title: Anti-tumor effects of canine adipose tissue-derived mesenchymal stromal cell-based interferon-β gene therapy and cisplatin in a mouse melanoma model.
abstract: OBJECTIVE
  Adipose tissue (AT)-derived mesenchymal stromal cells (MSC) (AT-MSC) represent a novel tool for delivering therapeutic genes to tumor cells. Interferon (IFN)-β is a cytokine with pleiotropic cellular functions, including anti-proliferative, immunomodulatory and anti-angiogenic activities. The purpose of this study was to engineer canine AT-MSC (cAT-MSC) producing IFN-β and to evaluate the anti-tumor effect of cAT-MSC-IFN-β combined with cisplatin in mouse melanoma model.
  
  
  METHODS
  cAT-MSC engineered to express mouse IFN-β were generated using a lentiviral vector (cAT-MSC-IFN-β) and the secreted IFN-β-induced inhibition of tumor cell growth and apoptosis on B16F10 cells was investigated in vitro prior to in vivo studies. Melanoma-bearing mouse was developed by injecting B16F10 cells subcutaneously into 6-week-old C57BL/6 mice. After 14 days, cisplatin (10 mg/kg) was injected intratumorally, and 3 days later the engineered cAT-MSC were injected subcutaneously every 3 days to death. Tumor volume and survival times were measured.
  
  
  RESULTS
  The combination treatment of cAT-MSC-IFN-β with cisplatin was more effective in inhibiting the growth of melanoma and resulted in significantly extended survival time than both an unengineered cAT-MSC-cisplatin combination group and a cisplatin-alone group. Interestingly, subcutaneously injected cAT-MSC-IFN-β were migrated to tumor sites.
  
  
  CONCLUSIONS
  Our data suggest that canine AT-MSC could serve as a powerful cell-based delivery vehicle for releasing therapeutic proteins to tumor lesions. Maximal anti-tumor effects were seen when this therapy was combined with a DNA-damaging chemotherapeutic agent. This study demonstrates the possible applicability of AT-MSC-mediated IFN-β in treating canine and human cancer patients.
authors.affiliation: Department of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kyoung-Won
authors.initials: KW
authors.lastname: Seo
authors.forename: Hee-Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Ye-In
authors.initials: YI
authors.lastname: Oh
authors.forename: Jin-Ok
authors.initials: JO
authors.lastname: Ahn
authors.forename: Ye-Rin
authors.initials: YR
authors.lastname: Koh
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Sung-Keun
authors.initials: SK
authors.lastname: Kang
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Youn
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D002465:Cell Movement; D002945:Cisplatin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004285:Dogs; D016503:Drug Delivery Systems; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation; D047368:Tumor Burden
chemical_list: D016899:Interferon-beta; D002945:Cisplatin