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

Abstract

Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.

Keywords: bone marrow mesenchymal stromal cells; multiple myeloma; myeloma progression.

Figure 1

Hypothetical transition from HD-MSCs to myeloma MM-MSCs mediated by interaction with MM cells. Interaction of MGUS and smMM plasma cells with MSCs is considered an initiating event. Direct contact of myeloma cells and MSCs, together with soluble factors (dashed arrows) and EVs (solid arrows) induce various layers of modifications in MSCs (phenotypic, gene expression, genomic, miRNA, and epigenetic), contributing to the transition from HD- to MM-MSCs and to myeloma pathology. Epigenetic modifications may be responsible for maintenance of MM-MSC features in absence of myeloma cell interactions.

Figure 2

MSC- mediated biological activity in the BM microenvironment of MM. The MSC and myeloma cell cross-talk (through adhesion molecules, via soluble factors, or by extracellular vesicles derived from MM cells or MSCs) actively contributes to the pathology of the disease. The MSC—MM cell interactions increase MM growth and survival, induce drug resistance, promote myeloma dissemination and homing, support myeloma bone disease through impaired OB while favoured adipocyte differentiation and promotion of OC formation, and additionally contribute to a pro-inflammatory and immunosuppressive microenvironment.