Hunterian Lecture. Characterisation of human prostate epithelial progenitor differentiation in response to androgens.

ABSTRACT

INTRODUCTION: A stem cell model of prostate cancer tumourigenesis explains progression to castration resistant prostate cancer (CRPC) and offers novel perspectives in targeting this cancer in its more advanced forms. Androgen receptor (AR) regulated pathways are central mechanisms in progression to CRPC. However, AR was thought to be lacking in prostate stem cell enriched fractions. Potential low levels of AR expression in stem cell enriched cells were investigated and potential direct effects of androgen were examined. METHODS: Human prostate stem cell enriched populations, based on high α(2)ß(1) integrin expression (α(2)ß(1)(hi)), were selected from primary human prostate tissue in men undergoing transurethral prostatectomy or cystoprostatectomy. Effects on differentiation were assayed with flow cytometry using differentiation-specific markers. RESULTS: Low levels of AR were demonstrable in α(2)ß(1)(hi) cells following inhibition of the proteasome using MG132. Furthermore, a direct effect of androgen was shown in stabilising/inducing AR expression. Androgen treatment of α(2)ß(1)(hi) cells was associated with the induction of differentiation using a number of differentiation-specific markers (prostatic acid phosphatase, cytokeratin 18 and AR) with increases ranging from 49% to 67% (p<0.05). These effects were blocked with the AR-specific inhibitor bicalutamide (p<0.05). These data support a role of direct androgen activity on stem cell enriched cells in the prostate and the implications of these findings are discussed.