PURPOSE: Lactate dehydrogenase 5 (LDH-5) regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition. Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors. The clinical significance of tissue LDH-5, however, remains largely unexplored. PATIENTS AND METHODS: We investigated the immunohistochemical expression of LDH-5 in a series of 128 stage II/III colorectal adenocarcinomas treated with surgery alone. In addition, markers of tumor hypoxia (hypoxia-inducible factor 1 alpha [HIF1alpha]), angiogenesis (vascular endothelial growth factor [VEGF] and phosporylated kinase domain receptor [pKDR]/flk-1 receptor) and the tumor vascular density (CD31 positive standard vascular density [sVD] and pKDR positive activated vascular density [aVD]) were assessed. RESULTS: The expression of LDH-5, together with that of HIF1alpha and pKDR, was both nuclear and cytoplasmic. Assessment, with minimal interobserver variability, was achieved using a previously described scoring system. LDH-5 was significantly associated with HIF1alpha (P = .01), aVD (P = .001) and, particularly, with pKDR expression in cancer cells (P = .0001). Tissue LDH-5 expression was linked with elevated serum LDH levels, but serum levels failed to reflect tissue expression in 71% of LDH-5 positive cases. In univariate analysis tissue LDH-5 was associated with poor survival (P = .0003, HR 15.1), whereas in multivariate analysis this isoenzyme was the strongest independent prognostic factor (P = .0009). VEGF, pKDR, aVD, sVD and vascular invasion were all significantly related to unfavorable prognosis. CONCLUSION: The immunohistochemical assessment of tissue LDH-5 and pKDR provides important prognostic information in operable colorectal cancer. The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor therapy.
PURPOSE:Lactate dehydrogenase 5 (LDH-5) regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition. Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors. The clinical significance of tissue LDH-5, however, remains largely unexplored. PATIENTS AND METHODS: We investigated the immunohistochemical expression of LDH-5 in a series of 128 stage II/III colorectal adenocarcinomas treated with surgery alone. In addition, markers of tumor hypoxia (hypoxia-inducible factor 1 alpha [HIF1alpha]), angiogenesis (vascular endothelial growth factor [VEGF] and phosporylated kinase domain receptor [pKDR]/flk-1 receptor) and the tumor vascular density (CD31 positive standard vascular density [sVD] and pKDR positive activated vascular density [aVD]) were assessed. RESULTS: The expression of LDH-5, together with that of HIF1alpha and pKDR, was both nuclear and cytoplasmic. Assessment, with minimal interobserver variability, was achieved using a previously described scoring system. LDH-5 was significantly associated with HIF1alpha (P = .01), aVD (P = .001) and, particularly, with pKDR expression in cancer cells (P = .0001). Tissue LDH-5 expression was linked with elevated serum LDH levels, but serum levels failed to reflect tissue expression in 71% of LDH-5 positive cases. In univariate analysis tissue LDH-5 was associated with poor survival (P = .0003, HR 15.1), whereas in multivariate analysis this isoenzyme was the strongest independent prognostic factor (P = .0009). VEGF, pKDR, aVD, sVD and vascular invasion were all significantly related to unfavorable prognosis. CONCLUSION: The immunohistochemical assessment of tissue LDH-5 and pKDR provides important prognostic information in operable colorectal cancer. The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor therapy.
Authors: F Graziano; A Ruzzo; E Giacomini; T Ricciardi; G Aprile; F Loupakis; P Lorenzini; E Ongaro; F Zoratto; V Catalano; D Sarti; E Rulli; C Cremolini; M De Nictolis; G De Maglio; A Falcone; G Fiorentini; M Magnani Journal: Pharmacogenomics J Date: 2016-03-01 Impact factor: 3.550
Authors: Alexandra Giatromanolaki; Efthimios Sivridis; Nikolaos E Bechrakis; Gregor Willerding; Georgios St Charitoudis; Michael H Foerster; Kevin C Gatter; Adrian L Harris; Michael I Koukourakis Journal: Clin Exp Metastasis Date: 2011-10-09 Impact factor: 5.150
Authors: Aaron Boudreau; Hans E Purkey; Anna Hitz; Kirk Robarge; David Peterson; Sharada Labadie; Mandy Kwong; Rebecca Hong; Min Gao; Christopher Del Nagro; Raju Pusapati; Shuguang Ma; Laurent Salphati; Jodie Pang; Aihe Zhou; Tommy Lai; Yingjie Li; Zhongguo Chen; Binqing Wei; Ivana Yen; Steve Sideris; Mark McCleland; Ron Firestein; Laura Corson; Alex Vanderbilt; Simon Williams; Anneleen Daemen; Marcia Belvin; Charles Eigenbrot; Peter K Jackson; Shiva Malek; Georgia Hatzivassiliou; Deepak Sampath; Marie Evangelista; Thomas O'Brien Journal: Nat Chem Biol Date: 2016-08-01 Impact factor: 15.040
Authors: M I Koukourakis; A Giatromanolaki; E Sivridis; M Pitiakoudis; K C Gatter; A L Harris Journal: Br J Cancer Date: 2010-09-14 Impact factor: 7.640