Samenvatting
MSCs are currently used in several pre-clinical and clinical studies to support hematopoiesis after hematopoietic stem cell transplantation (HSCT) and to control graft versus host disease after allogeneic HSCT. They give rise to bone marrow (BM) stromal cells that interact with MM cells and some recent studies revealed that MSCs in myeloma patients might be different from those in normal individuals. In this study we examined at which level MSCs directly affect growth and survival of MM cells. By co-culturing human or murine myeloma cell lines with human or murine MSCs, we found that MSCs favor the proliferation of stroma-dependent MM cells by secreting soluble factors and cell-cell
contact, which was confirmed by co-engraftment experiments in the in vivo 5T33MM mouse model. We also demonstrated that MSCs protect in vitro MM cells against spontaneous and Bortezomib-induced apoptosis. Moreover we found that after co-culturing with MSCs, murine MM cells show an up-regulation of phosphorylated AKT and ERK, accompanied with increased CyclinD2, CDK4 and Bcl-XL, and decreased cleaved
caspase-3 and PARP. In vitro migration assays revealed that both human and murine MSCs can be attracted by MM cells. Accordingly we found by fluorescence microscopic analysis of paraffin sections from various tissues that DiI-labeled murine MSCs home in the 5T33MM model after intraveneous injection to MM-invaded organs (tibia and spleen) at a higher level as compared to the naive mice. We further identified CCL25, CXCL10 and CXCL9 as MM cell-produced chemokines that have the potential to attract MSCs.
In conclusion our results provide evidence that MSCs contribute to the microenvironmentmediated growth control of MM cells. Our data also suggest that therapeutical infusion of normal donor-derived MSCs should be considered with caution as these adult stem cells might enhance tumor progression in vivo resulting/contributing in disease relapse after MSC-based cytotherapy.
contact, which was confirmed by co-engraftment experiments in the in vivo 5T33MM mouse model. We also demonstrated that MSCs protect in vitro MM cells against spontaneous and Bortezomib-induced apoptosis. Moreover we found that after co-culturing with MSCs, murine MM cells show an up-regulation of phosphorylated AKT and ERK, accompanied with increased CyclinD2, CDK4 and Bcl-XL, and decreased cleaved
caspase-3 and PARP. In vitro migration assays revealed that both human and murine MSCs can be attracted by MM cells. Accordingly we found by fluorescence microscopic analysis of paraffin sections from various tissues that DiI-labeled murine MSCs home in the 5T33MM model after intraveneous injection to MM-invaded organs (tibia and spleen) at a higher level as compared to the naive mice. We further identified CCL25, CXCL10 and CXCL9 as MM cell-produced chemokines that have the potential to attract MSCs.
In conclusion our results provide evidence that MSCs contribute to the microenvironmentmediated growth control of MM cells. Our data also suggest that therapeutical infusion of normal donor-derived MSCs should be considered with caution as these adult stem cells might enhance tumor progression in vivo resulting/contributing in disease relapse after MSC-based cytotherapy.
| Originele taal-2 | English |
|---|---|
| Titel | 25th General Meeting of the Belgian Hematological Society – Abstracts Oral Presentations p 20 |
| Uitgeverij | Belgian Hematological Society |
| Status | Published - 29 jan 2010 |