Biomarkers of Oxidative Stress, Proliferation, Inflammation and Invasivity in Saliva from Oral Cancer Patients

• Radu Radulescu

  Department of Biochemistry, Faculty of Dental Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

• Alexandra Totan

  Department of Biochemistry, Faculty of Dental Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

• Bogdan Calenic

  Department of Biochemistry, Faculty of Dental Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

• Cosmin Totan

  Department of Oro Maxillo Facial Surgery, Faculty of Dental Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

• Maria Greabu

  Department of Biochemistry, Faculty of Dental Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

 Cancer represents the main cause of death in the economically developed countries and the second cause of death in developing ones. Head and neck squamous cell carcinomas are the sixth most common malignancies worldwide with oral cavity and pharynx cancers being the most common. Saliva qualifies as one of the most suitable diagnostic fluids due to the non-invasivity nature, simple handling procedures, easy collection and storage and good cooperation with patient groups such as children or persons with disabilities.

The aim of the present study is to assess the presence in saliva of several cancer biomarkers such as: tumor cells proliferation - Ki-67 Antigen and Squamous Cell Carcinoma Antigen (SCCA), inflammation - Interleukin-6 (IL-6), extracellular matrix collagen degradation - Matrix Metallo-proteinase-9 (MMP-9) and Tissue Inhibitor of Metalloproteinases 2 (TIMP-2), oxidative stress - total antioxidant capacity and uric acid. Both uric acid and total antioxidant capacity showed decreased levelsin the saliva of oral cancer patients. IL-6, Ki-67, SCCA and MMP-9 showed increased levels in the saliva of oral patients compared to the control group. Salivary TIMP-2 levels were also decreased in the patients group. We can conclude that salivary diagnosis has the potential of becoming a powerful tool in detecting and monitoring oral cancer patients.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127(12): 2893-917. http://dx.doi.org/10.1002/ijc.25516

Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013; 49(6): 1374-403. http://dx.doi.org/10.1016/j.ejca.2012.12.027

Malamud D. Saliva as a diagnostic fluid. Dental clinics of North America 2011; 55(1): 159-78. http://dx.doi.org/10.1016/j.cden.2010.08.004

Miller CS, King CP, Jr., Langub MC, Kryscio RJ, Thomas MV. Salivary biomarkers of existing periodontal disease: a cross-sectional study. J Am Dent Assoc 2006; 137(3): 322-9. http://dx.doi.org/10.14219/jada.archive.2006.0181

Giannobile WV, Beikler T, Kinney JS, Ramseier CA, Morelli T, Wong DT. Saliva as a diagnostic tool for periodontal disease: current state and future directions. Periodontology 2000 2009; 50: 52-64. http://dx.doi.org/10.1111/j.1600-0757.2008.00288.x

Lamster IB, Ahlo JK. Analysis of gingival crevicular fluid as applied to the diagnosis of oral and systemic diseases. Annals of the New York Academy of Sciences 2007; 1098: 216-29. http://dx.doi.org/10.1196/annals.1384.027

Miricescu D, Totan A, Calenic B, Mocanu B, Didilescu A, Mohora M, et al. Salivary biomarkers: Relationship between oxidative stress and alveolar bone loss in chronic periodontitis. Acta Odontologica Scandinavica 2014; 72(1): 42-7. http://dx.doi.org/10.3109/00016357.2013.795659

Greabu M, Calenic B. Salivary Biomarkers of Oxidative Stress Associated with Periodontal Diseases. Studies on Periodontal Disease: Springer 2014; pp. 329-43.

