Abstract
Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.
Highlights
Benign prostatic hyperplasia (BPH) is extremely common in aging men, contributing to the pattern of morbidity known as lower urinary tract symptoms (LUTS) and resulting in significant annual healthcare costs [1]
Histopathologic Analysis and Sample Selection To determine the severity of BPH pathology changes for cases utilized for RNA extraction, transition zone (TZ) areas affected by glandular and stromal hyperplasia were outlined in whole mount sections from radical prostatectomy (RP) samples obtained via the Department of Pathology in accordance with Vanderbilt IRB protocols
Preference was given to cases with small volume peripheral zone (PZ) tumors, so that any overall prostate enlargement will be due to TZ enlargement and to reduce the likelihood that hormonal metabolism potentially relevant to BPH would be altered by large volume prostate cancer [26]
Summary
Benign prostatic hyperplasia (BPH) is extremely common in aging men, contributing to the pattern of morbidity known as lower urinary tract symptoms (LUTS) and resulting in significant annual healthcare costs [1]. Despite the availability of medical and surgical treatments for BPH there is still inadequate understanding of the processes involved in benign pathological growth of the human prostate in vivo [2]. The reawakening of the embryonic inductive potential in the prostatic stroma has been proposed as a cause of BPH [3,5,6,7] This is based on the idea that prostate growth results from the local interplay of growth factors between the epithelial and stromal elements of the organ under the influence of testicular androgens, suggesting that androgen regulated genes play a major role in the disease. This hypothesis is supported by considerable experimental evidence in particular from tissue recombination models [8,9,10]
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