Inhibition of multiple myeloma-derived exosomes uptake suppresses the functional response in bone marrow stromal cell

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.