Exosomal communication in the bone marrow microenvironment: a significant player in multiple myeloma progression

Multiple Myeloma (MM) is an incurable plasma cell neoplasm characterized by an accumulation of malignant plasma cells in the bone marrow (BM). Its pathogenesis and progression largely rely on the cells and extracellular factors in the BM microenvironment. The interplay between bone marrow stromal cells (BMSCs) and MM cells plays a crucial role in MM pathogenesis by the secretion of growth factors, cytokines, and extracellular vesicles. Exosomes are 40-100 nm diameter membranous vesicles constitutively released by almost all cell types and they mediate local cell-cell communication by transferring mRNAs, miRNAs and proteins. However, the roles of BMSC- or MM cell-derived exosomes in the cell-to-cell communication and MM progression have not been elucidated yet. In the present study, we demonstrated the involvement of exosomes in the communication between BMSCs and MM cells, and revealed that BMSC-derived exosomes directly facilitated MM progression by promoting MM cell proliferation, migration, survival, and induction of drug resistance through multiple signaling pathways including JNK, p38, p53, and Akt. In addition, BMSC-derived exosomes activated MDSCs in the BM through STAT3 and STAT1 pathways, leading to increased immunosuppression which favors MM progression. Moreover, MM cell-derived exosomes can modify the BM microenvironment by promoting BMSC growth, angiogenesis, and enhancement of the immunosuppressive capacity of MDSCs. The modified BM microenvironment by both BMSC- and MM cell-derived exosomes will further facilitate MM cell growth, MM progression, and induction of drug resistance. This study highlights a novel communication mechanism between BMSCs and MM cells through exosome secretion and confirms that exosomes secreted by these cells support MM progression. This work contributes to our better understanding of the BM interactions in MM development and could lead to identification of novel therapeutic targets.