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Tumor Biology
Published in: Tumor Biology 4/2016

01-04-2016 | Original Article

Equating salivary lactate dehydrogenase (LDH) with LDH-5 expression in patients with oral squamous cell carcinoma: An insight into metabolic reprogramming of cancer cell as a predictor of aggressive phenotype

Authors: Tajindra Singh Saluja, Anita Spadigam, Anita Dhupar, Shaheen Syed

Published in: Tumor Biology | Issue 4/2016

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Abstract

Oral squamous cell carcinoma (OSCC) is the sixth most common human malignancy. According to World Health Organization, oral cancer has been reported to have the highest morbidity and mortality and a survival rate of approximately 50 % at 5 years from diagnosis. This is attributed to the subjectivity in TNM staging and histological grading which may result in less than optimum treatment outcomes including tumour recurrence. One of the hallmarks of cancer is aerobic glycolysis also known as the Warburg effect. This glycolytic phenotype (hypoxic state) not only confers immortality to cancer cells, but also correlates with the belligerent behaviour of various malignancies and is reflected as an increase in the expression of lactate dehydrogenase 5 (LDH-5), the main isoform of LDH catalysing the conversion of pyruvate to lactate during glycolysis. The diagnostic role of salivary LDH in assessing the metabolic phenotype of oral cancer has not been studied. Since salivary LDH is mainly sourced from oral epithelial cells, any pathological changes in the epithelium should reflect diagnostically in saliva. Thus in our current research, we made an attempt to ascertain the biological behaviour and aggressiveness of OSCC by appraising its metabolic phenotype as indirectly reflected in salivary LDH activity. We found that salivary LDH can be used to assess the aggressiveness of different histological grades of OSCC. For the first time, an evidence of differing metabolic behaviour in similar histologic tumour grade is presented. Taken together, our study examines the inclusion of salivary LDH as potential diagnostic parameter and therapeutic index in OSCC.
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed
2.
Pfaffe T, Cooper-White J, Beyerlein P, Kostner K, Punyadeera C. Diagnostic potential of saliva: current state and future applications. Clin Chem. 2011;57(5):675–87.CrossRefPubMed
3.
Slavkin HC. Toward molecularly based diagnostics for the oral cavity. J Am Dent Assoc. 1998;129(8):1138–43.CrossRefPubMed
4.
5.
Shah FD, Begum R, Vajaria BN, Patel KR, Patel JB, Shukla SN, et al. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian J Clin Biochem. 2011;26(4):326–34.CrossRefPubMedPubMedCentral
6.
Pujari M, Bahirwani S, Balaji P, Kaul R, Shah B, Daryani D. Saliva as a diagnostic tool in oral cancer. J Minim Interv Dent. 2011;4(4):77–83.
7.
Shetty SR, Chadha R, Babu S, Kumari S, Bhat S, Achalli S. Salivary lactate dehydrogenase levels in oral leukoplakia and oral squamous cell carcinoma: a biochemical and clinicopathological study. J Cancer Res Ther. 2012;8 Suppl 1:S123–5.PubMed
8.
D'Cruz AM, Pathiyil V. Histopathological differentiation of oral squamous cell carcinoma and salivary lactate dehydrogenase: a biochemical study. South Asian J Cancer. 2015;4(2):58–60.CrossRefPubMedPubMedCentral
9.
Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL. Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins. 2001;43(2):175–85.CrossRefPubMed
10.
Nagler RM, Lischinsky S, Diamond E, Klein I, Reznick AZ. New insights into salivary lactate dehydrogenase of human subjects. J Lab Clin Med. 2001;137(5):363–9.CrossRefPubMed
11.
Bittar PG, Charnay Y, Pellerin L, Bouras C, Magistretti PJ. Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. Cereb Blood Flow Metab. 1996;16(6):1079–89.CrossRef
12.
Good JS, Harrington KJ. The hallmarks of cancer and the radiation oncologist: updating the 5Rs of radiobiology. Clin Oncol. 2013;25(10):569–77.CrossRef
13.
14.
López-Lázaro M. The Warburg effect: Why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem. 2008;8(3):305–12.CrossRefPubMed
15.
Augoff K, Hryniewicz-Jankowska A, Tabola R. Lactate dehydrogenase 5: an old friend and a new hope in the war on cancer. Cancer Lett. 2015;358(1):1–7.CrossRefPubMed
16.
Lu J, Tan M, Cai Q. The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett. 2015;356(2 Pt A):156–64.CrossRefPubMed
17.
Younes M, Lechago LV, Lechago J. Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. Clin Cancer Res. 1996;2(7):1151–4.PubMed
18.
Yasuda S, Fujii H, Nakahara T, Nishiumi N, Takahashi W, Ide M, et al. 18F-FDG PET detection of colonic adenomas. J Nucl Med. 2001;42(7):989–92.PubMed
19.
20.
Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, et al. Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol. 1997;150(2):409–15.PubMedPubMedCentral
21.
Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51(2):349–53.CrossRefPubMed
22.
Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38(2):285–9.CrossRefPubMed
23.
Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9 Suppl 5:10–7.CrossRefPubMed
24.
Durand RE. Keynote address: the influence of microenvironmental factors on the activity of radiation and drugs. Int J Radiat Oncol Biol Phys. 1991;20(2):253–8.CrossRefPubMed
25.
Suh SY, Ahn HY. Lactate dehydrogenase as a prognostic factor for survival time of terminally ill cancer patients: a preliminary study. Eur J Cancer. 2007;43(6):1051–9.CrossRefPubMed
26.
Zhou GQ, Tang LL, Mao YP, Chen L, Li WF, Sun Y, et al. Baseline serum lactate dehydrogenase levels for patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma: a predictor of poor prognosis and subsequent liver metastasis. Int J Radiat Oncol Biol Phys. 2012;82(3):e359–65.CrossRefPubMed
27.
Jin Y, Ye X, Shao L, Lin BC, He CX, Zhang BB, et al. Serum lactic dehydrogenase strongly predicts survival in metastatic nasopharyngeal carcinoma treated with palliative chemotherapy. Eur J Cancer. 2013;49(7):1619–26.CrossRefPubMed
28.
Kolev Y, Uetake H, Takagi Y, Sugihara K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol. 2008;15(8):2336–44.CrossRefPubMed
29.
Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, et al. 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. 2003;89(5):877–85.CrossRefPubMedPubMedCentral
30.
Giatromanolaki A, Koukourakis MI, Pezzella F, Sivridis E, Turley H, Harris AL, et al. Lactate dehydrogenase 5 expression in non-Hodgkin B-cell lymphomas is associated with hypoxia regulated proteins. Leuk Lymphoma 2008;49(11):2181–6.
31.
Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis. 2005;22(1):25–30.CrossRefPubMed
32.
Yuan C, Li Z, Wang Y, Qi B, Zhang W, Ye J, et al. Overexpression of metabolic markers PKM2 and LDH5 correlates with aggressive clinicopathological features and adverse patient prognosis in tongue cancer. Histopathology. 2014;65(5):595–605.CrossRefPubMed
33.
Koukourakis MI, Giatromanolaki A, Winter S, Leek R, Sivridis E, Harris AL. Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology. 2009;77:285–92.CrossRefPubMed
34.
Yao F, Zhao T, Zhong C, Zhu J, Zhao H. LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma. Tumour Biol. 2013;34(1):25–31.CrossRefPubMed
