title: Low phosphorylated AKT expression in laryngeal cancer: indications for a higher metastatic risk.
abstract: OBJECTIVE
  To validate the association of phosphorylated (p)AKT with lymph node metastasis in an independent, homogeneous cohort of patients with larynx cancer.
  
  
  METHODS
  Seventy-eight patients with laryngeal cancer were included. Epidermal growth factor receptor, pAKT, vimentin, E-cadherin, hypoxia, and blood vessels were visualized in biopsy material using immunohistochemistry. Positive tumor areas and spatial relationships between markers were assessed by automated image analysis. In 6 laryngeal cancer cell lines, E-cadherin and vimentin messenger RNA was quantified by real-time polymerase chain reaction and by immunohistochemistry before and after treatment with the pAKT inhibitor MK-2206.
  
  
  RESULTS
  A significant correlation was found between low pAKT in the primary tumor and positive lymph node status (P=.0005). Tumors with lymph node metastases had an approximately 10-fold lower median pAKT value compared with tumors without lymph node metastases, albeit with large intertumor variations, validating our previous results. After inhibition of pAKT in laryngeal cancer cells with MK-2206, up-regulation of vimentin and a downregulation of E-cadherin occurred, consistent with epithelial-mesenchymal transition.
  
  
  CONCLUSIONS
  Low pAKT expression in larynx tumors is associated with lymph node metastases. Further, inhibition of pAKT in laryngeal cancer induces epithelial-mesenchymal transition, predisposing for an increased metastatic risk.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Nijkamp
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Hanneke
authors.initials: H
authors.lastname: Stegeman
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007822:Laryngeal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
chemical_list: D015820:Cadherins; D014746:Vimentin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt