title: Expression of EGFR under tumor hypoxia: identification of a subpopulation of tumor cells responsible for aggressiveness and treatment resistance.
abstract: OBJECTIVE
  Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena.
  
  
  METHODS
  In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry.
  
  
  RESULTS
  Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome.
  
  
  CONCLUSIONS
  Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. i.hoogsteen@rther.umcn.nl
authors.forename: Ilse J
authors.initials: IJ
authors.lastname: Hoogsteen
authors.forename: Henri A M
authors.initials: HA
authors.lastname: Marres
authors.forename: Franciscus J A
authors.initials: FJ
authors.lastname: van den Hoogen
authors.forename: Paul F J W
authors.initials: PF
authors.lastname: Rijken
authors.forename: Jasper
authors.initials: J
authors.lastname: Lok
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D011379:Prognosis; D011836:Radiation Tolerance / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C033815:pimonidazole; D066246:ErbB Receptors