title: Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: spatial distribution and prognostic value of GLUT1 and MCT4.
abstract: BACKGROUND
  Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated.
  
  
  METHODS
  GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival.
  
  
  RESULTS
  Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032).
  
  
  CONCLUSIONS
  Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.
authors.affiliation: Department of Radiation Oncology, 874 Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. T.Meijer@rther.umcn.nl
authors.forename: Tineke W H
authors.initials: TW
authors.lastname: Meijer
authors.forename: Olga C J
authors.initials: OC
authors.lastname: Schuurbiers
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.forename: Monika G
authors.initials: MG
authors.lastname: Looijen-Salamon
authors.forename: Lioe-Fee
authors.initials: LF
authors.lastname: de Geus-Oei
authors.forename: Ad F T M
authors.initials: AF
authors.lastname: Verhagen
authors.forename: Jasper
authors.initials: J
authors.lastname: Lok
authors.forename: Henricus F M
authors.initials: HF
authors.lastname: van der Heijden
authors.forename: Saskia E
authors.initials: SE
authors.lastname: Rademakers
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C406962:SLC16A4 protein, human