| Benign prostatic hyperplasia (BPH) is a common condition affecting aging men. The aging Brown Norway (BN) rat develops age-dependent epithelial cell hyperplasia in the dorsal and lateral, but not the ventral, lobes of the prostate. To test the hypothesis that stem/progenitor cells might give rise to hyperplasia in aging BN rats, we examined whether the expression of progenitor/stem cell markers were lobe-specific and/or age-dependent. We found that p63 +AR- progenitor cells reside primarily within the proximal duct regions of the dorsal and lateral lobes in old rats. Although the levels of Oct4, Sox2, and beta-catenin mRNAs were age invariant in the proximal epithelia isolated by laser capture microdissection, levels of these gene transcripts in epithelia were greater in the proximal than non-proximal regions of these lobes. Importantly, CD133 and Sca-1 mRNA levels were higher in the proximal ducts of aged rats compared to young rats. These data support the increased presence of stem/progenitor cells within the proximal region of the prostatic lobes in rats. We also found that levels of telomerase activity and TERT expression are higher in the dorsal and lateral lobes, but not the ventral lobe, of aged compared to young BN rats.;In addition, we hypothesized that inflammation within the microenvironment of the prostate and the expression of cytokines associated with inflammation, could provoke cell proliferation leading to hyperplasia. We found that pro-inflammatory cytokines, such as MCP-1, MIP-3a, CINC-2, CINC-3, CNTF, beta-NGF, LIX, GM-CSF, IFN-gamma and IL-6 had lobe- or age-dependent differences in their expression. Expression of the anti-inflammatory cytokines, IL-4 and IL-10, was also lobe- or age-dependent. These findings suggest that cytokines may evoke changes in the prostatic microenvironment to alter prostate growth.;Lastly, rates of cell proliferation were up-regulated in the dorsal and lateral lobes of aged rats in response to androgens. These increased rates of cell proliferation were confirmed by BrdU labeling indices, changes in the levels of cell cycle regulatory proteins that control the GIS restriction point, and the time-dependent nuclear co-localization of cyclin D1-cdk4 protein complexes. Importantly, the lobe-specific and age-related differences in cell cycle regulatory proteins and cell proliferation in testosterone-treated castrated animals and intact animals reflect age-dependent changes in the endogenous hormonal milieu consistent with the development of prostatic hyperplasia.;Taken together, our studies revealed important differences in the proliferative potential of cells in response to androgen, localization of cells with proliferative potential to the proximal duct regions and the occurrence of inflammation as important factors that may contribute to the age-dependent and lobe-specific development of prostatic hyperplasia in the aging Brown Norway rat model. |
