Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis.
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.
Giatromanolaki
Alexandra
A
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
Sivridis
Efthimios
E
Gatter
Kevin C
KC
Turley
Helen
H
Harris
Adrian L
AL
Koukourakis
Michael I
MI
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*
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