Modeling Human Prostatitis in Mice
Creators: name: Khalili, May
Publisher: name: Maryland Shared Open Access Repository
Year: 2008
Subjects: Biology, Molecular (0307)
Prostate cancer
prostatitis
transgenic
mouse model
Cre-LoxP system
Nkx3.1

description: The prostate is one of the most disease-prone organs in the human body. Prostate cancer, prostate inflammation and benign prostatic hyperplasia are the three main diseases that affect the prostate. Virchow's original hypothesis linking inflammation and cancer has proved to be relevant in a number of organs, including the liver, stomach, and colon. Currently, a great deal of emphasis is being placed upon the possible link between prostate inflammation and carcinogenesis. A deficiency of mouse models of prostatitis and a complete lack of transgenic models has hindered the ability to further investigate the possible link between prostatitis and prostate cancer. Conditional gene expression in the prostate often necessitates the use of mice that express Cre specifically in the prostate. However, accurate modeling requires the development of systems that recapitulate the disease in etiology and progression. Probasin-Cre mice express Cre recombinase under the control of a composite rat promoter and represent a widely used model. Histological analyses of ß-galactosidase activity in stained prostates revealed high levels of Cre expression in the stromal compartment, a previously unreported finding. NK32-TCRE, a novel transgenic model that expresses Cre under the control of the Nkx3.1 regulatory elements was derived. NK32-TCRE mice were mated to the R26R reporter line, and double transgenic offspring were subsequently analyzed. Analysis of ß-galactosidase activity in double transgenic prostates revealed Cre activity in a pattern that closely parallels endogenous Nkx3.1. Cre activity is observed as early as gestational day 18.5 and persists for at least 20 months, enabling functional analysis of gene expression during branching morphogenesis and throughout adulthood. Histological analyses of double transgenic prostates demonstrate that Cre is functional mainly in the epithelial compartment with less than 1% activity observed in the stroma. Interestingly, the percentage of epithelial cells with functional Cre was variable among double transgenics. The focality of expression in mice with a low percentage of Cre-positive epithelial cells is a significant feature of this system that provides a tool to induce highly localized changes. Furthermore, the significantly lower incidence of stromal expression seen in the NK32-TCRE system compared to probasin-Cre mice may facilitate the development of mouse models that more closely mimic human prostate disease. Prostatitis was induced in the prostate by inoculating mice with a specific uropathogenic strain of E.coli. Inflamed ducts showed a marked increase in cellularity. The prostate was infiltrated mainly with neutrophils within the glandular lumens while macrophages, T-cells and B-cells were present in the stroma. Immunohistochemical analysis of inflamed prostates showed that Nkx3.1, a prostate-specific tumor suppressor, was significantly diminished in the presence of inflammation while Ki-67, a proliferation marker, was up-regulated. The androgen receptor, a prostate epithelial-cell differentiation marker was also down-regulated. Based upon these observations, inflammation in the prostate seemed to create a microenvironment in which the prostate is predisposed to develop neoplastic lesions in the absence of tumor suppressors and differentiation markers.