title: Suppression of the growth of human colorectal cancer cells by therapeutic stem cells expressing cytosine deaminase and interferon-β via their tumor-tropic effect in cellular and xenograft mouse models.
abstract: Genetically engineered stem cells (GESTECs) exhibit a potent therapeutic efficacy via their strong tumor tropism toward cancer cells. In this study, we introduced the human parental neural stem cells, HB1.F3, with the human interferon beta (IFN-β) gene which is a typical cytokine gene that has an antitumor effect and the cytosine deaminase (CD) gene from Escherichia coli (E. coli) that could convert the non-toxic prodrug, 5-fluorocytosine (5-FC), to a toxic metabolite, 5-fluorouracil (5-FU). Two types of stem cells expressing the CD gene (HB1.F3.CD cells) and both the CD and human IFN-β genes (HB1.F3.CD.IFN-β) were generated. The present study was performed to examine the migratory and therapeutic effects of these GESTECs against the colorectal cancer cell line, HT-29. When co-cultured with colorectal cancer cells in the presence of 5-FC, HB1.F3.CD and HB1.F3.CD.IFN-β cells exhibited the cytotoxicity on HT-29 cells via the bystander effect. In particular, HB1.F3.CD.IFN-β cells showed the synergistic cytotoxic activity of 5-FU and IFN-β. We also confirmed the migration ability of HB1.F3.CD and HB1.F3.CD.IFN-β cells toward HT-29 cells by a modified migration assay in vitro, where chemoattractant factors secreted by HT-29 cells attracted the GESTECs. In a xenograft mouse model, the volume of tumor mass was decreased up to 56% in HB1.F3.CD injected mice while the tumor mass was greatly inhibited about 76% in HB1.F3.CD.IFN-β injected mice. The therapeutic treatment by these GESTECs is a novel strategy where the combination of the migration capacity of stem cells as a vector for therapeutic genes towards colorectal cancer and a synergistic antitumor effect of CD and IFN-β genes can selectively target this type of cancer.
authors: Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea.
authors: Bo-Rim
authors: BR
authors: Yi
authors: Min-Ah
authors: MA
authors: Park
authors: Hye-Rim
authors: HR
authors: Lee
authors: Nam-Hee
authors: NH
authors: Kang
authors: Kelvin J
authors: KJ
authors: Choi
authors: Seung U
authors: SU
authors: Kim
authors: Kyung-Chul
authors: KC
authors: Choi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D060846:Cell Engineering / Q000379:methods*; D002460:Cell Line; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D016899:Interferon-beta / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D016899:Interferon-beta; D043525:Cytosine Deaminase; D005472:Fluorouracil
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