Vrije Universiteit Brussels, Brussel, Belgium Key Points• BMSCs and MM cells mutually communicate through exosomes, which carry selective cytokines.• BMSC-derived exosomes favor MM cell proliferation, migration, and survival and induce drug resistance to bortezomib.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. (Blood. 2014;124(4):555-566) IntroductionMultiple myeloma (MM) is a deadly hematological malignancy characterized by the uncontrolled growth and accumulation of monoclonal plasma cells in the bone marrow (BM), the presence of a monoclonal immunoglobulin fraction in the serum or urine, 1,2 renal failure, and osteolytic bone lesions.3 MM cells depend on the BM microenvironment for their growth and survival through interaction with the BM stromal cells (BMSCs). BMSCs consist mainly of fibroblasts and can secrete different kinds of cytokines, chemokines, growth factors, and small molecular mediators. 4 These functional components trigger MM growth, survival, and progression through several signaling pathways, such as mitogen-activated protein kinase kinase/mitogen-activated protein kinase, focal adhesion kinase, phosphatidylinositol 3-kinase/Akt, MEK/extracellular signal-regulated kinase, and signal transducer and activator of transcription 3, 5 which will ultimately lead to angiogenesis, bone disease, and drug resistance.Exosomes are small (40-100 nm) membrane vesicles secreted by various cell types, including dendritic cells, B cells, T cells, mast cells, epithelial cells, and tumor cells, 6 through the fusion of multivesicular bodies with the plasma membrane.7 Exosomes mediate local cell-to-cell communication by transferring mRNAs, miRNAs, and proteins. Because of their ability to transfer functional com...

Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or ‘exosomes’, not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.

Exosomes, extracellular nanovesicles secreted by various cell types, modulate the bone marrow (BM) microenvironment by regulating angiogenesis, cytokine release, immune response, inflammation, and metastasis. Interactions between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells play crucial roles in MM development. We previously reported that BMSC-derived exosomes directly promote MM cell growth, whereas the other possible mechanisms for supporting MM progression by these exosomes are still not clear. Here, we investigated the effect of BMSC-derived exosomes on the MM BM cells with specific emphasis on myeloid-derived suppressor cells (MDSCs). BMSC-derived exosomes were able to be taken up by MM MDSCs and induced their expansion in vitro. Moreover, these exosomes directly induced the survival of MDSCs through activating STAT3 and STAT1 pathways and increasing the anti-apoptotic proteins Bcl-xL and Mcl-1. Inhibition of these pathways blocked the enhancement of MDSC survival. Furthermore, these exosomes increased the nitric oxide release from MM MDSCs and enhanced their suppressive activity on T cells. Taken together, our results demonstrate that BMSC-derived exosomes activate MDSCs in the BM through STAT3 and STAT1 pathways, leading to increased immunosuppression which favors MM progression.

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