Department of Hematology, The Third Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510630, P.R. China.
Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China.
Int J Oncol. 2019 Mar;54(3):1061-1070. doi: 10.3892/ijo.2019.4685. Epub 2019 Jan 11.
The communication between multiple myeloma (MM) cells and bone marrow stromal cells (BMSCs) serves a pivotal role in MM progression by supporting MM cell growth, proliferation and drug resistance. An exosomes‑based endogenous transport system has been determined as a novel mechanism of this communication by revealing the capacity for exchange of functional components between cells. An exosomes transfer‑mediated biological response in recipient cells is strongly determined by the detailed routes and mechanisms of exosomes internalization, which are diverse and can depend on surface molecules on the membrane of the vesicle and the recipient cell. Understanding the routes of exosomes uptake during MM cell‑BMSC communication is of great importance for the development of blocking strategies beneficial for MM treatment. In the present study, fluorescently‑labeled exosomes and pharmacological inhibitors, which are known to interfere with different internalization pathways, were used to characterize the cellular mechanisms involved in the uptake of MM cell‑derived exosomes by BMSCs. MM cell‑derived exosomes can promote BMSC viability and induce changes in multiple pro‑survival and pro‑proliferation pathways in BMSCs. As determined by flow cytometry and confocal microscopy, the uptake of MM cell‑derived exosomes proceeded primarily through endocytosis, via special caveolin‑dependent endocytosis, and partially through macropinocytosis and membrane fusion. Furthermore, treatment with endocytosis inhibitors suppressed the exosomes‑induced changes in pathways in BMSCs. Collectively, these results indicate that endocytosis is the primary route of internalization of MM cell‑derived exosomes by BMSCs and indicate that inhibition of exosomes uptake can interrupt the communication between MM cells and BMSCs and thus serve as a potential adjunctive strategy for MM treatment.
多发性骨髓瘤（MM）细胞与骨髓基质细胞（BMSC）之间的通讯在 MM 进展中起着关键作用，可支持 MM 细胞的生长、增殖和耐药性。通过揭示细胞间功能成分交换的能力，基于外泌体的内源性转运系统已被确定为这种通讯的新机制。外泌体转移介导的受体细胞生物学反应强烈取决于外泌体内化的详细途径和机制，这些途径和机制多种多样，并且可能取决于囊泡和受体细胞膜上的表面分子。了解 MM 细胞-BMSC 通讯中外泌体摄取的途径对于开发有利于 MM 治疗的阻断策略非常重要。在本研究中，使用荧光标记的外泌体和药理学抑制剂（已知可干扰不同的内化途径）来表征 MM 细胞衍生的外泌体被 BMSC 摄取所涉及的细胞机制。MM 细胞衍生的外泌体可促进 BMSC 活力，并诱导 BMSC 中多种促生存和促增殖途径的改变。通过流式细胞术和共聚焦显微镜确定，MM 细胞衍生的外泌体的摄取主要通过内吞作用进行，通过特殊的 caveolin 依赖性内吞作用，部分通过巨胞饮作用和膜融合进行。此外，内吞作用抑制剂的处理抑制了外泌体诱导的 BMSC 中途径的变化。总之，这些结果表明内吞作用是 BMSC 摄取 MM 细胞衍生的外泌体的主要途径，并表明抑制外泌体摄取可以阻断 MM 细胞与 BMSCs 之间的通讯，因此可作为 MM 治疗的潜在辅助策略。
