Tumor-derived Exosomes Induced M2 Macrophage Polarization and Promoted the Metastasis of Osteosarcoma Cells Through Tim-3
Tumor-derived Exosomes Induced M2 Macrophage Polarization and Promoted the Metastasis of Osteosarcoma Cells Through Tim-3
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DOI：
10.1016/j.arcmed.2020.10.018
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发表时间：
2021-02-25
影响因子：
7.7
通讯作者：
Xue, Wei
中科院分区：
文献类型：
--
作者：
Cheng, Zhonghua;Wang, Liqin;Xue, Wei
导论.骨肉瘤是最常见的原发性骨恶性肿瘤，常表现为高度亚临床转移性疾病，在非常早期就发生转移。外泌体作为分子信息载体，通过肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）的致癌分子重编程，在肿瘤的发生发展中发挥重要作用。在这项研究中，我们将研究骨肉瘤来源的外泌体对TAM极化的影响，并解释其潜在的分子机制。从MG 63细胞中分离骨肉瘤来源的外泌体，并通过透射电子显微镜和纳米粒度分析进行表征。进行双重荧光染色以确认巨噬细胞对外来体的吞噬作用。进行蛋白质印迹、qRT-PCR和transwell测定以评估外来体对迁移、侵袭和巨噬细胞分化的影响。建立小鼠骨肉瘤模型，观察exosomes对小鼠骨肉瘤肺转移的影响。成功分离出MG 63外泌体，并通过荧光共聚焦显微镜证实其被巨噬细胞吞噬。结果显示，骨肉瘤细胞可通过外泌体介导的Tim-3诱导巨噬细胞向M2型分化，而巨噬细胞通过分泌IL-10、TGF-β和VEGF等细胞因子促进骨肉瘤细胞的迁移、侵袭、上皮间质转化（EMT）和肺转移。我们的研究结果表明，骨肉瘤源性exosomes诱导M2极化的巨噬细胞，并通过Tim-3促进肿瘤的侵袭和转移;此外，该研究也为未来的研究提供了一个新的治疗靶点。(C)2021年IMSS。爱思唯尔公司出版
Introduction. Osteosarcoma, the most prevalent primary malignancy of the bone, is often presented with high-grade subclinical metastatic disease that metastasizes at very early stages. Exosomes, as molecular information carriers, may play a potent role in the occurrence and development of tumors through oncogenic molecular reprogramming of tumor-associated macrophages (TAMs). In this study, we will investigate the effect of osteosarcoma-derived exosomes on the polarization of TAMs and decipher its underlying molecular mechanism.Material and Methods. Osteosarcoma-derived exosomes from MG63 cells were isolated and characterized by transmission electron microscopy, and nano-particle size analysis. Double fluorescence staining was performed to confirm the macrophages phagocytosis of exosomes. Western blot, qRT-PCR, and transwell assays were conducted to assess the effect of exosomes on migration, invasion, and macrophage differentiation. The mouse model of osteosarcoma was established to evaluate the effects of exosomes on lung metastasis in vivo.Results. MG63 exosomes were successfully isolated and verified to be phagocytized by macrophages through fluorescence confocal microscopy. The results revealed that osteosarcoma cells could induce M2 type differentiation of macrophages largely through Tim-3 mediated by exosomes, which in turn could promote the migration, invasion, epithelialmesenchymal transition (EMT), and lung metastasis of osteosarcoma cells through the secretion of cytokines including IL-10, TGF-beta, and VEGF.Conclusions. Our results demonstrated that osteosarcoma-derived exosomes induced M2 polarization of macrophages and promoted the invasion and metastasis of tumors through Tim-3; besides, the study also suggests a novel therapeutic target for future studies. (C) 2021 IMSS. Published by Elsevier Inc.