Inhibition of M2-like macrophages by all-trans retinoic acid prevents cancer initiation and stemness in osteosarcoma cells

Xue-jing Shao1, Sen-feng Xiang1, Ying-qian Chen1, Ning Zhang2, Ji Cao1, Hong Zhu1, Bo Yang1, Qian Zhou1,3, Mei-dan Ying1, Qiao-jun He1
1 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou 310009, China
3 Department of Pharmacy, Hangzhou Medical College, Hangzhou 310053, China
Correspondence to: Qian Zhou:, Mei-dan Ying:, Qiao-jun He:,
DOI: 10.1038/s41401-019-0262-4
Received: 24 January 2019
Accepted: 22 May 2019
Advance online: 11 July 2019


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.
Keywords: osteosarcoma; ATRA; tumor-associated macrophages; M2 polarization; cancer initiation; stemness

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