Mesenchymal stem cells (MSCs) have recently been used in several pre-clinical and clinical studies to support hematopoiesis after hematopoietic stem cell transplantation (HSCT), to control graft versus host disease after allogeneic HSCT or for gene therapy in cancer. Although it is believed that MSCs have therapeutical potential for these particular applications,several studies have shown that MSCs might also play an active role in the pathogenesis and progression of tumors.
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells (PCs), which are predominantly localized in the bone marrow (BM). Mesenchymal stem cells (MSCs) give rise to most bone marrow stromal cells that interact with MM cells. However, the direct effect of MSCs on the growth control of MM cells has not been addressed. In the present study, we showed by in vitro migration assays that human MSCs are attracted by MM cells and that CCL25 is a major MM cell-produced chemoattractant stimulating chemotaxis of MSCs through CCR9. By coculture experiments we found that MSCs favor the proliferation of stroma-dependent MM cells through secretion of soluble factors and cell to cell contact.
This growth promoting effect was also demonstrated by intrafemoral co-engraftment experiments in the in vivo mouse myeloma model 5T33MM. In addition we demonstrated that MSCs protect MM cells in vitro against spontaneous and Bortezomib-induced apoptosis. The tumor-promoting effects of MSCs correlates with their capacity to activate in MM cells AKT and ERK activities, accompanied with increased expresson of CyclinD2, CDK4 and Bcl-XL, and decreased cleaved caspase-3 and PARP expression. In turn, MM cells were found to upregulate 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, we demonstrated that intraveneous injection of in vitro expanded murine MSCs (mMSCs) in 5T33MM mice results in a signifi cantly shorter survival as compared to the control group, being injected with MM cells without mMSCs (p<0.05). Our data suggest that MSC-based cytotherapy has a potential risk to stimulate MM disease progression and/or relapse and should therefore be considered with caution in the treatment of MM patients after hematopoietic stem cell transplantation.
Original languageEnglish
Pages (from-to)254-255
Number of pages2
JournalBone Marrow Transplantation
Volume46
Issue number2011
Publication statusPublished - 4 Apr 2011
EventUnknown -
Duration: 4 Apr 2011 → …

    Research areas

  • multiple myeloma, stem cell transplantation

ID: 2024238