Exosomes in the Pathogenesis and Treatment of Multiple Myeloma in the Context of the Bone Marrow Microenvironment

Abstract

Multiple myeloma (MM), the second most common hematological malignancy, is an incurable cancer of plasma cells. MM cells diffusely involves the bone marrow (BM) and establish a close interaction with the BM niche that in turn supports MM survival, proliferation, dissemination and drug resistance. In spite of remarkable progress in understanding MM biology and developing drugs targeting MM in the context of the BM niche, acquisition of multi-class drug resistance is almost universally inevitable. Exosomes are small, secreted vesicles that have been shown to mediate bidirectional transfer of proteins, lipids, and nucleic acids between BM microenvironment and MM, supporting MM pathogenesis by promoting angiogenesis, osteolysis, and drug resistance. Exosome content has been shown to differ between MM patients and healthy donors and could potentially serve as both cancer biomarker and target for novel therapies. Furthermore, the natural nanostructure and modifiable surface properties of exosomes make them good candidates for drug delivery or novel immunomodulatory therapy. In this review we will discuss the current knowledge regarding exosome's role in MM pathogenesis and its potential role as a novel biomarker and therapeutic tool in MM.

Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression

“…More recently, also membrane-limited extracellular vesicles (EVs), both exosomes (Ø 50–150 nm) and microvesicles (Ø 150 nm–1 µm), which in MM are essentially produced by myeloma cells and MSCs, mediate the horizontal transfer of protein, lipids, and nucleic acids in their cargo, conveying information either locally or to cells at distant sites of the BM [ 22 , 23 ]. In fact, EVs have already been described to play roles in myeloma proliferation, development of osteolytic lesions, drug resistance, angiogenesis, and progression (see reviews [ 24 , 25 ]).…”

“…Similarly, ncRNAs are also conveyed from MM-MSC-derived EVs into myeloma cells. The role of EVs targeting MSCs or derived from MM-MSCs in MM pathophysiology will be reviewed in the next section of this manuscript; for the roles of EVs on MSCs in MM, also see comprehensive reviews [ 24 , 58 ].…”

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

“…In addition to their immune-suppressive activity mediated by their secretion of IL-10 (an activator of Tregs and M2 macrophages), and TGF-β (an inhibitor of both cytotoxic T-cells and NK cells), M2 macrophages also promote MM cell proliferation, angiogenesis, and chemotherapy resistance [ 11 , 12 , 13 ] ( Figure 1 A). Nonclinical studies in animal models of MM have demonstrated that exosomes serve as regulators of the signaling networks within the BM microenvironment, activate anti-apoptotic mechanisms promoted by oncogenic proteins such as the signal transducer and activator of transcription 3 (STAT3), and cause immunosuppression by facilitating the growth of MDSCs [ 14 , 15 , 16 , 17 , 18 , 19 ]. Exosome-activated MDSCs have been implicated in development of other immunosuppressive cells, such as Tregs, tumor-promoting angiogenesis, proliferation of MM cells, and increased osteoclast activity contributing to the lytic bone lesions [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Nonclinical studies in animal models of MM have demonstrated that exosomes serve as regulators of the signaling networks within the BM microenvironment, activate anti-apoptotic mechanisms promoted by oncogenic proteins such as the signal transducer and activator of transcription 3 (STAT3), and cause immunosuppression by facilitating the growth of MDSCs [ 14 , 15 , 16 , 17 , 18 , 19 ]. Exosome-activated MDSCs have been implicated in development of other immunosuppressive cells, such as Tregs, tumor-promoting angiogenesis, proliferation of MM cells, and increased osteoclast activity contributing to the lytic bone lesions [ 14 , 15 , 16 , 17 , 18 , 19 ]. Complementing the immunosuppressive TME, T-cell exhaustion combined with high-level expression of immune-checkpoint ligands on MM cells are the main contributors to the immune evasion of MM cells [ 20 , 21 , 22 , 23 ].…”

The Lipoprotein Transport System in the Pathogenesis of Multiple Myeloma: Advances and Challenges

“…Myeloma-derived exosomes are found to promote angiogenesis, osteolysis, plasma cell proliferation, and drug resistance ( 17 – 19 ). Furthermore, compounds that alter the production or the uptake of exosomes are under investigation in preclinical and clinical trials ( 20 ).…”