All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages
All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages
复制标题
全反式视黄酸通过抑制肿瘤相关巨噬细胞的 M2 极化来预防骨肉瘤转移
DOI：
10.1158/2326-6066.cir-16-0259
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发表时间：
2017-07-01
影响因子：
10.1
通讯作者：
He, Qiaojun
中科院分区：
文献类型：
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作者：
Zhou, Qian;Xian, Miao;He, Qiaojun
骨肉瘤肺转移依赖于肿瘤相关巨噬细胞。全反式维甲酸（ATRA）抑制小鼠的这种转移。ATRA下调巨噬细胞分泌的弹性蛋白酶MMP 12的分泌。结果表明，ATRA作为一种可能的抗转移治疗。M2极化的肿瘤相关巨噬细胞（TAM）在肿瘤侵袭和转移中起着关键作用。在这里，我们报告了M2巨噬细胞增强了小鼠K7 M2 WT骨肉瘤细胞向肺的转移，从而建立了M2 TAMs作为阻断骨肉瘤转移的治疗靶点。我们发现全反式维甲酸（ATRA）通过抑制TAM的M2极化而抑制骨肉瘤转移。ATRA可抑制IL 13或IL 4诱导的M2型巨噬细胞的增殖，进而抑制M2型巨噬细胞促进的骨肉瘤细胞迁移。ATRA能减少骨肉瘤肺转移瘤的数目，并能降低骨肉瘤肺转移瘤中M2型巨噬细胞的表达。ATRA的作用不依赖于调节巨噬细胞M2样极化的常规STAT 3/6或C/EBPβ信号。定量基因组和功能分析表明，MMP 12，巨噬细胞分泌的弹性蛋白酶，升高IL 13偏TAM极化，而ATRA治疗下调IL 13诱导的MMP 12分泌。这种下调与ATRA的抗转移作用有关。我们的研究结果显示了TAM极化在骨肉瘤转移中的作用，确定了抗转移治疗的治疗机会，并表明ATRA治疗是通过M2型极化干预预防骨肉瘤转移的一种方法。Cancer Immunol Res; 5（7）; 547-59.©2017 AACR.
Metastasis of osteosarcoma to lung depends on tumor-associated macrophages. All-trans retinoic acid (ATRA) inhibited this metastasis in mice. ATRA downregulated secretion of MMP12, a macrophage-secreted elastase. The results identify ATRA as a possible antimetastasis therapeutic. 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.