The antitumor effect of mesenchymal stem cells transduced with a lentiviral vector expressing cytosine deaminase in a rat glioma model

Abstract

Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of gliomas. The purpose of this study was to evaluate the antitumor effect of cytosine deaminase (CD)-expressing MSCs in a rat C6 glioma model. Lentiviral vectors expressing cytosine deaminase (CD) or enhanced green fluorescent protein (eGFP) were constructed and transduced into rat MSCs to generate MSC-CD/eGFP cells. By intracranially injecting C6 glioma cells (1 × 10(6)) alone or in combination with parental MSCs (1 × 10(6) or 2 × 10(6)) or MSC-CD/eGFP cells (1 × 10(6) or 2 × 10(6)) into rats, we examined the effect of engineered MSCs on tumor growth, tumor cell apoptosis, and rat survival in the presence of 5-fluorocytosine (5-FC). MSC-CD/eGFP cells were largely localized at the junction of the tumor with normal tissue. The mean survival time of rats co-injected with C6 glioma cells and MSC-CD/eGFP cells was significantly extended (C6 + MSC-CD/eGFP (1:1), 32.3 days; C6 + MSC-CD/eGFP (1:2), 45.9 days) when compared with rats injected with C6 glioma cells alone (15.3 days) or those co-injected with C6 glioma cells and parental cells (C6 + MSCs (1:1), 16.0 days; C6 + MSCs (1:2), 16.6 days). MSC-CD/eGFP-mediated gene therapy significantly reduced the tumor volume in C6 glioma-bearing rats. On day 14 after cell injection, the reduction in the mean tumor volume in rats co-injected with C6 + MSC-CD/eGFP cells (1:1 and 1:2) was 77.24 and 83.28%, respectively. In addition, MSC-CD/eGFP-mediated gene therapy promoted tumor cell apoptosis in rat C6 gliomas. Genetically engineered MSCs have good therapeutic efficacy against experimental gliomas in rats.