Validation of stem cell markers in clinical prostate cancer: α6-Integrin is predictive for non-aggressive disease

• Published in: The Prostate Vol. 74; no. 5; pp. 488 - 496
• Main Authors: Hoogland, A. Marije, Verhoef, Esther I., Roobol, Monique J., Schröder, Fritz H., Wildhagen, Mark F., van der Kwast, Theo H., Jenster, Guido, van Leenders, Geert J.L.H.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.05.2014
• Subjects: Aged; Biomarkers, Tumor - metabolism; Disease Progression; Enhancer of Zeste Homolog 2 Protein; EZH2; Humans; Immunohistochemistry; Integrin alpha6 - metabolism; Male; Middle Aged; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Polycomb Repressive Complex 2 - metabolism; Prognosis; prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-kit - metabolism; Receptors, OX40 - metabolism; stem cells; α2-integrin; α2-integrin; stem cells; prostate cancer; immunohistochemistry; EZH2
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.22768

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. Prostate 74:488–496, 2014. © 2013 Wiley Periodicals, Inc.