Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium; Research Center for Immunology, Xinxiang Medical University, Xinxiang, Henan, People's Republic of China;
Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium; and.
Blood. 2014 Jul 24;124(4):555-66. doi: 10.1182/blood-2014-03-562439. Epub 2014 Jun 13.
The interplay between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells performs a crucial role in MM pathogenesis by secreting growth factors, cytokines, and extracellular vesicles. Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and they mediate local cell-to-cell communication by transferring mRNAs, miRNAs, and proteins. Although BMSC-induced growth and drug resistance of MM cells has been studied, the role of BMSC-derived exosomes in this action remains unclear. Here we investigate the effect of BMSC-derived exosomes on the viability, proliferation, survival, migration, and drug resistance of MM cells, using the murine 5T33MM model and human MM samples. BMSCs and MM cells could mutually exchange exosomes carrying certain cytokines. Both naive and 5T33 BMSC-derived exosomes increased MM cell growth and induced drug resistance to bortezomib. BMSC-derived exosomes also influenced the activation of several survival relevant pathways, including c-Jun N-terminal kinase, p38, p53, and Akt. Exosomes obtained from normal donor and MM patient BMSCs also induced survival and drug resistance of human MM cells. Taken together, our results demonstrate the involvement of exosome-mediated communication in BMSC-induced proliferation, migration, survival, and drug resistance of MM cells.
骨髓基质细胞（BMSCs）与多发性骨髓瘤（MM）细胞之间的相互作用通过分泌生长因子、细胞因子和细胞外囊泡在 MM 发病机制中发挥关键作用。外泌体是几乎所有细胞类型都持续释放的直径为 40 至 100nm 的膜性囊泡，通过转移 mRNAs、miRNAs 和蛋白质来介导局部细胞间通讯。尽管已经研究了 BMSC 诱导的 MM 细胞生长和耐药性，但 BMSC 衍生的外泌体在这种作用中的作用尚不清楚。在这里，我们使用鼠 5T33MM 模型和人 MM 样本研究了 BMSC 衍生的外泌体对 MM 细胞活力、增殖、存活、迁移和耐药性的影响。BMSCs 和 MM 细胞可以相互交换携带某些细胞因子的外泌体。幼稚和 5T33 BMSC 衍生的外泌体均增加 MM 细胞生长并诱导硼替佐米耐药。BMSC 衍生的外泌体还影响几种存活相关途径的激活，包括 c-Jun N 末端激酶、p38、p53 和 Akt。来自正常供体和 MM 患者 BMSCs 的外泌体也诱导人 MM 细胞的存活和耐药性。总之，我们的结果表明，外泌体介导的通讯参与了 BMSC 诱导的 MM 细胞增殖、迁移、存活和耐药性。
