title: Putative stem cell markers in non-small-cell lung cancer: a clinicopathologic characterization.
abstract: BACKGROUND
  The cancer stem cell (CSC) theory postulates the existence of a distinct population of undifferentiated cells responsible for tumor initiation and maintenance. CSCs may be naturally resistant to the cytotoxic effect of radio-chemotherapy because of slow cell cycling, lower proliferation, and increased expression of DNA repair and antiapoptosis genes. To date, a universal marker for CSCs has not been identified. Proposed CSC markers are expressed both by cancer cells as well as by benign stem cells. Although many putative CSC markers exist, a precise characterization for non-small-cell lung cancer (NSCLC) is lacking.
  
  
  METHODS
  We explored the expression of multiple alleged stemness associated markers in 371 surgically resected NSCLCs. Extensive clinical data and a postoperative follow-up period of up to 15 years enabled detailed clinicopathological correlations. ABCG5, ALDH1, CD24, CD44, CD133, CD166, epithelial cell adhesion molecule epitopes (ESA, MOC-31, Ber-EP4), nestin, OCT4, and sex-determining region Y-box 2 were analyzed immunohistochemically by using a standardized tissue microarray platform.
  
  
  RESULTS
  Sex-determining region Y-box 2, CD44, ABCG5, ALDH1, and nestin were associated with poorer tumor differentiation and/or an increased proliferation index. ALDH1, CD44, and SOX2 were frequently found in squamous cell carcinoma, whereas CD24, CD166, and epithelial cell adhesion molecule markers were encountered in adenocarcinomas. CD44 expression was an independent marker associated with better overall survival in squamous cell carcinoma and Ber-EP4 was associated with tumor recurrences.
  
  
  CONCLUSIONS
  The expression and prognostic significance of CSC markers obviously varies depending on histologic NSCLC subtype. Importantly, our findings suggest that CD44 and Ber-EP4 may be promising for ongoing targeted therapies in specific NSCLC subgroups.
authors.affiliation: *Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany; †Institute of Pathology, University Hospital Basel, Basel, Switzerland; and ‡Department of Internal Medicine, Division of Hematology and Oncology, Medical University Innsbruck, Austria.
authors.forename: Willam
authors.initials: W
authors.lastname: Sterlacci
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
authors.forename: Ellen
authors.initials: E
authors.lastname: Obermann
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
mesh_terms: D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D014408:Biomarkers, Tumor; D051927:CD24 Antigen / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D010455:Peptides / Q000032:analysis
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D006023:Glycoproteins; D018960:Hyaluronan Receptors; C000606023:PROM1 protein, human; D010455:Peptides