Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer

Brizel, David M.; Schroeder, Thies; Scher, Richard L.; Walenta, Stefan; Clough, Robert; Dewhirst, Mark W.; Mueller‐Klieser, Wolfgang

doi:10.1016/s0360-3016(01)01630-3

Cited by 491 publications

(303 citation statements)

References 13 publications

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“…This may be a result of the different tumor burden that radiotherapy has to eradicate in the 2 groups, which results in a stronger impact of LDH5 on the locoregional control of tumors treated with radical radiotherapy. This finding stresses the importance of the LDH pathway in radioresistance in accordance with the study by Brizel et al [28]. High LDH5 tissue levels significantly compromised the OS both in patients treated with postoperative and radical radiotherapy.…”

Section: Discussionsupporting

confidence: 91%

“…Other studies have also focused on the end product of LDH5’s catalytic activity, namely lactate. Increased lactate tumor content in nude mice xenografted with different SCHNC lines showed a marked radioresistance [27], a finding clinically confirmed by Brizel et al [28] in a series of HNC patients treated with postoperative or radical radiotherapy.…”

Section: Discussionmentioning

confidence: 80%

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Lactate Dehydrogenase 5 Expression in Squamous Cell Head and Neck Cancer Relates to Prognosis following Radical or Postoperative Radiotherapy

et al. 2009

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Objectives: We assessed the expression and the prognostic role of lactate dehydrogenase 5 (LDH5, the major LDH isoenzyme involved in anaerobic glycolysis) in patients with squamous cell head and neck cancer (SCHNC). Methods: LDH5 was assessed immunohistochemically in whole tissue sections from 141 patients with SCHNC. Of these, 102 were subjected to surgery with (90 patients) or without (12 patients) postoperative radiotherapy (group A), while 39 patients were treated with radical radiotherapy (group B). Results: Mixed nuclear/cytoplasmic LDH5 expression was detected in 72.5% of group A and 61.5% of group B patients. This was significantly related to T4-stage (p = 0.04) and hypoxia-inducible factor-1α (HIF-1α) expression (p = 0.002). In group A, high LDH5 was linked with poorer distant metastasis-free survival (p = 0.01) and disease-specific overall survival (OS; p = 0.009). In multivariate analysis, LDH5 (p = 0.002) and HIF-1α (p = 0.01) were independently linked with distant metastasis. LDH5 was also linked with death events (p = 0.005). In group B, high LDH5 expression was significantly associated with poorer local relapse-free survival (p = 0.009) and OS (p = 0.01). In multivariate analysis, only T stage was a significant predictor of death events (p = 0.04). Conclusions: LDH5 is highly expressed in SCHNC and is linked with local relapse, survival and distant metastasis, suggesting that LDH5 is a marker of radioresistance and a target for therapeutic interventions.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 80%

Lactate Dehydrogenase 5 Expression in Squamous Cell Head and Neck Cancer Relates to Prognosis following Radical or Postoperative Radiotherapy

et al. 2009

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“…Other studies have shown that high tumour lactate levels can enhance the in vitro migration and invasion of cancer cells (MartinezZaguilan et al, 1996;Shi et al, 2001;Stern et al, 2002). Furthermore, the production of lactate in solid malignant tumours has been correlated with a high incidence of distant metastasis (Brizel et al, 2001). Although using the in vitro kinetic enzyme assay and zymography we showed a lower overall LDH enzyme activity in the LNCaP-LN3 variant compared to LNCaP cells, these results may not represent the in vivo scenario, where tumour cells frequently encounter hypoxic conditions (Vaupel and Harrison, 2004).…”

