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Published in: Clinical Oral Investigations 8/2016

01-11-2016 | Original Article

Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma (HNSCC) post radiation: a prospective study over 15 years

Authors: Sebastian Blatt, Nadine Voelxen, Keyvan Sagheb, Andreas Max Pabst, Stefan Walenta, Thies Schroeder, Wolfgang Mueller-Klieser, Thomas Ziebart

Published in: Clinical Oral Investigations | Issue 8/2016

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Abstract

Objectives

Lactate as a key regulator of the glycolytic phenotype has been recently described in fueling tumor growth and metastatic spread in head and neck squamous cell carcinoma (HNSCC). However, in context of tumor recurrence following adjuvant radiation, the underlying mechanisms remain uncertain. We therefore investigate the role of lactate towards radioresistance in HNSCC in this prospective study for the first time in vivo.

Materials and methods

Herein, we analyzed biopsies of primary squamous cell carcinoma after surgery and adjuvant irradiation in 17 patients. Tumor tissue levels of ATP, glucose, and lactate were detected using induced metabolic bioluminescence imaging (imBI) and correlated with clinical data within an observation period of up to 15 years.

Results

High amounts of lactate levels in tumors of HNSCC are significantly negatively correlated with overall patient survival. Moreover, high expression of lactate in a primary tumor site is significantly correlated with tumor recurrence post radiation, whereas ATP and/or glucose showed no such correlation.

Conclusion

Lactate can be seen not only as a waste product of altered glycolytic metabolism but also as a key master of malignancy as well as resistance mechanism towards irradiation.

