Tropism of mesenchymal stem cell toward CD133+ stem cell of glioblastoma in vitro and promote tumor proliferation in vivo
Pavon, Lorena Favaro; Sibov, Tatiana Tais; Souza, Andrea Vieira de; Cruz, Edgar Ferreira da; Malheiros, Suzana M. F.; Cabral, Francisco Romero; Souza, Jean Gabriel de ; Boufleur, Pâmela ; Oliveira, Daniela Mara de; Toledo, Silvia Regina Caminada de; Marti, Luciana C.; Malheiros, Jackeline Moraes; Paiva, Fernando F.; Tannús, Alberto; Oliveira, Sergio Mascarenhas de; Chudzinski-Tavassi, Ana Marisa ; Paiva Neto, Manoel A. de; Cavalheiro, Sérgio
Background Previous studies have demonstrated remarkable tropism of mesenchymal stem cells (MSCs) toward malignant gliomas, making these cells a potential vehicle for delivery of therapeutic agents to disseminated glioblastoma (GBM) cells. However, the potential contribution of MSCs to tumor progression is a matter of concern. It has been suggested that CD133+ GBM stem cells secrete a variety of chemokines, including monocytes chemoattractant protein-1 (MCP-1/CCL2) and stromal cell-derived factor-1(SDF-1/CXCL12), which could act in this tropism. However, the role in the modulation of this tropism of the subpopulation of CD133+ cells, which initiate GBM and the mechanisms underlying the tropism of MSCs to CD133+ GBM cells and their effects on tumor development, remains poorly defined. Methods/results We found that isolated and cultured MSCs (human umbilical cord blood MSCs) express CCR2 and CXCR4, the respective receptors for MCP-1/CCL2 and SDF-1/CXCL12, and demonstrated, in vitro, that MCP-1/CCL2 and SDF-1/CXC12, secreted by CD133+ GBM cells from primary cell cultures, induce the migration of MSCs. In addition, we confirmed that after in vivo GBM tumor establishment, by stereotaxic implantation of the CD133+ GBM cells labeled with Qdots (705 nm), MSCs labeled with multimodal iron oxide nanoparticles (MION) conjugated to rhodamine-B (Rh-B) (MION-Rh), infused by caudal vein, were able to cross the blood-brain barrier of the animal and migrate to the tumor region. Evaluation GBM tumors histology showed that groups that received MSC demonstrated tumor development, glial invasiveness, and detection of a high number of cycling cells. Conclusions Therefore, in this study, we validated the chemotactic effect of MCP-1/CCL2 and SDF-1/CXCL12 in mediating the migration of MSCs toward CD133+ GBM cells. However, we observed that, after infiltrating the tumor, MSCs promote tumor growth in vivo probably by release of exosomes. Thus, the use of these cells as a therapeutic carrier strategy to target GBM cells must be approached with caution.
CD133+ cells; MSCs; Tropism; Chemokines; Experimental model; Exosomes
Pavon LF, Sibov TT, Souza AV, Cruz EF, Malheiros SM.F., Cabral FR, et al. Tropism of mesenchymal stem cell toward CD133+ stem cell of glioblastoma in vitro and promote tumor proliferation in vivo. Stem Cell Res. Ther.. 2018;9:310. doi:10.1186/s13287-018-1049-0.
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