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Tumor-derived Exosomes Induced M2 Macrophage Polarization and Promoted the Metastasis of Osteosarcoma Cells Through Tim-3.

肿瘤来源的外泌体诱导M2巨噬细胞极化,并通过Tim-3促进骨肉瘤细胞的转移。

  • 影响因子:2.10
  • DOI:10.1016/j.arcmed.2020.10.018
  • 作者列表:"Cheng Z","Wang L","Wu C","Huang L","Ruan Y","Xue W
  • 发表时间:2021-02-01
Abstract

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, epithelial-mesenchymal transition (EMT), and lung metastasis of osteosarcoma cells through the secretion of cytokines including IL-10, TGF-β, 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.

摘要

前言: 骨肉瘤是最常见的骨原发性恶性肿瘤,常表现为高度亚临床转移性疾病,在极早期转移。外泌体作为分子信息载体,可能通过肿瘤相关巨噬细胞 (TAMs) 的致癌分子重编程,在肿瘤的发生发展过程中发挥强有力的作用。在这项研究中,我们将研究骨肉瘤衍生的外泌体对TAMs极化的影响,并破译其潜在的分子机制。 材料和方法: 从MG63细胞中分离骨肉瘤来源的外泌体,并通过透射电镜和纳米粒径分析进行表征。进行双重荧光染色以确认巨噬细胞对外泌体的吞噬作用。进行蛋白质印迹、qRT-PCR和transwell测定以评估外泌体对迁移、侵袭和巨噬细胞分化的影响。建立骨肉瘤小鼠模型,评价外泌体对体内肺转移的影响。 结果: 成功分离出MG63外泌体,并通过荧光共聚焦显微镜证实其被巨噬细胞吞噬。结果表明,骨肉瘤细胞主要通过外泌体介导的Tim-3诱导M2型巨噬细胞分化,并通过分泌IL-10、TGF-β 、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。 结论: 骨肉瘤来源的外泌体可诱导巨噬细胞的M2极化,促进肿瘤的侵袭和转移达到Tim-3,为今后的研究提供了新的治疗靶点。

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