Abstract
Background
Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector‐producing MSCs that enhance tumor transduction via progeny vector production.
Methods
Rat bone marrow‐derived MSCs were nucleofected with the proviral plasmids (vesicular stomatitis virus‐G protein‐pseudotyped retroviral vector components) (VP‐MSCs) or pLTR plasmid alone (non‐VP‐MSCs). The luciferase‐based in vivo imaging system was used to assess gene expression periodically. To evaluate the anticancer effects, we administered MSCs expressing herpes simplex virus‐thymidine kinase (HSV‐tk) into the left ventricular cavity of nude mice engrafted with 9L glioma cells subcutaneously.
Results
In vivo imaging revealed that administration of luciferase‐expressing non‐VP‐MSCs enhanced the bioluminescence signal at the inoculation sites of 9L cells, whereas no accumulation was observed in mice at the site of the control Rat‐1 fibroblasts. Compared to non‐VP‐MSCs, the administration of VP‐MSCs resulted in significant augmentation of the signal with an increase in transgene copy number. Immunohistochemical analysis showed marked luciferase expression at the tumor periphery in mice injected with VP‐MSCs, whereas little expression was detected in those injected with non‐VP‐MSCs. Under the continuous infusion of ganciclovir, systemic administration of VP‐MSCs expressing HSV‐tk suppressed tumor growth more effectively than non‐VP‐MSC administration, whereas no anticancer effect was observed without ganciclovir treatment. Furthermore, VP‐MSC administration caused no transgene transduction in the normal tissues and organs.
Conclusions
VP‐MSCs accumulated at the site of tumors after intravascular injection in tumor‐bearing mice, followed by in situ gene transfer to tumors without transduction of normal organs. When applied to the HSV‐tk/ganciclovir suicide gene therapy, more efficient tumor growth suppression was observed using VP‐MSCs compared to non‐VP‐MSCs. This VP‐MSC‐based system has great potential for improved cancer gene therapy. Copyright © 2009 John Wiley & Sons, Ltd.