Investigation of differential gene expression in stroma and epithelium of PIN and prostate carcinoma by gene microarray analysis. Free

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Prostatic intraepithelial neoplasia (PIN) is often associated with prostate cancer. Although PIN diagnosis increases risk for prostate cancer, currently there is no accepted therapy available. Recent studies indicate an active role of the surrounding stroma in prostate carcinogenesis. Stromal - epithelial crosstalk has been shown to facilitate tumor cell proliferation and survival in both primary and metastatic sites. Gene expression analyses of the stromal and epithelial compartments of PIN can reveal markers of progression, thereby facilitating early diagnosis as well as potential therapeutic targets.

The present study aims to identify genes with altered expression in stromal and epithelial compartments of PIN and prostate cancer, and to assess whether molecular changes are restricted to the tumor margin or occur throughout the prostate as a part of malignant progression. We collected tissue cores from 11 men undergoing prostatectomy for primary prostate cancer with Gleason scores of 6 or 7/10. Biopsies were collected and material frozen from the surgically resected prostates at each of three sites: within the tumor margin, adjacent to the tumor, and distant (1-2 cm) from the tumor. Laser capture microdissection was used to isolate stromal and epithelial cells. Extracted RNA from both compartments was amplified, and thirty-nine (39) samples from 8 patients had adequate amounts and quality of RNA for subsequent microarray analysis using 19k cDNA microarrays. Supervised and unsupervised computational analysis of array data using machine learning and statistical tools combined with interaction network and pathway analysis using OPHID database (http://ophid.utoronto.ca/) identified five targets of particular interest: caveolin-1, discoidin domain receptor 1 (DDR1), endothelin B receptor (ETBR) precursor, apoptosis associated speck-like protein 1 (ASC1) and bax inhibitor 1 (BI1). These targets are currently being further assessed.

Our study provides information on the changes in gene expression in both the epithelium and stroma that precede tumor development or occur as a result of malignant transformation and proximity to the tumor. This knowledge may lead to an improved diagnosis of PIN and identification of novel therapeutic targets.