Skip to main content

Advertisement

SpringerLink
Log in

Metabolic and proteomic differentials in head and neck squamous cell carcinomas and normal gingival tissue

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

A high lactate content in malignant head and neck cancer (Head and neck squamous cell carcinomas, HNSCC) is associated with a higher risk of metastatic spread and lower overall patient survival. However, until present, the underlying mechanisms are not clearly understood. Here, a systematic comparison of glucose metabolism in HNSCC and homologous normal tissue is presented for the first time.

Methods

The concentrations of glucose, lactate and ATP were measured in cryobiopsies of 29 human HNSCC and of 9 normal mucosa using bioluminescence imaging. The protein expression of lactate dehydrogenase (LDH) was analyzed by Western blotting.

Results

Tumors own a higher content of lactate and LDH in comparison with normal tissues. However, within the tumor group, the grade of LDH expression shows substantially strong variation and overlap with normal values. Furthermore, LDH expression was not correlated with tumor lactate content. Investigating a small subpopulation, patients with a short-term survival had significantly higher tumor lactate levels compared to patients with long-term survival.

Conclusions

The data provide clear evidence of an enhanced glycolysis in tumors compared to normal tissue. This may partially but not completely attributable to an elevated expression of LDH. High tumor lactate levels may be predictive for restricted patient survival. In conclusion, lactate measurements, for example non-invasively with MRT, should be advanced for use in clinical routine as a supportive tool for tumor diagnosis and prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Albers MJ, Bok R, Chen AP, Cunningham CH, Zierhut ML, Zhang VY, Kohler SJ, Tropp J, Hurd RE, Yen YF, Nelson SJ, Vigneron DB, Kurhanewicz J (2008) Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. Cancer Res 68:8607–8615

    Article  CAS  PubMed  Google Scholar 

  • Bier J (1981) Definitionen zum radikalchirurgischen Vorgehen bei Plattenepithelkarzinomen der Mundhöhle. Dtsch Z Mund Kiefer Gesichts Chir 6:369–372

    Google Scholar 

  • Brindle K (2008) New approaches for imaging tumour responses to treatment. Nat Rev Cancer 8:94–107

    Article  CAS  PubMed  Google Scholar 

  • Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W (2001) Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 51:349–353

    CAS  PubMed  Google Scholar 

  • Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F, Wang J, Shindo M, Higashino F, Takeda K, Asaka M, Katoh H, Sugiyama T, Hosokawa M, Kobayashi M (2003) Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am J Pathol 162:1283–1291

    CAS  PubMed  Google Scholar 

  • DeBerardinis RJ, Cheng T (2009) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–314

    Article  PubMed  Google Scholar 

  • Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb E, Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5:857–866

    Article  CAS  PubMed  Google Scholar 

  • Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153

    Article  CAS  PubMed  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL (2003) Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer 89:877–885

    Article  CAS  PubMed  Google Scholar 

  • Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63:1138–1143

    CAS  PubMed  Google Scholar 

  • Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482

    Article  CAS  PubMed  Google Scholar 

  • Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115

    Article  CAS  PubMed  Google Scholar 

  • Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653

    Article  CAS  PubMed  Google Scholar 

  • Matoba M, Tonami H, Kondou T, Yokota H, Higashi K, Toga H, Sakuma T (2007) Lung carcinoma: diffusion-weighted MR imaging—preliminary evaluation with apparent diffusion coefficient. Radiology 243:570–577

    Article  PubMed  Google Scholar 

  • Mueller-Klieser W, Walenta S (1993) Geographical mapping of metabolites in biological tissue with quantitative bioluminescence and single photon imaging. Histochem J 25:407–420

    Article  CAS  PubMed  Google Scholar 

  • Mueller-Klieser W, Schaefer C, Walenta S, Rofstad EK, Fenton BM, Sutherland RM (1990) Assessment of tumor energy and oxygenation status by bioluminescence, nuclear magnetic resonance spectroscopy, and cryospectrophotometry. Cancer Res 50:1681–1685

    CAS  PubMed  Google Scholar 

  • Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A (2006) EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 66:3197–3204

