The effect of cytosine deaminase-expressing mesenchymal stem cells in orthotopic glioma model of immune competent mice

Abstract

Glioblastoma multiforme (GBM) is the tumor common deriving from glia and aggressive primary brain tumor. Current standard therapy provides only modest improvements in progression-free and overall survival of patients. Most of the preclinical studies for glioma utilize immune deficient animals, which limits the assessment of role of immune system in glioma progression and therapy. However, the contribution of innate immune system in glioma progression cannot be excluded in clinical settings. In this study, an orthotopic glioma mouse model were established using a syngeneic mouse glioma cell line, GL261 in immune competent wild type C57BL/6 mice. GL261 cells (3x104 cells) were transplanted to the striatum and tumor growth kinetics was assessed by MRI imaging and histological analyses. The therapeutic effects of mesenchymal stem cells (MSC) that was previously engineered to express a suicide gene, cytosine deaminase (MSC/CD) was evaluated in this model. MSC/CD with administration of a prodrug 5-florocytosine (5-FC) was effective to suppress tumor growth. Therapeutic effect of MSC/CD with 5-FC was further enhanced when followed by treatment of temozolomide. Compared to nude mice, the overall survival of the animals treated with MSC/CD and 5-FC was higher in C57BL/6 mice, suggesting contribution of systemic immune system. Histological analysis revealed that more immune cells including macrophage/microglia, T lymphocytes were infiltrated to the tumor sites. The result indicate that combination therapy of MSC/CD with 5-FC and TMZ possess potent anticancer effects by direct chemoablation and subsequent activation of innate immune system.