Clinical relevance

High expression of lactate levels in tumor tissue, obtained by metabolic bioluminescence imaging, may therefore serve as a predictor for overall and recurrence-free survival and could represent a future biomarker in the validation of adjuvant irradiation.
Literature
1.
go back to reference Rassouli A, Saliba J, Castano R, Hier M, Zeitouni AG (2015) Systemic inflammatory markers as independent prognosticators of head and neck squamous cell carcinoma. Head & Neck 37(1):103–110. doi:10.1002/hed.23567 CrossRef Rassouli A, Saliba J, Castano R, Hier M, Zeitouni AG (2015) Systemic inflammatory markers as independent prognosticators of head and neck squamous cell carcinoma. Head & Neck 37(1):103–110. doi:10.​1002/​hed.​23567 CrossRef
5.
go back to reference Chai RC, Lambie D, Verma M, Punyadeera C (2015) Current trends in the etiology and diagnosis of HPV-related head and neck cancers. Cancer Medicine. doi:10.1002/cam4.424 Chai RC, Lambie D, Verma M, Punyadeera C (2015) Current trends in the etiology and diagnosis of HPV-related head and neck cancers. Cancer Medicine. doi:10.​1002/​cam4.​424
6.
go back to reference Grimm M, Alexander D, Munz A, Hoffmann J, Reinert S (2013) Increased LDH5 expression is associated with lymph node metastasis and outcome in oral squamous cell carcinoma. Clinical & Experimental Metastasis 30(4):529–540. doi:10.1007/s10585-012-9557-2 CrossRef Grimm M, Alexander D, Munz A, Hoffmann J, Reinert S (2013) Increased LDH5 expression is associated with lymph node metastasis and outcome in oral squamous cell carcinoma. Clinical & Experimental Metastasis 30(4):529–540. doi:10.​1007/​s10585-012-9557-2 CrossRef
8.
go back to reference O. Warburg KP, E. Negelein (1924) Über den Stoffwechsel der Carcinomzelle. Biochem Z 152:pp. 319–344 O. Warburg KP, E. Negelein (1924) Über den Stoffwechsel der Carcinomzelle. Biochem Z 152:pp. 319–344
9.
go back to reference Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71(7):2550–2560. doi:10.1158/0008-5472.CAN-10-2828 PubMedCrossRef Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71(7):2550–2560. doi:10.​1158/​0008-5472.​CAN-10-2828 PubMedCrossRef
11.
go back to reference Ziebart T, Walenta S, Kunkel M, Reichert TE, Wagner W, Mueller-Klieser W (2011) Metabolic and proteomic differentials in head and neck squamous cell carcinomas and normal gingival tissue. J Cancer Res Clin Oncol 137(2):193–199. doi:10.1007/s00432-010-0875-y PubMedCrossRef Ziebart T, Walenta S, Kunkel M, Reichert TE, Wagner W, Mueller-Klieser W (2011) Metabolic and proteomic differentials in head and neck squamous cell carcinomas and normal gingival tissue. J Cancer Res Clin Oncol 137(2):193–199. doi:10.​1007/​s00432-010-0875-y PubMedCrossRef
12.
go back to reference Goetze K, Meyer SS, Yaromina A, Zips D, Baumann M, Mueller-Klieser W (2013) Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Markers for radiation responsiveness of human tumor xenografts. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al] 189(9):782–788. doi:10.1007/s00066-013-0371-9 CrossRef Goetze K, Meyer SS, Yaromina A, Zips D, Baumann M, Mueller-Klieser W (2013) Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Markers for radiation responsiveness of human tumor xenografts. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al] 189(9):782–788. doi:10.​1007/​s00066-013-0371-9 CrossRef
13.
go back to reference Sattler UG, Meyer SS, Quennet V, Hoerner C, Knoerzer H, Fabian C, Yaromina A, Zips D, Walenta S, Baumann M, Mueller-Klieser W (2010) Glycolytic metabolism and tumour response to fractionated irradiation. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 94(1):102–109. doi:10.1016/j.radonc.2009.11.007 CrossRef Sattler UG, Meyer SS, Quennet V, Hoerner C, Knoerzer H, Fabian C, Yaromina A, Zips D, Walenta S, Baumann M, Mueller-Klieser W (2010) Glycolytic metabolism and tumour response to fractionated irradiation. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 94(1):102–109. doi:10.​1016/​j.​radonc.​2009.​11.​007 CrossRef
16.
go back to reference Feron O (2009) Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiotherapy and Oncology: journal of the European Society for Therapeutic Radiology and Oncology 92(3):329–333. doi:10.1016/j.radonc.2009.06.025 CrossRef Feron O (2009) Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiotherapy and Oncology: journal of the European Society for Therapeutic Radiology and Oncology 92(3):329–333. doi:10.​1016/​j.​radonc.​2009.​06.​025 CrossRef
17.
go back to reference Jensen DH, Therkildsen MH, Dabelsteen E (2014) A reverse Warburg metabolism in oral squamous cell carcinoma is not dependent upon myofibroblasts. Journal of Oral pathology & Medicine: Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. doi:10.1111/jop.12297 Jensen DH, Therkildsen MH, Dabelsteen E (2014) A reverse Warburg metabolism in oral squamous cell carcinoma is not dependent upon myofibroblasts. Journal of Oral pathology & Medicine: Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. doi:10.​1111/​jop.​12297
19.
go back to reference Walenta S, Schroeder T, Mueller-Klieser W (2002) Metabolic mapping with bioluminescence: basic and clinical relevance. Biomol Eng 18(6):249–262PubMedCrossRef Walenta S, Schroeder T, Mueller-Klieser W (2002) Metabolic mapping with bioluminescence: basic and clinical relevance. Biomol Eng 18(6):249–262PubMedCrossRef
21.
go back to reference Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, Leiby B, Cognetti DM, Sotgia F, Lisanti MP, Martinez-Outschoorn UE (2013) Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle 12(9):1371–1384. doi:10.4161/cc.24092 PubMedPubMedCentralCrossRef Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, Leiby B, Cognetti DM, Sotgia F, Lisanti MP, Martinez-Outschoorn UE (2013) Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle 12(9):1371–1384. doi:10.​4161/​cc.​24092 PubMedPubMedCentralCrossRef