Segal A, Wong DT. Salivary diagnostics: enhancing disease detection and making medicine better. European journal of dental education : official journal of the Association for Dental Education in Europe 2008; 12(Suppl 1): 22-9.

de Oliveira MV, Fraga CA, Gomez RS, Paula AM. Immunohistochemical expression of interleukin-4, -6, -8, and -12 in inflammatory cells in surrounding invasive front of oral squamous cell carcinoma. Head & Neck 2009; 31(11): 1439-46. http://dx.doi.org/10.1002/hed.21121

Gasche JA, Hoffmann J, Boland CR, Goel A. Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. International journal of cancer Journal International du Cancer 2011; 129(5): 1053-63. http://dx.doi.org/10.1002/ijc.25764

Wang YF, Chang SY, Tai SK, Li WY, Wang LS. Clinical significance of interleukin-6 and interleukin-6 receptor expressions in oral squamous cell carcinoma. Head & neck 2002; 24(9): 850-8. http://dx.doi.org/10.1002/hed.10145

Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 1997; 89(23): 1763-73. http://dx.doi.org/10.1093/jnci/89.23.1763

Katakura A, Kamiyama I, Takano N, Shibahara T, Muramatsu T, Ishihara K, et al. Comparison of salivary cytokine levels in oral cancer patients and healthy subjects. The Bulletin of Tokyo Dental College 2007; 48(4): 199-203. http://dx.doi.org/10.2209/tdcpublication.48.199

Vairaktaris E, Yapijakis C, Serefoglou Z, Avgoustidis D, Critselis E, Spyridonidou S, et al. Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma. Journal of Cancer Research and Clinical Oncology 2008; 134(8): 821-32. http://dx.doi.org/10.1007/s00432-008-0360-z

Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 2008; 113(4): 750-7. http://dx.doi.org/10.1002/cncr.23615

Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular Research 2006; 69(3): 562-73. http://dx.doi.org/10.1016/j.cardiores.2005.12.002

Murphy G. Tissue inhibitors of metalloproteinases. Genome Biology 2011; 12(11): 233. http://dx.doi.org/10.1186/gb-2011-12-11-233

Curran S, Murray GI. Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. European journal of cancer (Oxford, England: 1990) 2000; 36(13 Spec No): 1621-30.

Li M, Wang Z, Xing Y, Yu J, Tian L, Zhang D, et al. A multicenter study on expressions of vascular endothelial growth factor, matrix metallopeptidase-9 and tissue inhibitor of metalloproteinase-2 in oral and maxillofacial squamous cell carcinoma. Iranian Red Crescent Medical Journal 2014; 16(3): e13185.

Groblewska M, Mroczko B, Gryko M, Pryczynicz A, Guzinska-Ustymowicz K, Kedra B, et al. Serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinases 2 (TIMP-2) in colorectal cancer patients. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 2014; 35(4): 3793-802. http://dx.doi.org/10.1007/s13277-013-1502-8

Ozden F, Saygin C, Uzunaslan D, Onal B, Durak H, Aki H. Expression of MMP-1, MMP-9 and TIMP-2 in prostate carcinoma and their influence on prognosis and survival. Journal of Cancer Research and Clinical Oncology 2013; 139(8): 1373-82. http://dx.doi.org/10.1007/s00432-013-1453-x

Miricescu D, Totan A, Calenic B, Mocanu B, Didilescu A, Mohora M, et al. Salivary biomarkers: relationship between oxidative stress and alveolar bone loss in chronic periodontitis. Acta Odontologica Scandinavica 2014; 72(1): 42-7. http://dx.doi.org/10.3109/00016357.2013.795659

Shpitzer T, Hamzany Y, Bahar G, Feinmesser R, Savulescu D, Borovoi I, et al. Salivary analysis of oral cancer biomarkers. British Journal of Cancer 2009; 101(7): 1194-8. http://dx.doi.org/10.1038/sj.bjc.6605290

Bruey JM, Kantarjian H, Estrov Z, Zhang Z, Ma W, Albitar F, et al. Circulating Ki-67 protein in plasma as a biomarker and prognostic indicator of acute lymphoblastic leukemia. Leukemia Research 2010; 34(2): 173-6. http://dx.doi.org/10.1016/j.leukres.2009.07.030

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