Abstract
Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.
Highlights
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada
T-regulatory cells (Tregs) numbers are increased in prostate cancer patients with bone metastasis [183], and this may be due in part to active recruitment and retention of Tregs in the bone marrow by CXCR4/CXCL12-mediated signaling [184], a pathway that is often upregulated in disseminated tumor cells (DTC) [185,186,187]
With regard to inducing tumor cell dormancy, Sosa et al have shown that the nuclear receptor NR2F1 which participates in transcriptional regulation [300] is upregulated in DTC in 43% of prostate cancer patients with dormant disease compared to 10% of DTCs in patients with advanced metastatic disease [293]
Summary
Bone marrow is a primary lymphoid organ that fills the medullary cavity in bones. It is highly vascularized being intersected by arterioles and capillaries and surrounded by calcified bone. Osteoblasts have been shown to induce dormancy in prostate cancer tumor cell lines PC3 and DU145 through transforming growth factor (TGF)β signaling [61]. MSC, which can differentiate into osteoblasts, have been shown to produce miRNA-containing exosomes or express soluble factors that alter tumor cell signaling and translation resulting in promotion of quiescence in tumor cells [62,63,64]. This period of microenvironment-induced DTC quiescence may eventually be overcome and the DTC will proliferate and form a micrometastasis. As a result of extensive tumor cell crosstalk with bone-resident cells, micrometastases may overcome tumor mass dormancy to form a highly bone-destructive and pain-inducing macrometastasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
