title: Anti-proliferative Effect of Engineered Neural Stem Cells Expressing Cytosine Deaminase and Interferon-β against Lymph Node-Derived Metastatic Colorectal Adenocarcinoma in Cellular and Xenograft Mouse Models.
abstract: OBJECTIVE
  Genetically engineered stem cells may be advantageous for gene therapy against various human cancers due to their inherent tumor-tropic properties. In this study, genetically engineered human neural stem cells (HB1.F3) expressingEscherichia colicytosine deaminase (CD) (HB1.F3.CD) and human interferon-β (IFN-β) (HB1.F3.CD.IFN-β) were employed against lymph node-derived metastatic colorectal adenocarcinoma.
  
  
  METHODS
  CD can convert a prodrug, 5-fluorocytosine (5-FC), to active 5-fluorouracil, which inhibits tumor growth through the inhibition of DNA synthesis,while IFN-β also strongly inhibits tumor growth by inducing the apoptotic process. In reverse transcription polymerase chain reaction analysis, we confirmed that HB1.F3.CD cells expressed the CD gene and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β genes.
  
  
  RESULTS
  In results of a modified trans-well migration assay, HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward SW-620, human lymph node-derived metastatic colorectal adenocarcinoma cells. The viability of SW-620 cells was significantly reduced when co-cultured with HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC. In addition, it was found that the tumor-tropic properties of these engineered human neural stem cells (hNSCs) were attributed to chemoattractant molecules including stromal cell-derived factor 1, c-Kit, urokinase receptor, urokinase-type plasminogen activator, and C-C chemokine receptor type 2 secreted by SW-620 cells. In a xenograft mouse model, treatment with hNSC resulted in significantly inhibited growth of the tumor mass without virulent effects on the animals.
  
  
  CONCLUSIONS
  The current results indicate that engineered hNSCs and a prodrug treatment inhibited the growth of SW-620 cells. Therefore, hNSC therapy may be a clinically effective tool for the treatment of lymph node metastatic colorectal cancer.
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.
authors.forename: Geon-Tae
authors.initials: GT
authors.lastname: Park
authors.affiliation: Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.|TheraCell Bio & Science, Cheongju, Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D064987:Cell- and Tissue-Based Therapy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000556:secondary* / Q000628:therapy; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005437:Flucytosine / Q000494:pharmacology; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D016899:Interferon-beta; D005437:Flucytosine; D043525:Cytosine Deaminase
keywords: Colorectal neoplasms; Flucytosine; Interferon-beta; Lymphatic metastasis; Neural stem cells