    Article  CAS  PubMed  Google Scholar 

  • Quennet V, Yaromina A, Zips D, Rosner A, Walenta S, Baumann M, Mueller-Klieser W (2006) Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice. Radiother Oncol 81:130–135

    Article  CAS  PubMed  Google Scholar 

  • Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol 76:589–605

    Article  CAS  PubMed  Google Scholar 

  • Sattler UG, Hirschhaeuser F, Mueller-Klieser WF (2010) Manipulation of glycolysis in malignant tumors: fantasy or therapy? Curr Med Chem 17:96–108

    Article  CAS  PubMed  Google Scholar 

  • Schwickert G, Walenta S, Sundfor K, Rofstad EK, Mueller-Klieser W (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 55:4757–4759

    CAS  PubMed  Google Scholar 

  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (2002) HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 8:S62–S67

    Article  CAS  PubMed  Google Scholar 

  • Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700

    Article  CAS  PubMed  Google Scholar 

  • Walenta S, Mueller-Klieser WF (2004) Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol 14:267–274

    Article  PubMed  Google Scholar 

  • Walenta S, Dotsch J, Mueller-Klieser W (1990) ATP concentrations in multicellular tumor spheroids assessed by single photon imaging and quantitative bioluminescence. Eur J Cell Biol 52:389–393

    CAS  PubMed  Google Scholar 

  • Walenta S, Dellian M, Goetz AE, Kuhnle GE, Mueller-Klieser W (1992) Pixel-to-pixel correlation between images of absolute ATP concentrations and blood flow in tumours. Br J Cancer 66:1099–1102

    CAS  PubMed  Google Scholar 

  • Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, Mueller-Klieser W (1997) Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol 150:409–415

    CAS  PubMed  Google Scholar 

  • Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–921

    CAS  PubMed  Google Scholar 

  • Walenta S, Schroeder T, Mueller-Klieser W (2002) Metabolic mapping with bioluminescence: basic and clinical relevance. Biomol Eng 18:249–262

    Article  CAS  PubMed  Google Scholar 

  • Walenta S, Chau TV, Schroeder T, Lehr HA, Kunz-Schughart LA, Fuerst A, Mueller-Klieser W (2003) Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists? J Cancer Res Clin Oncol 129:321–326

    Article  PubMed  Google Scholar 

  • Walenta S, Schroeder T, Mueller-Klieser W (2004) Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem 11:2195–2204

    CAS  PubMed  Google Scholar 

  • Yaromina A, Quennet V, Zips D, Meyer S, Shakirin G, Walenta S, Mueller-Klieser W, Baumann M (2009) Co-localisation of hypoxia and perfusion markers with parameters of glucose metabolism in human squamous cell carcinoma (hSCC) xenografts. Int J Radiat Biol 85:972–980

    Article  CAS  PubMed  Google Scholar 

  • Zhou S, Kachhap S, Singh KK (2003) Mitochondrial impairment in p53-deficient human cancer cells. Mutagenesis 18:287–292

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Deutsche Forschungsgemeinschaft (Mu 576/14-1) and the Stiftung fuer Innovation Rheinland-Pfalz (15202-38 62 61/606).

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, 55131, Mainz, Germany

    Thomas Ziebart & Wilfried Wagner

  2. Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg-University of Mainz, 55099, Mainz, Germany

    Stefan Walenta & Wolfgang Mueller-Klieser

  3. Department of Oral and Maxillofacial Surgery, University Hospital Bochum, 44892, Bochum, Germany

    Martin Kunkel

  4. Department of Cranio-Maxillofacial Surgery, University of Regensburg, 93053, Regensburg, Germany

    Torsten E. Reichert

Authors
  1. Thomas Ziebart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefan Walenta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Kunkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Torsten E. Reichert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilfried Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wolfgang Mueller-Klieser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Walenta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ziebart, T., Walenta, S., Kunkel, M. et al. Metabolic and proteomic differentials in head and neck squamous cell carcinomas and normal gingival tissue. J Cancer Res Clin Oncol 137, 193–199 (2011). https://doi.org/10.1007/s00432-010-0875-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-010-0875-y

Keywords

Search

Navigation