Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, which are predominantly localized in the bone marrow (BM). Mesenchymal stromal cells (MSCs) give rise to most bone marrow stromal cells that interact with MM cells. However, the direct involvement of MSCs in the pathophysiology of MM has not been well addressed. In this study, in vitro and in vivo migration assays revealed that MSCs have tropism towards MM cells and CCL25 was identified as a major MM cell-produced chemoattractant for MSCs. By coculture experiments, we found that MSCs favor the proliferation of stroma-dependent MM cells through soluble factors and cell to cell contact, which was confirmed by intrafemoral co-engraftment experiments. We also demonstrated that MSCs protected MM cells against spontaneous and Bortezomib-induced apoptosis. The tumor-promoting effect of MSCs correlated with their capacity to enhance in MM cells AKT and ERK activities, accompanied with increased expression of CyclinD2, CDK4 and Bcl-XL, and decreased cleaved caspase-3 and PARP expression. In turn, MM cells upregulated interleukin-6 (IL-6), interleukin-10 (IL-10), insulin growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF) and dickkopf homolog 1 (DKK1) expression in MSCs. Finally, infusion of in vitro expanded murine MSCs in 5T33MM mice resulted in a significantly shorter survival. MSC infusion is a promising way to support hematopoietic recovery and to control GVHD in patients after allogeneic hematopoietic stem cell transplantation. However, our data suggest that MSC-based cytotherapy has a potential risk for MM disease progression or relapse and should be considered with caution in MM patients.
Original languageEnglish
Pages (from-to)266-279
Number of pages14
JournalStem Cells
Issue number2
Publication statusPublished - Feb 2012

    Research areas

  • multiple myeloma, mesenchymal stromal cells, microenvironment, chemokine

ID: 2116280