title: HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells.
abstract: Previously we have reported adipose-tissue derived human mesenchymal stem cells (AT-MSC) as cellular delivery vehicles for tumor-targeted cancer gene therapy. In this report we aimed to determine whether Herpes simplex virus - thymidine kinase (HSV-tk) expressing AT-MSC (TK-MSC) could exert cytotoxic effect on tumor cells upon treatment with prodrug ganciclovir (GCV). Direct co-cultures of human glioblastoma cells 8-MG-BA, 42-MG-BA and U-118 MG with TK-MSC/GCV resulted in substantial viability decrease in vitro. This therapeutic paradigm was most efficient against 8-MG-BA glioblastoma cells exhibiting cytotoxicity (>50%) in the presence of TK-MSC and 0.1microM GCV. Rapid apoptosis induction in three glioblastoma cell lines and TK-MSC demonstrated both bystander cytotoxic effect on tumor cells and GCV conversion-mediated suicide effect on TK-MSC. Furthermore, we were able to demonstrate formation of gap junctions between AT-MSC and human glioblastoma cells as a mechanism contributing to bystander cytotoxicity. Inability of human HeLa and MCF7 to form gap junctions with AT-MSC rendered these cell refractory to the TK-MSC/GCV mediated cytotoxicity. Gap junction intercellular communication (GJIC) capability of AT-MSC with tumor cells further supports the exploitation of mesenchymal stem cells for approaches relying on the bystander effect. Biological consequences of these capabilities remain to be further explored.
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Matuskova
authors.forename: Kristina
authors.initials: K
authors.lastname: Hlubinova
authors.forename: Andrea
authors.initials: A
authors.lastname: Pastorakova
authors.forename: Luba
authors.initials: L
authors.lastname: Hunakova
authors.forename: Veronika
authors.initials: V
authors.lastname: Altanerova
authors.forename: Cestmir
authors.initials: C
authors.lastname: Altaner
authors.forename: Lucia
authors.initials: L
authors.lastname: Kucerova
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024201:Bystander Effect / Q000502:physiology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D018920:Coculture Techniques; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D017629:Gap Junctions / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir