Endocrine Abstracts

Genetically engineered stem cells may be advantageous for gene therapy against various human cancers due to their inherent tumor-tropic properties. In this study, we employed human neural stem cells (HB1.F3; hNSCs) transduced with genes expressing Escherichia coli cytosine deaminase (HB1.F3.CD) and human interferon-beta (HB1.F3.CD.IFN-β) as a treatment strategy for human lymph node metastatic colorectal cancer. CD can convert the prodrug 5-fluorocytosine (5-FC) to its active chemotherapeutic form, 5-fluorouracil (5-FU), which induces a tumor-killing effect through DNA synthesis inhibition. IFN-β also slightly inhibits tumor growth by inducing apoptotic process. In RT-PCR analysis, we confirmed that HB1.F3.CD cells expressed CD gene and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β genes. A modified transwell migration assay showed that HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward SW-620 human lymph node metastatic colorectal cancer cells. When co-cultured with HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC, the viability of SW-620 cells were significantly reduced. In a xenografted mouse model, hNSCs treatment significantly inhibited the growth of tumor mass and the expression of proliferative marker without any harmful effects on the animals. In addition, fluorescent-labeled hNSCs could be found in the excised tumor mass. The tumor-tropic properties of these engineered hNSCs were found to be attributed to chemoattractant factors secreted by SW-620 cells, SDF-1, c-kit, uPAR, uPA and CCR2. Consequently, the present results represent that engineered hNSCs and prodrug treatment inhibits the growth of human lymph node metastatic colorectal cancer. Therefore, hNSC therapy may be a clinically effective tool for the treatment of human lymph node metastatic colorectal cancer.