Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis.
Lactate dehydrogenase-5 (LDH-5) catalyses the reversible transformation of pyruvate to lactate, having a principal position in the anaerobic cellular metabolism. Induction of LDH-5 occurs during hypoxia and LDH-5 transcription is directly regulated by the hypoxia-inducible factor 1 (HIF1). Serum LDH levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy in various neoplastic diseases. The expression, however, of LDH in tumours has never been investigated in the past. In the present study, we established an immunohistochemical method to evaluate the LDH-5 overexpression in tumours, using two novel antibodies raised against the rat muscle LDH-5 and the human LDH-5 (Abcam, UK). The subcellular patterns of expression in cancer cells were mixed nuclear and cytoplasmic. In direct contrast to cancer cells, stromal fibroblasts were reactive for LDH-5 only in a minority of cases. Serum LDH, although positively correlated with, does not reliably reflect the intratumoral LDH-5 status. Lactate dehydrogenase-5 overexpression was directly related to HIF1alpha and 2alpha, but not with the carbonic anhydrase 9 expression. Patients with tumours bearing high LDH-5 expression had a poor prognosis. Tumours with simultaneous LDH-5 and HIF1alpha (or HIF2alpha) overexpression, indicative of a functional HIF pathway, had a particularly aggressive behaviour. It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity.
Koukourakis
M I
MI
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece. targ@her.forthnet.gr
Giatromanolaki
A
A
Sivridis
E
E
Bougioukas
G
G
Didilis
V
V
Gatter
K C
KC
Harris
A L
AL
D000328:Adult; D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000032:analysis*; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis* / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis* / Q000097:blood; D000080864:Lactate Dehydrogenase 5; D008175:Lung Neoplasms / Q000097:blood / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000096:biosynthesis; D011379:Prognosis; D051381:Rats; D015996:Survival Rate; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D043925:Angiogenesis Inducing Agents; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D002256:Carbonic Anhydrases; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497444:Hif1a protein, rat