Exosomal miRNAs in the Tumor Microenvironment of Multiple Myeloma

Abstract

Multiple myeloma (MM) is a malignancy of plasma cells in the bone marrow and is characterized by the clonal proliferation of B-cells producing defective monoclonal immunoglobulins. Despite the latest developments in treatment, drug resistance remains one of the major challenges in the therapy of MM. The crosstalk between MM cells and other components within the bone marrow microenvironment (BME) is the major determinant of disease phenotypes. Exosomes have emerged as the critical drivers of this crosstalk by allowing the delivery of informational cargo comprising multiple components from miniature peptides to nucleic acids. Such material transfers have now been shown to perpetuate drug-resistance development and disease progression in MM. MicroRNAs(miRNAs) specifically play a crucial role in this communication considering their small size that allows them to be readily packed within the exosomes and widespread potency that impacts the developmental trajectory of the disease inside the tumor microenvironment (TME). In this review, we aim to provide an overview of the current understanding of the role of exosomal miRNAs in the epigenetic modifications inside the TME and its pathogenic influence on the developmental phenotypes and prognosis of MM.

Keywords: drug resistance; exosomal miRNA; exosome; multiple myeloma.

Figure 1

Exosomal miRNAs profile in the pathogenesis of MM. During the progression of MGUS to SMM, the profile of exosomal miRNAs changes towards an immune-suppressive and tumorigenic profile [18].

Figure 2

Schematic representation of the potential exosomal miRNA-mediated interactions in the BM microenvironment. Exosomes mediate bidirectional crosstalks between the TME components through shuttling functional molecules, including exosomal miRNAs. MM cells release exosomes with oncomiR cargo that supports tumor progression and/or drug resistance, produces cancer-associated fibroblasts (CAFs), prevents apoptosis, promotes angiogenesis, promotes the expansion of myeloid-derived suppressor cells (MDSCs), and induces an immunosuppressive microenvironment. Other components, in turn, promote the proliferation and survival of tumor cells and support disease progression by the secretion of specific exosomal miRNAs.

Figure 3

The applications of the exosomal miRNAs in the clinical practice: Exosomal miRNAs are potential diagnostic biomarkers for early detection of MM progress and they are examined for their prognostic potential. In addition, exosomes can be engineered for delivery of therapeutic miRNAs to increase their expression or targeting them to improve the immune response or induction of MM cell apoptosis by reprograming gene expression in the target cells (blue downward arrow shows downregulation and orange upward arrow shows upregulation of miRNAs).