title: Additional effects of engineered stem cells expressing a therapeutic gene and interferon-β in a xenograft mouse model of endometrial cancer.
abstract: Endometrial cancer is the most common gynecologic malignancy in women worldwide. In the present study, we evaluated the effects of neural stem cell-directed enzyme/prodrug therapy (NDEPT) designed to more selectively target endometrial cancer. For this, we employed two different types of neural stem cells (NSCs), HB1.F3.CD and HB1.F3.CD.IFN-β cells. Cytosine deaminase (CD) can convert the non-toxic prodrug, 5-fluorocytosine (5-FC), into a toxic agent, 5-fluorouracil (5-FU), which inhibits DNA synthesis. IFN-β is a powerful cytotoxic cytokine that is released by activated immune cells or lymphocytes. In an animal model xenografted with endometrial Ishikawa cancer cells, the stem cells stained with CM-DiI were injected into nearby tumor masses and 5-FC was delivered by intraperitoneal injection. Co-expression of CD and IFN-β significantly inhibited the growth of cancer (~50-60%) in the presence of 5-FC. Among migration-induced factors, VEGF gene was highly expressed in endometrial cancer cells. Histological analysis showed that the aggressive nature of cancer was inhibited by 5-FC in the mice treated with the therapeutic stem cells. Furthermore, PCNA expression was more decreased in HB1.F3.CD.IFN-β treated mice rather than HB1.F3.CD treated mice. To confirm the in vitro combined effects of 5-FU and IFN-β, 5-FU was treated in Ishikawa cells. 5-FU increased the IFN-β/receptor 2 (IFNAR2) and BXA levels, indicating that 5-FU increased sensitivity of endometrial cancer cells to IFN-β, leading to apoptosis of cancer cells. Taken together, these results provide evidence for the efficacy of therapeutic stem cell-based immune therapy involving the targeted expression of CD and IFN-β genes at endometrial cancer sites.
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Bo-Rim
authors.initials: BR
authors.lastname: Yi
authors.affiliation: Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, 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, Chungbuk, Republic of Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage* / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D007274:Injections, Intraperitoneal; D016899:Interferon-beta / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000201:enzymology / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C508033:IFNAR2 protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil