RT Journal Article
SR Electronic
T1 All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 547
OP 559
DO 10.1158/2326-6066.CIR-16-0259
VO 5
IS 7
A1 Zhou, Qian
A1 Xian, Miao
A1 Xiang, Senfeng
A1 Xiang, Danyan
A1 Shao, Xuejing
A1 Wang, Jincheng
A1 Cao, Ji
A1 Yang, Xiaochun
A1 Yang, Bo
A1 Ying, Meidan
A1 He, Qiaojun
YR 2017
UL http://cancerimmunolres.aacrjournals.org/content/5/7/547.abstract
AB M2-polarized tumor-associated macrophages (TAM) play a critical role in cancer invasion and metastasis. Here, we report that M2 macrophages enhanced metastasis of K7M2 WT osteosarcoma cells to the lungs in mice, thus establishing M2 TAMs as a therapeutic target for blocking osteosarcoma metastasis. We found that all-trans retinoic acid (ATRA) inhibited osteosarcoma metastasis via inhibiting the M2 polarization of TAMs. ATRA suppressed IL13- or IL4-induced M2-type macrophages, and then inhibited migration of osteosarcoma cells as promoted by M2-type macrophages in vitro. ATRA reduced the number of pulmonary metastatic nodes of osteosarcoma and decreased expression of M2-type macrophages in metastatic nodes both in intravenous injection and orthotopic transplantation models. ATRA's effect was independent of conventional STAT3/6 or C/EBPβ signaling, which regulate M2-like polarization of macrophages. Quantitative genomic and functional analyses revealed that MMP12, a macrophage-secreted elastase, was elevated in IL13-skewed TAM polarization, whereas ATRA treatment downregulated IL13-induced secretion of MMP12. This downregulation correlates with the antimetastasis effect of ATRA. Our results show the role of TAM polarization in osteosarcoma metastasis, identify a therapeutic opportunity for antimetastasis treatment, and indicate ATRA treatment as an approach for preventing osteosarcoma metastasis via M2-type polarization intervention. Cancer Immunol Res; 5(7); 547–59. ©2017 AACR.