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.