title: Elevated intrinsic cancer stem cell population in human papillomavirus-associated head and neck squamous cell carcinoma.
abstract: BACKGROUND
  Human papillomavirus 16 (HPV16) is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), particularly the development of oropharyngeal squamous cell carcinoma (OPSCC). Cancer stem cells (CSCs) are resistant to conventional therapies, and it is postulated that they are responsible for disease recurrence and/or progression. Because the prognoses of patients with HPV16-positive and HPV-negative HNSCC are distinct, the authors sought to determine whether differences in the number of CSCs could account for this clinical observation.
  
  
  METHODS
  CSC populations in HPV16-positive and HPV-negative HNSCC were assessed using a proprietary assay based on expression of the enzyme aldehyde dehydrogenase (ALDH), an in vitro tumorsphere formation assay, and an in vivo limiting cell dilution in nonobese diabetic/severe combined immunodeficiency mice. A high-density tissue microarray was stained with ALDH1, a CSC marker, to determine the association between CSCs and HPV16-positive/HPV-negative OPSCC.
  
  
  RESULTS
  HPV16-positive HNSCC had a greater intrinsic CSC pool than HPV-negative HNSCC. Inactivation of p53 has been identified as a major mechanism for the elevated CSC population in HPV16-positive HNSCC. In vivo limiting cell dilution experiments using tumors from patients with HPV16-positive and HPV-negative OPSCC indicated that the CSC frequency was 62.5-fold greater in an HPV16-positive OPSCC tumor than in an HPV-negative OPSCC tumor. Primary tumors from patients with HPV16-positive OPSCC were associated with elevated tumor ALDH1 staining, further extending the association between HPV16 and CSCs.
  
  
  CONCLUSIONS
  The current data and the clinical observation that patients with HPV16-positive HNSCC respond more favorably to current treatment paradigms than patients with HPV-negative HNSCC support the suggestion that CSC phenotype is not homogeneous. Therefore, the reliance on the CSC number may be insufficient to accurately assess the potential of a particular tumor for disease recurrence and/or progression.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Manchao
authors.initials: M
authors.lastname: Zhang
authors.forename: Bhavna
authors.initials: B
authors.lastname: Kumar
authors.forename: Longzhu
authors.initials: L
authors.lastname: Piao
authors.forename: Xiujie
authors.initials: X
authors.lastname: Xie
authors.forename: Alessandra
authors.initials: A
authors.lastname: Schmitt
authors.forename: Nicole
authors.initials: N
authors.lastname: Arradaza
authors.forename: Michael
authors.initials: M
authors.lastname: Cippola
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.forename: Amit
authors.initials: A
authors.lastname: Agrawal
authors.forename: Enver
authors.initials: E
authors.lastname: Ozer
authors.forename: David E
authors.initials: DE
authors.lastname: Schuller
authors.forename: Theodoros N
authors.initials: TN
authors.lastname: Teknos
authors.forename: Quintin
authors.initials: Q
authors.lastname: Pan
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000821:virology*; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000821:virology*; D052162:Human papillomavirus 16 / Q000302:isolation & purification*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000821:virology; D030361:Papillomavirus Infections / Q000473:pathology* / Q000821:virology; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck
keywords: ALDH1; cancer stem cells; cancer-initiating cells; head and neck cancer; human papillomavirus; prognostic biomarker