Wang Piaopiao, Yang Lei, Dong Jing, Liu Wenjing, Xie Fan, Lu Yan, Li Wenyan
Department of Clinical Pharmacy, Gongli Hospital of Shanghai Pudong New Area, 219, Miaopu Road, Pudong New Area, 200135, Shanghai, China.
Department of Orthopedics, Taizhou School of Clinical Medicine, Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 225300, Taizhou, Jiangsu, China.
Cancer Cell Int. 2024 Aug 31;24(1):301. doi: 10.1186/s12935-024-03488-x.
Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).
小细胞外囊泡（sEVs）是肿瘤细胞与其周围环境之间细胞间通讯的重要介质。此外，肿瘤sEVs中携带的miRNAs调节巨噬细胞极化的机制在很大程度上仍不清楚。为了浓缩sEVs，我们使用了传统的超速离心方法。采用蛋白质免疫印迹法、纳米可视技术和透射电子显微镜对sEVs进行鉴定。为了确定sEVs-miR-487a的功能，我们进行了体内和体外研究。通过荧光素酶报告基因检测、Transwell检测和蛋白质免疫印迹分析，验证了携带miR-487a的sEVs介导的骨肉瘤细胞与M2巨噬细胞之间的细胞间通讯机制。在体外，富含miR-487a的sEVs将miR-487a传递给巨噬细胞，促进巨噬细胞向M2样类型极化，从而促进骨肉瘤细胞的增殖、迁移、侵袭和上皮-间质转化（EMT）。在体内，富含miR-487a的sEVs促进骨肉瘤的肺转移。此外，sEVs中的血浆miR-487a被证明是一种适用于骨肉瘤诊断的潜在生物标志物。总之，源自骨肉瘤细胞的miR-487a可通过sEVs转移至巨噬细胞，然后通过靶向Notch2并激活GATA3途径促进巨噬细胞向M2样类型极化。在一个反馈回路中，巨噬细胞的激活加速上皮-间质转化（EMT），进而促进骨肉瘤细胞的迁移、侵袭和肺转移。活化的巨噬细胞与骨肉瘤细胞之间的这种相互作用促进了疾病的进展。我们的数据证明了一种新机制，即骨肉瘤肿瘤细胞衍生的外泌体-miR-487a通过调节肿瘤微环境（TME）中的巨噬细胞极化参与骨肉瘤的发展。
