Progressive loss of AR expression

Numerous studies have focused on AR expression in the epithelial cells during prostate carcinogenesis and the progression of prostate cancer from primary to metastatic cancer and from hormone sensitive to castration resistant prostate cancer (CRPC). It has been established that epithelial AR is continuously expressed throughout prostate cancer disease progression. Increased AR expression has been associated with aggressive disease and decreased progression free survival (PFS) in patients [19].

The expression and function of stromal AR may be distinct from epithelial AR. As a result of the structural, genetic and genomic [11,15] modifications of the stromal cells, there are behavioral modifications expressed in tumor associated stroma. AR expression in stroma is progressively decreased during the transition from benign tissue to cancer and during progression of prostate cancer from low grade to high grade, primary to metastatic, hormone sensitive to CRPC, as well as aggressive prostate cancer in African Americans.

In immunohistochemistry (IHC) studies, some investigators [20] found that AR expression declines in the peri-epithelial stroma as early as in high grade prostatic intraepithelial neoplasia (HGPIN) compared to normal prostate. In their analysis using tissue samples of HGPIN, expression of AR was found to be absent in 80% and weak in 20% of peri-epithelial stromal cell sections.

Analysis of stromal tissue of prostate cancer showed that loss of AR expression increased linearly with higher histological grades in several studies. AR expression was absent in 67% of peri-epithelial stromal tissue in well differentiated (Gleason score 2-4), 91% in moderately differentiated (Gleason score 5-7) and 94% in poorly differentiated (Gleason score 8-10)

prostate cancer [20]. In our study [21], we have shown a statistically significant decrease of stromal AR expression (p < 0.001) in the areas of prostate cancer compared with benign prostate with up to a 6% decrease in stromal AR expression. When stratified with Gleason score, we established a trend of greater decrease of AR-positive stromal cells in cancerous areas compared to benign areas with increased tumor grade. Later on, other investigators have also demonstrated that magnitude of loss of stromal AR is directly proportional to advanced pathological stage along with higher Gleason scores [22]. By AR antibody immunostaining of TURP (Trans Urethral Resection of Prostate) specimens obtained from patients with varying Gleason scores and pathological stages, they found lower expression of AR in tumor stroma compared to areas with normal stroma. This difference was notable (p < 0.05) in tumor specimens of stage T2 and tumors with Gleason score of 7, while it was more statistically significant (p <0.01) in tumor stage T3 and T4 and in specimens with Gleason score of 8-10.

Decreased stromal AR expression has also been correlated to disease progession including metastasis and androgen-independence. Bergh et al. showed [22] that specimens with metastatic disease displayed significantly lower (p < 0.01) stromal AR expression. The AR staining was only 1.6% in metastatic tumor stroma compared to 18 % in normal stroma which was equivalent to a loss of expression by 11 fold. While in the non-metastatic disease specimens, the AR staining was 13% in tumor stroma compared to 48 % in normal stroma, equivalent to a loss of expression by 3.5 fold. Evidence is available [21] that during transition of prostate cancer from hormone sensitive to CRPC, there is a significant decrease in stromal AR expression. AR levels were determined in the prostate stroma of 44 cases of hormone sensitive prostate cancer and in 22 cases of CRPC by IHC analysis using affinity purified polyclonal AR antibodies. Scoring was performed by selecting three areas with 100 cells each in benign and cancerous regions in prostate stromal tissue sections to determine the relative percentages of stromal cells that were AR-positive and AR-negative, respectively. The levels of stromal AR expression were expressed as an average percentage of AR-positive stromal cells. When comparing hormone sensitive and CRPC tumor sections, a statistically significant 3-fold decrease of AR-positive stromal cells was observed, from 4 % in hormone sensitive to 12 % in CRPC tumors. Most importantly, some investigators have also reported an association of loss of stromal AR expression with clinical outcome or prostate cancer specific death in patients [25].

These studies suggest that there is a natural selection of stromal AR negative cells over AR positive cells as the tumor progresses. With these results, we established that stromal AR expression proportionately decreases as tumor grade increases and as cancer advances towards metastatic and androgen independent disease. The mechanism behind the loss of AR expression in the peri-epithelial stroma is not well understood. It has been attributed that during the malignant transformation of epithelial cells, there is a shift in AR axis from stromal cell dependent paracrine pathways to autocrine dependent pathways [23] and is increased during tumor progression. When these cancer cells shift to autocrine mechanism of proliferation, it appears that epithelial AR regulates a new series of genes for survival and proliferation, not normally expressed by prostate epithelial cells [7]. The consequence of this may be that malignant epithelial cells no longer depend upon stromal-epithelial interactions and stromal AR mediated growth factors for their survival and proliferation.

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