement with the niche, these cells enter a state of G0-G1 cell-cycle arrest. 3) In the dormant state, tumour cells are resistant to therapeutic agents. 4) Dormant tumour cells are able to avoid immune-mediated destruction for extended periods. 5) Eventually, these cells are able to reactivate and grow into a metastatic tumour. 6) Even post-reactivation, tumour cells are able to revert back into a dormant state, indicating that this transition is reversible.

Fig. 2

Schematic of the haematopoietic stem cell (HSC) niche in bone. The long-term quiescence of HSCs in the bone microenvironment is maintained by specific cellular niches, which involve signalling contributions from tissue-resident stromal cells, immune cells, the vasculature, the extracellular matrix and neuronal cells.

Fig. 3

Schematic of the dormant tumour cell niche in bone. Like HSCs, dormant tumour cells are maintained in a state of long-term quiescence within bone by specific cellular niches. Comparative studies have identified a variety of shared signalling pathways that regulate both HSC and dormant tumour cell quiescence, suggesting the niches occupied by these cells may involve similar cell types. Dormant tumour cell niches remain poorly characterised however, and it therefore remains unclear whether these cells occupy the same or distinct but similar niches as HSCs.