title: Validation of stem cell markers in clinical prostate cancer: α6-integrin is predictive for non-aggressive disease.
abstract: BACKGROUND
  Stem cells are postulated to mediate prostate cancer progression, and represent a small fraction of the entire tumor. Various proteins (α2-integrin, α6-integrin, CD117, CD133, EZH2, OCT3/4) are associated with a prostate cancer stem cell phenotype in cell lines and xenografts. Our objective was to investigate expression of stem cell markers in clinical prostate cancer in relation to outcome.
  
  
  METHODS
  We validated immunohistochemical expression of stem cell markers in 481 prostate cancer patients and correlated expression with clinicopathologic parameters.
  
  
  RESULTS
  Sporadic expression of α2-integrin was present in a fraction of tumor cells (<5%) in 94.7% of tumors and associated with PSA > 10 ng/ml (P = 0.04). α6-Integrin expression (<5%) occurred in 28.4% patients, while ≥5% α6-integrin expression was associated with PSA≤10 ng/ml (P = 0.01), Gleason score <7 (P < 0.01) and pT2-disease (P = 0.02). α6-integrin was predictive for biochemical recurrence (P < 0.01), local recurrence (P = 0.03) and disease specific death (P = 0.03). EZH2 expression was generally low with 2.6% of tumors showing ≥1% positive cells. EZH2 was associated with Gleason score ≥7 (P = 0.01) and biochemical recurrence (P = 0.01). We did not identify expression of CD117, CD133, and OCT3/4 in prostate cancer samples.
  
  
  CONCLUSIONS
  Expression of α2-integrin and EZH2 in a small fraction of prostate cancer cells is supportive for their role as stem cell marker. Although α6-integrin was not a unique stem cell marker, it was predictive for prostate cancer biochemical and local recurrence, and disease specific death. The validity of CD117, CD133, and OCT3/4 as prostate cancer stem cell marker is questionable since these proteins were not expressed in clinical prostate cancer.
authors.affiliation: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A Marije
authors.initials: AM
authors.lastname: Hoogland
authors.forename: Esther I
authors.initials: EI
authors.lastname: Verhoef
authors.forename: Monique J
authors.initials: MJ
authors.lastname: Roobol
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Schröder
authors.forename: Mark F
authors.initials: MF
authors.lastname: Wildhagen
authors.forename: Theo H
authors.initials: TH
authors.lastname: van der Kwast
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.forename: Geert J L H
authors.initials: GJ
authors.lastname: van Leenders
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D007150:Immunohistochemistry; D039503:Integrin alpha6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D053262:Receptors, OX40 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D039503:Integrin alpha6; D053262:Receptors, OX40; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D019009:Proto-Oncogene Proteins c-kit
keywords: EZH2; immunohistochemistry; prostate cancer; stem cells; α2-integrin