Several tumours either develop in the skeleton, such as multiple myeloma, or metastasize to bone, such as breast and prostate cancers.
The skeleton provides a unique microenvironment that supports the development of these tumours, although the nature of this microenvironment has until recently been poorly defined.
Our understanding of the early, crucial events of tumour cell colonization, survival and dormancy, and reactivation of dormant cancer cells has been limited. However, progress in single cell imaging and molecular techniques has provided new insights.
Tumour cell dormancy in the skeleton is induced by interactions with specific cells in the local bone microenvironment. Cells of the osteoblast lineage, present on the endosteal bone surface, provide a supportive niche to keep tumour cells in a dormant state.
Reactivation of dormant tumour cells is mediated by extrinsic changes in the bone microenvironment. Osteoclasts, by remodelling the endosteal bone surface, represent one mechanism by which dormant cells can be reactivated.
Our improved understanding of the control of tumour dormancy in the skeleton has revealed new therapeutic opportunities. These include using bone-active drugs to promote long-term tumour cell dormancy, or conversely, promoting reactivation and targeting dormant cells to eradicate them and 'cure' tumours that develop in bone.
During the past decade preclinical studies have defined many of the mechanisms used by tumours to hijack the skeleton and promote bone metastasis. This has led to the development and widespread clinical use of bone-targeted drugs to prevent skeletal-related events. This understanding has also identified a critical dependency between colonizing tumour cells and the cells of bone. This is particularly important when tumour cells first arrive in bone, adapt to their new microenvironment and enter a long-lived dormant state. In this Review, we discuss the role of different bone cell types in supporting disseminated tumour cell dormancy and reactivation, and highlight the new opportunities this provides for targeting the bone microenvironment to control dormancy and bone metastasis.
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P.I.C. acknowledges the support of Mrs Janice Gibson and the Ernest Heine Family Foundation, the Cancer Council New South Wales, the Prostate Cancer Foundation of Australia, the Wellcome Trust, Leukaemia and Lymphoma Research and Cancer Research UK. T.J.M. acknowledges research support from the National Health and Medical Research Council (Australia) and the Victorian Government OIS Program.
The authors declare no competing financial interests.
- Bone resorption
The process by which bone-resorbing cells break down bone.
- Osteoblast lineage
The lineage of cells responsible for making new bone.
Cells that are derived from skeletal stem cells with the ability to transition through the osteogenic lineage.
Cells that are committed to forming functional bone-forming osteoblasts.
The process by which mineral, including hydroxyapatite, is precipitated and deposited on a collagen matrix.
Cells located adjacent to endothelial cells of capillaries.
Macrophages associated with the bone surface.
- Osteogenic lineage
The lineage that gives rise to cells that can make new bone; these include bone lining cells, osteoblasts and osteocytes.
- Basic multicellular units
The cells responsible for the coordinated removal and replacement of a quantum of bone in bone remodelling.
A disorder of the parathyroid gland resulting in increased concentrations of circulating parathyroid hormone.
- Bone marrow stromal progenitor cells
A population of stromal cells found in the bone marrow that can differentiate into a range of cell types including cells of the osteogenic lineage.
- Reversal phase
The phase of bone remodelling between bone formation and bone resorption.
- Endochondral ossification
One of the essential processes by which bone is formed via a cartilage cell precursor.
The microscopic canals that link the lacunae occupied by osteocytes.
- Innate immune system
The cells and mechanisms present in readiness to fight microorganisms.
- Elastic modulus
A measure of the elasticity or stiffness of a material.
- Metaphyseal region
The section of a long bone between the diaphysis (shaft) and epiphysis (end).
- Diaphyseal region
The midsection or shaft of a long bone.
- Metastasis initiating cells
Cancer cells with the ability to give rise to overt metastasis in distant organs.
- Cancer stem cells
Cancer cells with self-renewal and tumour-initiating abilities.
- Monoclonal gammopathy of unknown significance
(MGUS). A disorder characterized by the presence in the blood of an abnormal protein that is produced by plasma cells that in some individuals can transition to multiple myeloma.
- Perivascular niche
A specialized microenvironment located adjacent to blood vessels that supports the long-term survival of specific cell types, including stem or progenitor cells.
The bones of the skull (cranium) that protect the brain.
- Two-photon photoconversion
The use of two-photon excitation light to convert the emission spectra of a photoconvertible fluorescent probe from one colour (for example, green) to another (for example, red).
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Croucher, P., McDonald, M. & Martin, T. Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer 16, 373–386 (2016). https://doi.org/10.1038/nrc.2016.44
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