22.
go back to reference 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(2):349–353PubMedCrossRef 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(2):349–353PubMedCrossRef
23.
go back to reference Grotius J, Dittfeld C, Huether M, Mueller-Klieser W, Baumann M, Kunz-Schughart LA (2009) Impact of exogenous lactate on survival and radioresponse of carcinoma cells in vitro. Int J Radiat Biol 85(11):989–1001. doi:10.3109/09553000903242156 PubMedCrossRef Grotius J, Dittfeld C, Huether M, Mueller-Klieser W, Baumann M, Kunz-Schughart LA (2009) Impact of exogenous lactate on survival and radioresponse of carcinoma cells in vitro. Int J Radiat Biol 85(11):989–1001. doi:10.​3109/​0955300090324215​6 PubMedCrossRef
25.
go back to reference Barnes L. EJW, Reichart P., Sdransky D. (2005) World Health Organization classification of tumours. Pathology and genetics of head and neck tumours. IARC Press, Lyon 2005 Barnes L. EJW, Reichart P., Sdransky D. (2005) World Health Organization classification of tumours. Pathology and genetics of head and neck tumours. IARC Press, Lyon 2005
26.
go back to reference Mueller-Klieser W, Walenta S (1993) Geographical mapping of metabolites in biological tissue with quantitative bioluminescence and single photon imaging. Histochem J 25(6):407–420PubMedCrossRef Mueller-Klieser W, Walenta S (1993) Geographical mapping of metabolites in biological tissue with quantitative bioluminescence and single photon imaging. Histochem J 25(6):407–420PubMedCrossRef
27.
go back to reference Walenta S, Voelxen N, Sattler U, Mueller-Klieser W (2014) Localizing and quantifying metabolites in situ with luminometry: induced metabolic bioluminescence imaging (imBI). In: Johannes Hirrlinger HSW (ed) Neuromethods 90 (invited review). Special volume “brain energy metabolism” Springer Science and Business Media New York New York. doi:10.1007/ 978-1-4939-1059-5 Walenta S, Voelxen N, Sattler U, Mueller-Klieser W (2014) Localizing and quantifying metabolites in situ with luminometry: induced metabolic bioluminescence imaging (imBI). In: Johannes Hirrlinger HSW (ed) Neuromethods 90 (invited review). Special volume “brain energy metabolism” Springer Science and Business Media New York New York. doi:10.​1007/​ 978-1-4939-1059-5
28.
go back to reference Mankoff DA, Eary JF, Link JM, Muzi M, Rajendran JG, Spence AM, Krohn KA (2007) Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 13(12):3460–3469. doi:10.1158/1078-0432.CCR-07-0074 CrossRef Mankoff DA, Eary JF, Link JM, Muzi M, Rajendran JG, Spence AM, Krohn KA (2007) Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 13(12):3460–3469. doi:10.​1158/​1078-0432.​CCR-07-0074 CrossRef
29.
go back to reference 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(21):4757–4759PubMed 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(21):4757–4759PubMed
30.
go back to reference 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. The American Journal of Pathology 150(2):409–415PubMedPubMedCentral 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. The American Journal of Pathology 150(2):409–415PubMedPubMedCentral
31.
go back to reference Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One 7(3):e33418. doi:10.1371/journal.pone.0033418 PubMedPubMedCentralCrossRef Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One 7(3):e33418. doi:10.​1371/​journal.​pone.​0033418 PubMedPubMedCentralCrossRef
32.
go back to reference Gillies RJ, Robey I, Gatenby RA (2008) Causes and consequences of increased glucose metabolism of cancers. Journal of Nuclear Medicine: official publication, Society of Nuclear Medicine 49 Suppl 2:24S-42S. doi:10.2967/jnumed.107.047258 Gillies RJ, Robey I, Gatenby RA (2008) Causes and consequences of increased glucose metabolism of cancers. Journal of Nuclear Medicine: official publication, Society of Nuclear Medicine 49 Suppl 2:24S-42S. doi:10.2967/jnumed.107.047258
34.
go back to reference Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E (2015) Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clinical Cancer research: An Official Journal of the American Association for Cancer Research 21(4):680–686. doi:10.1158/1078-0432.CCR-14-2198 CrossRef Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E (2015) Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clinical Cancer research: An Official Journal of the American Association for Cancer Research 21(4):680–686. doi:10.​1158/​1078-0432.​CCR-14-2198 CrossRef
37.
38.
go back to reference Groussard C, Morel I, Chevanne M, Monnier M, Cillard J, Delamarche A (2000) Free radical scavenging and antioxidant effects of lactate ion: an in vitro study. Journal of Applied physiology (Bethesda, Md: 1985) 89(1):169–175 Groussard C, Morel I, Chevanne M, Monnier M, Cillard J, Delamarche A (2000) Free radical scavenging and antioxidant effects of lactate ion: an in vitro study. Journal of Applied physiology (Bethesda, Md: 1985) 89(1):169–175
40.
Metadata
Title
Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma (HNSCC) post radiation: a prospective study over 15 years
Authors
Sebastian Blatt
Nadine Voelxen
Keyvan Sagheb
Andreas Max Pabst
Stefan Walenta
Thies Schroeder
Wolfgang Mueller-Klieser
Thomas Ziebart
Publication date
01-11-2016
Publisher
Springer Berlin Heidelberg
Published in
Clinical Oral Investigations / Issue 8/2016
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI
https://doi.org/10.1007/s00784-015-1699-6

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