The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells

Abstract

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.

EphA4 promotes cell proliferation and cell adhesion–mediated drug resistance via the AKT pathway in multiple myeloma

“…9 Here, the malignant plasma cells disseminate in the BM microenvironment through interactions of the adhesion molecules on the surface of MM cells and the BM extracellular matrix (ECM) components and receive multiple signals that maintain their long survival and exert protective effects against drug-induced apoptosis. 10,11 The phenomenon was widely known as cell adhesion-mediated EphA4 promotes cell proliferation and cell adhesion-mediated drug resistance via the AKT pathway in multiple myeloma drug resistance (CAM-DR). Unfortunately, we know little about the molecular mechanisms underlying the CAM-DR which facilitates many people to explore further.…”

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography

“…The pre-clinical study indicates the role of local bone marrow environment and survival of leukemia cells or leukemia resistance leading to treatment relapse (8–11). Similarly, the role of bone marrow microenvironment in multiple myeleoma development is also reported (12). Following HCT, expanded adipocyte populations may negatively influence post-transplant hematopoietic engraftment (13).…”

Prostate cancer exosomes as modulators of the tumor microenvironment

“…Similar modulation of myeloid cells are seen using pancreatic cancer exosomes, giving a suppressive CD14 + HLA-DR low/neg phenotype akin to those elevated within the circulation of patients [94] . Similarly, myeloma-derived EV present within the bone marrow microenvironment can activate myeloid-derived suppressor cells (MDSC) and promote progression [95] . In acute myeloid leukemia, vesicles may play a role in modulating normal myeloporesis and select for cells destined for suppressor-like differentiation [96,97] .…”