Many previous studies have suggested that inflammation may be a causative process in prostatic carcinogenesis. As such, the histological classification of Proliferative Inflammatory Atrophy (PIA) has been hypothesized to be a precursor lesion to prostatic intraepithelial neoplasias (PIN) and early adenocarcinomas. In a recently initiated project, we propose to test this hypothesis by directly expressing pro-inflammatory cytokines, as well as their activated signal transducing molecules, in the prostate and assessing the effect on prostatic oncogenesis. In collaboration with Bill Farrar and Lionel Feigenbaum, we have generated transgenic mice that bear a transgene carrying the IL-6 gene downstream from a LoxP-flanked stop signal. These transgenic mice were crossed to mice bearing a prostate-specific CRE recombinase gene, thereby removing the trasnlational stop signal so expression of IL-6 can progress. Similarly, we generated interferon-g transgenic lines. These mice were studies for expression of luciferase, an indicator gene linked to the cytokine gene, and potential founders identified. these founders expressed low, but detectable levels of IFN or IL-6. We are now examining these mice for histopathological changes of the prostate. Our future studies will involve crossing to a cancer-prone genetic background and molecular profiling to determine mechanisms of transformation. In a second set of studies, mice were intraurethrally infected with a urotropic strain of E coli. Mice were followed for infection. Since susceptible strains of mice develop chronic infection, some mice were treated with antibiotics at twelve weeks after infection so they could be maintained for extended periods. Another resistant strain of mice was repeatedly innoculated to simulate chronic infection. Mice were euthanized at various points after infection and prostatic tissues harvested for histopathological analysis. Very preliminary results suggest that prolonged infection followed by antibiotic treatment promotes initial stages of transformation. On-going studies will characterize these different models of murine bacterial prostatitis.
| Shafer-Weaver, Kimberly A; Watkins, Stephanie K; Anderson, Michael J et al. (2009) Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells. Cancer Res 69:6256-64 |