Section: Discussionmentioning

confidence: 97%

Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer

et al. 2006

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In order to identify novel candidates associated with prostate cancer metastasis, we compared the proteomic profile of the poorly metastatic human prostate cancer cell line LNCaP, with its highly metastatic variant LNCaP-LN3, by two-dimensional gel electrophoresis. A major protein spot (pI of 5.9 and molecular weight of 37 kDa) was seen in LNCaP cells, but not in LNCaP-LN3 cells and was identified as lactate dehydrogenase-B (LDHB), by tandem mass spectrometry. Furthermore, enzyme kinetic assays and zymography showed a higher LDH enzyme activity in LNCaP cells compared with LNCaP-LN3. Bisulphite-modified DNA sequencing showed promoter hypermethylation in LNCaP-LN3 cells but not in LNCaP, Du145, PC3, CWR22 or BPH45 cells. Treatment of LNCaP-LN3 cells with 5 0 -azacytidine caused reexpression of LDHB transcripts. In tissues, LDHB promoter hypermethylation occurred at a higher frequency in prostate cancer, 14/ 31 (45%), compared to adjacent nonmalignant or benign tissue, 2/19 (11%) (Po0.025). Immunohistochemistry showed a higher frequency of LDHB expression in benign or nonmalignant tissues, 59/ 73 (81%), compared to cancer cases, 3/53 (6%) (Po0.001). Absent LDHB expression was also seen in 7/7 (100%) cases of metastatic cancer in bone. Our data are the first to show loss of LDHB expression in prostate cancer, the mechanism of which appears to involve promoter hypermethylation.

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“…11, C and D). DISCUSSION It has long been recognized that the glycolytic pathway is important for tumor growth especially under hypoxic conditions (13,31). The glucose carbons can be degraded to lactate with a concomitant production of energy or can be channeled into synthetic processes, such as nucleic acid, lipid, and amino acid synthesis (32,33).…”

Section: Effect Of Extracellular Pyruvate On the Pgmtide-induced Inhimentioning

confidence: 99%

Phosphoglycerate Mutase-derived Polypeptide Inhibits Glycolytic Flux and Induces Cell Growth Arrest in Tumor Cell Lines

Engel

Mazurek

Eigenbrodt

et al. 2004

Journal of Biological Chemistry

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The putative tumor metastasis suppressor protein Nm23-H1 is a nucleoside diphosphate kinase that exhibits a novel protein kinase activity when bound to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In this study we show that the glycolytic enzyme phosphoglycerate mutase B (PGM) becomes phosphorylated in the presence of the Nm23-H1⅐GAPDH complex in vitro. Mutation of His-10 in PGM abolishes the Nm23-H1⅐GAPDH complex-induced phosphorylation. Nm23-H1, GAPDH, and PGM are known to co-localize as shown by free flow isoelectric focusing. In association with Nm23-H1 and GAPDH, PGM could be activated by dCTP, which is a substrate of Nm23-H1, in addition to the well known PGM activator 2,3-bisphosphoglycerate. A synthetic cell-penetrating peptide (PGMtide) encompassing the phosphorylated histidine and several residues from PGM (LIRHGE) promoted growth arrest of several tumor cell lines, whereas proliferation of tested non-tumor cells was not influenced. Analysis of metabolic activity of one of the tumor cell lines, MCF-7, indicated that PGMtide inhibited glycolytic flux, consistent with in vivo inhibition of PGM. The specificity of the observed effect was further determined experimentally by testing the effect of PGMtide on cells growing in the presence of pyruvate, which helps to compensate PGM inhibition in the glycolytic pathway. Thus, growth of MCF-7 cells was not arrested by PGMtide in the presence of pyruvate. The data presented here provide evidence that inhibition of PGM activity can be achieved by exogenous addition of a polypeptide, resulting in inhibition of glycolysis and cell growth arrest in cell culture.

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Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer

Cited by 491 publications

References 13 publications

Lactate Dehydrogenase 5 Expression in Squamous Cell Head and Neck Cancer Relates to Prognosis following Radical or Postoperative Radiotherapy

Lactate Dehydrogenase 5 Expression in Squamous Cell Head and Neck Cancer Relates to Prognosis following Radical or Postoperative Radiotherapy

Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer

Phosphoglycerate Mutase-derived Polypeptide Inhibits Glycolytic Flux and Induces Cell Growth Arrest in Tumor Cell Lines

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