title: Cancer stem cell phenotype relates to radio-chemotherapy outcome in locally advanced squamous cell head-neck cancer.
abstract: BACKGROUND
  Cancer stem cells (CSCs) tend to repopulate malignant tumours during radiotherapy and, therefore, prolongation of the overall treatment time may result in radiotherapy failure. Thus, an estimate of the number of CSCs in tumour biopsies may prove most useful in predicting resistance to radiotherapy and a guide for development therapies aimed to eradicate a cancer cell population with effects on radiotherapy-related cancer regrowth.
  
  
  METHODS
  The CSC population was investigated semi-quantitatively in 74 locally advanced squamous cell head-neck cancers (HNSCC) from an equal number of patients, treated with accelerated platinum-based radiotherapy. A standard immunohistochemical technique and the CSC markers CD44, CD24, Oct4, integrin-β1 and aldehyde dehydrogenase isoform 1A1 (ALDHA1) was used, in parallel with the proliferation marker MIB-1. The results were correlated with the site of the tumour, the MIB-1 index, the tumour grade and stage, and prognosis.
  
  
  RESULTS
  The expression of CD44, CD24 and Oct4 were significantly associated with the MIB-1 proliferation index. In addition, the CD44 was linked with the better differentiated HNSCC. The CD44, Oct4 and integrin-β1 were all associated with poor prognosis but, in a multivariate analysis, the integrin-β1 had an independent statistical significance in terms of local relapse, distant metastases and overall survival. Interestingly, ALDH1 was associated with favourable prognosis.
  
  
  CONCLUSIONS
  CSC markers are linked with poor radiotherapy outcome in HNSCC, with integrin-β1 being the strongest and independent prognostic factor. Targeting CSC molecules with monoclonal antibodies or pharmaceutical agents may prove important for the treatment of HNSCC.
authors.affiliation: Department of Radiotherapy/Oncology, Democritus University of Thrace and University General Hospital of Alexandroupolis, PO Box 12, Alexandroupolis 68100, Greece. targ@her.forthnet.gr
authors.forename: M I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: A
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: V
authors.initials: V
authors.lastname: Tsakmaki
authors.forename: V
authors.initials: V
authors.lastname: Danielidis
authors.forename: E
authors.initials: E
authors.lastname: Sivridis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000032:analysis; D000080924:Aldehyde Dehydrogenase 1 Family; D014408:Biomarkers, Tumor / Q000032:analysis; D051927:CD24 Antigen / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D039641:Integrin beta Chains / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D010641:Phenotype; D011379:Prognosis; D050697:Retinal Dehydrogenase; D000077195:Squamous Cell Carcinoma of Head and Neck; D044767:Ubiquitin-Protein Ligases / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D039641:Integrin beta Chains; D050814:Octamer Transcription Factor-3; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases