title: Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis.
abstract: OBJECTIVE
  Lactate dehydrogenase (LDH-5) is a major lactate dehydrogenase isoenzyme catalyzing the transformation of pyruvate to lactate for anaerobic acquisition energy. In this study, the expression of LDH-5 was assessed in the normal and malignant endometrium. Its role in prognosis and tumor angiogenesis and hypoxia was also examined.
  
  
  METHODS
  Tissue specimens from 68 patients with clinical stage I endometrial adenocarcinoma of the endometrioid cell type and 20 samples from normally cycling endometrium were investigated immunohistochemically for the expression of LDH-5. The vascular density and the expression of angiogenesis/hypoxia-related proteins (VEGF, HIF1alpha, HIF2alpha, phosphorylated VEGFR2/KDR, VEGF/KDR complex) were also assessed.
  
  
  RESULTS
  Unlike other normal epithelia, the glandular endometrial cells consistently expressed LDH-5 suggesting a role of this enzyme in the normal menstrual cycle. Endometrial adenocarcinomas displayed LDH-5 expression in 31/68 (45.5%) cases with those having a high LDH-5 expression being connected with a low lymphocytic response; this may suggest an important role of LDH-5 and, presumably, lactate release in tumor escape from host immuno-surveillance. More importantly, LDH-5 was significantly associated with the expression of phosphorylated VEGFR2/KDR receptors in cancer cells and tumor-associated vasculature. LDH-5 was one of the most powerful and independent prognostic variables.
  
  
  CONCLUSIONS
  LDH-5 expression is an independent prognostic marker in endometrial cancer, linked with impaired host immune response and activation of VEGFR2/KDR receptors in both cancer cells and tumor-associated vasculature. Adjuvant radio-chemotherapy may, therefore, be useful in these cases, while the administration of VEGF- tyrosine kinase receptor inhibitors emerges as a therapeutic option.
authors.affiliation: Department of Pathology, Democritus University of Thrace, Medical School, PO Box 12, Alexandroupolis 68100, Greece, and John Radcliffe Hospital, Oxford, UK. targ@her.forthnet.gr
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Gatter
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality; D014408:Biomarkers, Tumor / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000401:mortality; D004739:England; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D011379:Prognosis; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D007527:Isoenzymes; D042461:Vascular Endothelial Growth Factor A; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D040301:Vascular Endothelial Growth Factor Receptor-2