All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages

• Published in: Cancer immunology research 2017-07, Vol.5 (7), p.547-559
• Main Authors: Zhou, Qian, Xian, Miao, Xiang, Senfeng, Xiang, Danyan, Shao, Xuejing, Wang, Jincheng, Cao, Ji, Yang, Xiaochun, Yang, Bo, Ying, Meidan, He, Qiaojun
• Format: Article
• Language: English
• Subjects: Animals; CCAAT-Enhancer-Binding Protein-beta - genetics; Cell Line, Tumor; Humans; Interleukin-13 - genetics; Interleukin-4 - genetics; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Macrophages - drug effects; Macrophages - immunology; Macrophages - pathology; Matrix Metalloproteinase 12 - genetics; Mice; Neoplasm Metastasis; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - immunology; Osteosarcoma - pathology; RAW 264.7 Cells; Signal Transduction - drug effects; STAT3 Transcription Factor - genetics; Tretinoin - administration & dosage
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.cir-16-0259

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 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 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. .