35.
36.
Grimm M, Alexander D, Munz A, Hoffmann J, Reinert S. Increased LDH5 expression is associated with lymph node metastasis and outcome in oral squamous cell carcinoma. Clin Exp Metastasis. 2013;30(4):529–40.CrossRefPubMed
37.
Bahar G, Feinmesser R, Shpitzer T, Popovtzer A, Nagler RM. Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitrogen species, and antioxidant profile. Cancer. 2007;109(1):54–9.CrossRefPubMed
38.
Doshi N, Shah S, Patel K, Jhabuawala M. Histological grading of oral cancer: a comparison of different systems and their relation to lymph node metastasis. Natl J Res Community Med. 2011;2(1):136–42.
39.
Bologna-Molina R, Damián-Matsumura P, Molina-Frechero N. An easy cell counting method for immunohistochemistry that does not use an image analysis program. Histopathology. 2011;59(4):801–3.CrossRefPubMed
40.
Lu R, Jiang M, Chen Z, Xu X, Hu H, Zhao X, et al. Lactate dehydrogenase 5 expression in non-Hodgkin lymphoma is associated with the induced hypoxia regulated protein and poor prognosis. PLoS One. 2013;8(9), e74853.CrossRefPubMedPubMedCentral
41.
Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway–a report of the Tumour Angiogenesis Research Group. J Clin Oncol. 2006;24(26):4301–8.CrossRefPubMed
42.
Shpitzer T, Hamzany Y, Bahar G, Feinmesser R, Savulescu D, Borovoi I, et al. Salivary analysis of oral cancer biomarkers. Br J Cancer. 2009;101(7):1194–8.CrossRefPubMedPubMedCentral
43.
44.
Oliveira LR, Ribeiro-Silva A. Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2011;40(3):298–307.CrossRefPubMed
45.
Gonzalez-Moles MA, Caballero R, Rodriguez-Archilla A, Ruiz-Avila I, Bravo I. Prognostic value of the expression of ki-67 for squamous cell carcinoma of the oral cavity. Acta Stomatol Belg. 1996;93(4):159–65.PubMed
46.
Myoung H, Kim MJ, Lee JH, Ok YJ, Paeng JY, Yun PY. Correlation of proliferative markers (Ki-67 and PCNA) with survival and lymph node metastasis in oral squamous cell carcinoma: a clinical and histopathological analysis of 113 patients. Int J Oral Maxillofac Surg. 2006;35(11):1005–10.CrossRefPubMed
47.
Chan SW, Kallarakkal TG, Abraham MT. Changed expression of E-cadherin and galectin-9 in oral squamous cell carcinomas but lack of potential as prognostic markers. Asian Pac J Cancer Prev. 2014;15(5):2145–52.CrossRefPubMed
48.
Pai HH, Rochon L, Clark B, Black M, Shenouda G. Overexpression of p53 protein does not predict local-regional control or survival in patients with early-stage squamous cell carcinoma of the glottic larynx treated with radiotherapy. Int J Radiat Oncol Biol Phys. 1998;41(1):37–42.CrossRefPubMed
49.
Field JK, Pavelic ZP, Spandidos DA, Stambrook PJ, Jones AS, Gluckman JL. The role of the p53 tumor suppressor gene in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1993;119(10):1118–22.CrossRefPubMed
50.
Carlos de Vicente J, Junquera Gutiérrez LM, Zapatero AH, Fresno Forcelledo MF, Hernández-Vallejo G, López Arranz JS. Prognostic significance of p53 expression in oral squamous cell carcinoma without neck node metastases. Head Neck. 2004;26(1):22–30.CrossRefPubMed
51.
Naresh KN, Lakshminarayanan K, Pai SA, Borges AM. Apoptosis index is a predictor of metastatic phenotype in patients with early stage squamous carcinoma of the tongue: a hypothesis to support this paradoxical association. Cancer. 2001;91(3):578–84.CrossRefPubMed
52.
53.
Ortega AD, Sánchez-Aragó M, Giner-Sánchez D, Sánchez-Cenizo L, Willers I, Cuezva JM. Glucose avidity of carcinomas. Cancer Lett. 2009;276(2):125–35.CrossRefPubMed
54.
55.
Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59(22):5830–5.PubMed
56.
Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ. The expression and distribution of the hypoxia-inducible factors HIF-1 α and HIF-2 α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157(2):411–21.CrossRefPubMedPubMedCentral
57.
Begg AC. Predicting recurrence after radiotherapy in head and neck cancer. Semin Radiat Oncol. 2012;22(2):108–18.CrossRefPubMed
58.
Colgan SM, Mukherjee S, Major P. Hypoxia-induced lactate dehydrogenase expression and tumor angiogenesis. Clin Colorectal Cancer. 2007;6(6):442–6.CrossRefPubMed
59.
Avezov K, Reznick AZ, Aizenbud D. LDH enzyme activity in human saliva: the effect of exposure to cigarette smoke and its different components. Arch Oral Biol. 2014;59(2):142–8.CrossRefPubMed
60.
Zhang J, Yao YH, Li BG, Yang Q, Zhang PY, Wang HT. Prognostic value of pretreatment serum lactate dehydrogenase level in patients with solid tumors: a systematic review and meta-analysis. Sci Rep. 2015;5:9800.CrossRefPubMedPubMedCentral
61.
Zhuang L, Scolyer RA, Murali R, McCarthy SW, Zhang XD, Thompson JF, et al. Lactate dehydrogenase 5 expression in melanoma increases with disease progression and is associated with expression of Bcl-XL and Mcl-1, but not Bcl-2 proteins. Mod Pathol. 2010;23(1):45–53.CrossRefPubMed
62.
Sivaramakrishnan M, Sivapathasundharam B, Jananni M. Evaluation of lactate dehydrogenase enzyme activity in saliva and serum of oral submucous fibrosis patients. J Oral Pathol Med. 2015;44(6):449–52.CrossRefPubMed
63.
Joshi PS, Golgire S. A study of salivary lactate dehydrogenase isoenzyme levels in patients with oral leukoplakia and squamous cell carcinoma by gel electrophoresis method. J Oral Maxillofac Pathol. 2014;18 Suppl 1:S39–44.CrossRefPubMedPubMedCentral
64.
Humphrey SP, Williamson RT. A review of saliva: normal composition, flow, and function. J Prosthet Dent. 2001;85(2):162–9.CrossRefPubMed
65.
66.
Kugahara T, Shosenji Y, Ohashi K. Screening for periodontitis in pregnant women with salivary enzymes. J Obstet Gynaecol Res. 2008;34(1):40–6.PubMed
67.
Trivedi D, Trivedi C. Salivary proteome in periodontal diagnosis. Int J Pharma Bio Sci. 2012;3(2):B241–5.
68.
Todorovic T, Dozic I, Vicente-Barrero M, Ljuskovic B, Pejovic J, Marjanovic M. Salivary enzymes and periodontal disease. Med Oral Patol Oral Cir Bucal. 2006;11(2):E115–9.PubMed
69.
Lossos IS, Intrator O, Berkman N, Breuer R. Lactate dehydrogenase isoenzyme analysis for the diagnosis of pleural effusion in haemato-oncological patients. Respir Med. 1999;93(5):338–41.CrossRefPubMed
70.
Sevinc A, Sari R, Fadillioglu E. The utility of lactate dehydrogenase isoenzyme pattern in the diagnostic evaluation of malignant and nonmalignant ascites. J Natl Med Assoc. 2005;97(1):79–84.PubMedPubMedCentral
71.
Nishikawa A, Tanaka T, Takeuchi T, Fujihiro S, Mori H. The diagnostic significance of lactate dehydrogenase isoenzymes in urinary cytology. Br J Cancer. 1991;63(5):819–21.CrossRefPubMedPubMedCentral
72.
Fiume L, Manerba M, Vettraino M, Di Stefano G. Inhibition of lactate dehydrogenase activity as an approach to cancer therapy. Future Med Chem. 2014;6(4):429–45.CrossRefPubMed
73.
Metadata
Title
Equating salivary lactate dehydrogenase (LDH) with LDH-5 expression in patients with oral squamous cell carcinoma: An insight into metabolic reprogramming of cancer cell as a predictor of aggressive phenotype
Authors
Tajindra Singh Saluja
Anita Spadigam
Anita Dhupar
Shaheen Syed
Publication date
01-04-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4415-x

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