title: Hunterian Lecture. Characterisation of human prostate epithelial progenitor differentiation in response to androgens.
abstract: BACKGROUND
  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)β(1) integrin expression (α(2)β(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)β(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)β(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.
authors.affiliation: Department of Urology, Freeman Hospital, High Heaton, Newcastle upon Tyne, NE7 7DN, UK. rakesh.heer@ncl.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Heer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D045165:Testosterone Congeners / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D000943:Antigens, Differentiation; D014408:Biomarkers, Tumor; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009570:Nitriles; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D014105:Tosyl Compounds; D015741:Metribolone; C053541:bicalutamide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde