Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects

Abstract

Hematologic malignancies rely heavily on support from host cells through a number of well-documented mechanisms. Host cells, specifically mesenchymal stem cells (MSC), support tumor cell growth, metastasis, survival, bone marrow colonization, and evasion of the immune system. In multiple myeloma, similar to solid tumors, supporting cells have typically been considered healthy host cells. However, recent evidence reveals that many MSCs derived from patients with multiple myeloma (MM-MSC) show significant defects compared with MSCs from nondiseased donors (ND-MSC). These abnormalities range from differences in gene and protein expression to allelic abnormalities and can initiate after less than 1 day of coculture with myeloma cells or persist for months, perhaps years, after removal from myeloma influence. Alterations in MM-MSC function contribute to disease progression and provide new therapeutic targets. However, before the scientific community can capitalize on the distinctions between MM-MSCs and ND-MSCs, a number of confusions must be clarified, as we have done in this review, including the origin(s) of MM-MSCs, identification and characterization of MM-MSCs, and downstream effects and feedback circuits that support cancer progression. Further advances require more genetic analysis of MM-MSCs and disease models that accurately represent MSC-MM cell interactions.

Figure 1. MM-MSC Origination

Theories regarding how MM-MSCs originate have been proposed and include the following. A) Soluble mediators released from myeloma cells can activate MSCs. B) Cell-cell contact is required between myeloma cells and MSCs to activate MSCs. C) Effects of MM-MSCs can actually be traced back to contaminating CD11b+ myeloid cells, which are the true population of cells that are able to affect tumor cells. D) MM-MSCs and myeloma cells are derived from a common progenitor cell, a theory which has been proven incorrect. E) Genetic abnormalities and chromosomal aberrations within MM-MSCs may exist and could affect their phenotype.

Figure 2. Phenotypic Differences: MM-MSCs vs Healthy-MSCs

Diagram of the phenotypic differences currently described between MM-MSCs and healthy, non-diseased MSCs. As compared to healthy MSCs, MM-MSCs have the following trais. Increased expression of EphB4 receptor, ICAM, VCAM, IL3, IL6, IL10, IL1β, VEGF, SCF, TNFα, TGFβ1, BAFF, HGF, RANKL, DKK1, GDF15, HoxB, MMP1, and MMP2. Decreased expression of MMP3, TGF-β2, TGF-β3, FasL, and Has1. Increased production of fibronectin, osteopontin, and hyaluronan. Reduced immunosuppressive properties due to a loss in the ability to inhibit T-cells. Downstream effects of MM-MSCs on myeloma cells include increased chemotherapeutic resistance, Bcl-2 signaling, and NF-κB signaling and increased cancer stem cell population concentrations.