title: GLUT-1 expression is largely unrelated to both hypoxia and the Warburg phenotype in squamous cell carcinomas of the vulva.
abstract: BACKGROUND
  Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy.
  
  
  METHODS
  We have chosen squamous cell carcinomas of the vulva (SCC-V) as a representative solid tumor entity to study the central players of this pathway, namely glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX, hexokinase (HK)-2 and pyruvate kinase (PK)-M2, and have investigated their relationships to tumor microvessels (CD34, αSMA) and proliferation (Ki67). Expression of these proteins was analyzed in 38 SCC-Vs, 5 vulvar dysplasias and 10 non-neoplastic squamous epithelia of the vulva using multiparametric immunohistochemistry in registered serial sections (MIRSS).
  
  
  RESULTS
  Expression of GLUT-1 in invasive carcinomas was predominantly located in the outer layers of the tumor cell aggregates close to the vascularized tumor stroma, and only to a lesser extent colocalized with CA IX, which was repeatedly found at larger diffusion distances away from microvessels. CA IX expression was lower in invasive carcinomas compared to dysplasias and non-neoplastic tissue and higher in recurrent vs. primary tumors. Ki67-positive proliferating cells were partially colocalized with GLUT-1. However, HK-2 and PK-2--proteins centrally involved in the Warburg phenotype--did not show such a correlation.
  
  
  CONCLUSIONS
  Consistent with prior studies, the pattern of GLUT-1 clearly indicated that a large part of its expression is presumably unrelated to hypoxia. However, there was also no association with HK-2 and PK-M2, suggesting that the functional background of this expression is also independent of aerobic glycolysis. CA IX may be worth consideration as a marker of biological hypoxia, as should its pathophysiological consequences in SCC-V.
authors.affiliation: Department of Radiooncology and Radiotherapy, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany. arnmayer@uni-mainz.de.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Mayer
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.forename: Alexander
authors.initials: A
authors.lastname: Seeger
authors.forename: André Franke
authors.initials: AF
authors.lastname: Serras
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidberger
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D014846:Vulvar Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D051272:Glucose Transporter Type 1; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases