Abstract
Emerging evidence indicates that M2-polarized tumor-associated macrophages (TAMs) directly participate in tumor initiation, progression and metastasis. However, to date, few studies have investigated novel strategies for inhibiting TAMs in order to overcome osteosarcoma. In this study, we reported that M2 macrophages were enriched in osteosarcoma tissues from patients, and M2-polarized TAMs enhanced cancer initiation and stemness of osteosarcoma cells, thereby establishing M2-polarized TAMs as a therapeutic target for blocking osteosarcoma formation. We also found that all-trans retinoic acid (ATRA) weakened TAM-induced osteosarcoma tumor formation by inhibiting M2 polarization of TAMs in vivo, and inhibited the colony formation, as well as sphere-formation capacity of osteosarcoma cells promoted by M2-type macrophages in vitro. Furthermore, M2-type macrophages enhanced cancer stem cells (CSCs) properties as assessed by increasing the numbers of CD117+Stro-1+ cells accompanied by the upregulation of CSC markers (CD133, CXCR4, Nanog, and Oct4), which could clearly be reduced by ATRA. Taken together, the results of this study demonstrated the role of M2-polarized TAMs in osteosarcoma initiation and stemness by activating CSCs, and indicated that ATRA treatment is a promising approach for treating osteosarcoma by preventing M2 polarization of TAMs.
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Acknowledgements
This work was supported by the State Key Program of the National Natural Science Foundation of China (81830107 to QJH) and by grants from the National Natural Science Foundation of China (81473225 to QJH, 81803552 to XJS, and 81603126 to NZ).
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QJH, MDY, QZ, and XJS designed the research project; QZ, XJS, SFX, and YQC performed the experiments; QJH, MDY, QZ, XJS, JC, HZ, and BY analyzed the data; NZ contributed patient samples; and QJH, MDY, QZ, and XJS wrote the paper.
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Shao, Xj., Xiang, Sf., Chen, Yq. et al. Inhibition of M2-like macrophages by all-trans retinoic acid prevents cancer initiation and stemness in osteosarcoma cells. Acta Pharmacol Sin 40, 1343–1350 (2019). https://doi.org/10.1038/s41401-019-0262-4
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DOI: https://doi.org/10.1038/s41401-019-0262-4
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