Myeloid-Derived Suppressor Cells Function as Novel Osteoclast Progenitors Enhancing Bone Loss in Breast Cancer

Abstract

Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth but the factors contributing to aggressive bone destruction are not well understood. In this study, we demonstrate the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Since MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression.

Induction of osteoclast progenitors in inflammatory conditions: key to bone destruction in arthritis

“…In addition, OCPs shared the phenotype with the myeloid-derived suppressor cell (MDSC) population and exerted an immunomodulatory function upon a co-adoptive transfer with SKG CD4 + T lymphocytes. Sawant et al also observed that bone marrow CD11b + Gr-1 + CD80 lo CD115 + F4/80 -MDSCs of breast tumor-bearing mice, found among the immature myeloid population, can be differentiated into functional osteoclasts [34].…”

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

“…MDSCs (CD11b þ Gr-1 þ ) obtained from the bone marrow of mice with murine breast cancer cell line 4T1 bone metastases (MDSCs þ bone mets ) differentiate into TRAP-positive, bone resorptive osteoclasts in vitro and express CTSK, carbonic anhydrase-2, MMP-9 and NO. 56 However, MDSCs from the bone marrow of mice without bone metastases, regardless of other metastatic sites (lung, lymph node, spleen or blood), do not differentiate into osteoclasts, suggesting that the osteoclast differentiation of MDSCs is unique to the bone metastatic environment. 56 In addition, when MDSCs þ bone mets are transplanted, osteoclast differentiation of MDSCs þ bone mets and bone distraction are observed in recipient mice.…”

“…56 However, MDSCs from the bone marrow of mice without bone metastases, regardless of other metastatic sites (lung, lymph node, spleen or blood), do not differentiate into osteoclasts, suggesting that the osteoclast differentiation of MDSCs is unique to the bone metastatic environment. 56 In addition, when MDSCs þ bone mets are transplanted, osteoclast differentiation of MDSCs þ bone mets and bone distraction are observed in recipient mice. 56 Interestingly, both in vitro and in vivo osteoclastogenesis mediated by MDSCs þ bone mets are inhibited by blocking NO.…”

“…56 In addition, when MDSCs þ bone mets are transplanted, osteoclast differentiation of MDSCs þ bone mets and bone distraction are observed in recipient mice. 56 Interestingly, both in vitro and in vivo osteoclastogenesis mediated by MDSCs þ bone mets are inhibited by blocking NO. 56 The high NO production in MDSCs þ bone mets enhances HIF-1a expression through the PIK3 or ERK pathway.…”

“…56 Interestingly, both in vitro and in vivo osteoclastogenesis mediated by MDSCs þ bone mets are inhibited by blocking NO. 56 The high NO production in MDSCs þ bone mets enhances HIF-1a expression through the PIK3 or ERK pathway. 56 …”