title: Induction of invasive transitional cell bladder carcinoma in immune intact human MUC1 transgenic mice: a model for immunotherapy development.
abstract: A preclinical model of invasive bladder cancer was developed in human mucin 1 (MUC1) transgenic (MUC1.Tg) mice for the purpose of evaluating immunotherapy and/or cytotoxic chemotherapy. To induce bladder cancer, C57BL/6 mice (MUC1.Tg and wild type) were treated orally with the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) at 3.0 mg/day, 5 days/week for 12 weeks. To assess the effects of OH-BBN on serum cytokine profile during tumor development, whole blood was collected via submandibular bleeds prior to treatment and every four weeks. In addition, a MUC1-targeted peptide vaccine and placebo were administered to groups of mice weekly for eight weeks. Multiplex fluorometric microbead immunoanalyses of serum cytokines during tumor development and following vaccination were performed. At termination, interferon gamma (IFN-γ)/interleukin-4 (IL-4) ELISpot analysis for MUC1 specific T-cell immune response and histopathological evaluations of tumor type and grade were performed. The results showed that: (1) the incidence of bladder cancer in both MUC1.Tg and wild type mice was 67%; (2) transitional cell carcinomas (TCC) developed at a 2:1 ratio compared to squamous cell carcinomas (SCC); (3) inflammatory cytokines increased with time during tumor development; and (4) administration of the peptide vaccine induces a Th1-polarized serum cytokine profile and a MUC1 specific T-cell response. All tumors in MUC1.Tg mice were positive for MUC1 expression, and half of all tumors in MUC1.Tg and wild type mice were invasive. In conclusion, using a team approach through the coordination of the efforts of pharmacologists, immunologists, pathologists and molecular biologists, we have developed an immune intact transgenic mouse model of bladder cancer that expresses hMUC1.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California, Davis.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Vang
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Wurz
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Griffey
authors.forename: Chiao-Jung
authors.initials: CJ
authors.lastname: Kao
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Gutierrez
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Hanson
authors.forename: Michael
authors.initials: M
authors.lastname: Wolf
authors.forename: Michael W
authors.initials: MW
authors.lastname: DeGregorio
mesh_terms: D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D002273:Carcinogens; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000628:therapy*
chemical_list: D019496:Cancer Vaccines; D002273:Carcinogens; D016207:Cytokines; C060192:MUC1 protein, human; D018396:Mucin-1; D002085:Butylhydroxybutylnitrosamine