Bone Marrow-Derived Mesenchymal Stem Cell-Mediated Dual-Gene Therapy for Glioblastoma.

Abstract

Bone-marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. However, the optimal treatment time post-BMSC implantation and the assessment of the long-term fate of therapeutic BMSCs post-tumor treatment are critical if such promising therapies are to be translated into clinical practice. An efficient BMSC-based therapeutic strategy has been developed that simultaneously allows killing of tumor cells, inhibiting of tumor angiogenesis, and assessment and eradication of implanted BMSCs after treatment of glioblastoma. BMSCs were engineered to co-express the angiogenesis inhibitor kringle 5 (K5) of human plasminogen, under the control of the cytomegalovirus promoter (CMV) and the human sodium-iodide symporter (NIS), involved in uptake of radioisotopes, under the control of early growth response factor 1 (Egr1), a radiation-activated promoter. A significant decrease in tumor growth and tumor angiogenesis and a subsequent increase in survival were observed when mice bearing glioblastoma were treated with 188Re post-therapeutic intravenous BMSC implantation. Furthermore, the systemic administration of 188Re post-tumor treatment selectively eliminated therapeutic BMSCs expressing NIS, which was monitored in real time by 125I micro single photon emission computed tomography/computed tomography imaging. Meanwhile, the Egr1 promoter induced a 188Re radiation positive feedback effect absorbed by NIS. After intravenous BMSC implantation, BMSCs levels in the tumor and lung both peaked on day 10 and decreased to the lowest levels on days 24 and 17, respectively. These findings suggest that day 17 post-BMSC implantation could be an optimal time for 188Re treatment. These results provide a new adjuvant therapy mediated by BMSCs for glioblastoma treatment.