title: Endothelial differentiation of adipose tissue-derived mesenchymal stromal cells in glioma tumors: implications for cell-based therapy.
abstract: Multipotent human adipose tissue mesenchymal stromal cells (hAMSCs) are promising therapy vehicles with tumor-homing capacity that can be easily modified to deliver cytotoxicity activating systems in the proximity of tumors. In a previous work, we observed that hAMSCs are very effective delivering cytotoxicity to glioma tumors. However, these results were difficult to reconcile with the relatively few hAMSCs surviving implantation. We use a bioluminescence imaging (BLI) platform to analyze the behavior of bioluminescent hAMSCs expressing HSV-tTK in a U87 glioma model and gain insight into the therapeutic mechanisms. Tumor-implanted hAMSCs express the endothelial marker PECAM1(CD31), integrate in tumor vessels and associate with CD133-expressing glioma stem cells (GSC). Inhibition of endothelial lineage differentiation in hAMSCs by Notch1 shRNA had no effect on their tumor homing and growth-promoting capacity but abolished the association of hAMSCs with tumor vessels and CD133+ tumor cells and significantly reduced their tumor-killing capacity. The current strategy allowed the study of tumor/stroma interactions, showed that tumor promotion and tumor-killing capacities of hAMSCs are based on different mechanisms. Our data strongly suggest that the therapeutic effectiveness of hAMSCs results from their association with special tumor vascular structures that also contain GSCs.
authors.affiliation: Instituto de Química Avanzada de Cataluña CSIC, CIBER-BBN, Barcelona, Spain.
authors.forename: Juli R
authors.initials: JR
authors.lastname: Bagó
authors.forename: Maria
authors.initials: M
authors.lastname: Alieva
authors.forename: Carolina
authors.initials: C
authors.lastname: Soler
authors.forename: Núria
authors.initials: N
authors.lastname: Rubio
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Blanco
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D024201:Bystander Effect; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D005910:Glioma / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051881:Receptor, Notch1