BoneKEy Reports | BoneKEy Watch
The role of MDSCs in bone metastasis and cancer-related osteolysis
DOI:10.1038/bonekey.2013.45
Myeloid-derived suppressor cells (MDSCs) are responsible for cancer-associated immunosuppression during cancer progression, but their role in bone destruction in cancer is less well understood.
Danilin et al. investigated the role of MDSCs in the development of bone metastases using a nude mouse model, which eliminated the effects of interactions between MDSCs and T cells. Breast cancer cells were introduced into the 4th mammary fat pad and coinjected with either tumor-induced MDSCs or naive MDSCs. Mice in the first group developed tumors with a higher mean volume (2.7 times those in the naive group) and some developed lung metastases (there were none in the naive group). Although no bone metastases were detectable, bone mass in the tumor-induced MDSC group was compromised, with reduced bone volume, fewer trabeculae and reduced trabecular thickness.
Further studies showed that MDSCs cultured with macrophage colony-stimulating factor and RANK ligand differentiated into osteoclasts. Tumor-induced MDSCs were also able to increase parathyroid hormone-related protein mRNA levels within cancer cells, probably due to upregulation of transforming growth factor β expression.
Sawant et al used an immunocompetent mouse model of breast cancer metastasis to show that MDSCs derived from a tumor-bone microenvironment undergo differentiation into osteoclasts in vivo and in vitro. Significant elevation of nitric oxide (NO) levels was observed in MDSCs from bone metastases as they differentiated into osteoclasts, and treatment with an NO inhibitor in vitro prevented this process effectively, demonstrating that NO was essential. Further experiments revealed that the mechanism involved was dependent on HIF-1α signaling. The authors conclude that as part of the process of metastatic cancer, MDSCs in bone differentiate into functional osteoclasts, which then actively resorb and weaken bone.
Editor’s comment: These two elegant studies demonstrate that MDSCs from animals bearing breast tumors have the capacity to differentiate into bone-resorbing cells, thereby promoting osteolysis. Zhuang et al also recently showed that MDSCs from myeloma-bearing mice have a greater capacity to differentiate into osteoclast-like cells compared to MDSCs from control mice. Taken together, all of these findings highlight the importance of MDSCs in cancer-associated bone destruction and underline the potential of targeting MDSCs with anti-resorptive therapies to limit their expansion and differentiation in the bone marrow.
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