HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells.
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.
Matuskova
Miroslava
M
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
Hlubinova
Kristina
K
Pastorakova
Andrea
A
Hunakova
Luba
L
Altanerova
Veronika
V
Altaner
Cestmir
C
Kucerova
Lucia
L
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
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir