USE OF IPS CELL-DERIVED NEURAL STEM CELLS AS A CELLULAR VEHICLE FOR GLIOMA AND BREAST CANCER THERAPY

Abstract

Using neural stem cells with tumor tropic migratory capacity to deliver therapeutic genes is an attractive strategy in eliminating metastatic or disseminated tumor. Different methods have been studied and developed to isolate or generate NSCs, but it has not been assessed whether induced pluripotent stem cells (iPSCS), a type or pluripotent stem cells that hold great potential for regenerative medicine, can be used as a source for derivation of NSCs with tumor tropism. In this study, we used a conventional lentivirus transduction method to derive both mouse and human iPSCs from embryonic fibroblasts and then generated NSCs from these iPSCs. To investigate whether the iPSC-derived NSCs can be used in the treatment of disseminated brain tumor and metastatic breast cancer, the cells were transduced with baculoviral vector containing the herpes simplex virus thymidine kinase or the cytosine deaminase suicide gene. In the glioma study, the mouse iPSC-NSCtk were injected contralaterally to tumor inoculation site in a mouse intracranial human glioma xenograft model. In the breast cancer study, the human iPSC-NSCtk, iPSC-NSCFcy, iPSC-NSCCodA were injected either intravenously or directly into the tumor site. We observed that NSCs expressing the suicide gene were, in the presence of respective prodrugs ganciclovir or 5-fluorocytosine, effective with varying extents in inhibiting the cancer development of the glioma xenograft and breast cancer metastatic model and prolonging the survival of tumor-bearing mice. Our findings provide evidence for the feasibility of using iPSC derived NSCs as a vehicle for targeted anticancer gene therapy