Lin L Y, Du L M, Cao K, Huang Y, Yu P F, Zhang L Y, Li F Y, Wang Y, Shi Y F
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences and Shanghai Jiao Tong University of Medicine, Shanghai, China.
The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 199 Renai Road, Suzhou, China.
Oncogene. 2016 Nov 17;35(46):6038-6042. doi: 10.1038/onc.2016.131. Epub 2016 May 2.
Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.
间充质基质细胞(MSCs)是肿瘤微环境的主要组成部分。大量专注于肿瘤来源的MSCs的出色研究表明,与其他组织中的正常MSCs不同,它们具有强大的促进肿瘤进展的能力。然而,正常MSCs转化为肿瘤相关MSCs的潜在机制尚不清楚。我们在此报告肿瘤细胞衍生的外泌体在赋予骨髓来源的MSCs(BM-MSCs)肿瘤有利表型方面的关键作用。肿瘤细胞衍生的外泌体既不影响MSCs的生长因子产生,也不影响其免疫抑制特性;相反,它们赋予MSCs强大的促进巨噬细胞浸润到B16-F0黑色素瘤或EL-4淋巴瘤中的能力。通过氯膦酸盐脂质体给药清除巨噬细胞可逆转由肿瘤细胞衍生的外泌体(TE-MSCs)培养的MSCs对肿瘤生长的促进作用。通过比较BM-MSCs与TE-MSCs的趋化因子谱,我们发现TE-MSCs产生大量负责巨噬细胞募集的CCR2配体CCL2和CCL7。发现CCR2特异性抑制剂可阻断TE-MSCs的肿瘤促进作用。因此,我们的研究表明肿瘤细胞衍生的外泌体赋予BM-MSCs增强肿瘤生长的能力。因此,我们揭示了正常MSCs转化为肿瘤相关MSCs的一种新机制。
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