Salivary Cytokine Levels in Lung Cancer with Distant and Regional Metastasis

  • L. V. Bel'skaya KhimServis LLC, 4/2 Lugovaya Str., Skolkovo Innovation Center, Moscow, 143026, Russia
  • V. K. Kosenok Omsk State Medical University, 12 Lenina Str., Omsk, 644099, Russia
  • Gilbert Massard Strasbourg University Hospital, 67091 Strasbourg, France
  • E. E. Orlova Clinical Oncology Dispensary, 9/1 Zavertyaeva str., Omsk, 644013 Russia
Keywords: cytokines; C-reactive protein; saliva; lung cancer


Optimization of methods for diagnostics and prediction of lung cancer, which occupies a leading position in the structure of oncological diseases, still remains an important task. In this study we have investigated the level of cytokines and acute-phase proteins in saliva of patients with lung cancer in dependence on the tumor size, and distant and regional metastasis. The case-control study included 121 patients, which were divided into 3 groups: the main group (patients with diagnosed lung cancer, n = 70), the reference group (patients with non-malignant lung pathologies, n = 12) and the control group (conditionally healthy individuals, n = 39). All participants answered the questionnaire, underwent biochemical study of saliva and histological verification of the diagnosis. The content of IL-2 and IL-4 in saliva reduced in both lung cancer and inflammatory lung diseases, whereas the levels of IL-18, IL-8 and TNF-α decreasd in lung cancer and increased in non-malignant pathologies. Tumor progression was accompanied by an increase in the level of proinflammatory cytokines (IL-6, IL-8, IL-18, TNF-α), whereas the levels of IL-2, IL-4 and IL-10 decreased. Although saliva levels of C-reactive protein and tumor markers increased in lung cancer they did reach the level of statistical significance as compared with the reference group. Thus, with the only exception of IL-2 and IL-4, the saliva levels of cytokines in lung cancer patients insignificantly differ from the control group. However, the recognzied dynamics of the saliva cytokines level in patients with distant and regional metastasis opens the prospect of using these parameters for monitoring the treatment and controlling relapse occurrence.


  1. Brailo, V., Vucicevic-Boras, V., Lukac, J., Biocina-Lukenda, D., Zilic-Alajbeg, I., Milenovic, A. & Balija, M. (2012). Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer. Med Oral Patol Oral Cir Bucal, 17, e10-e15. DOI

  2. Byrne, M.L., O’Brien-Simpson, N.M., Reynolds, E.C., Walsh, K.A., Laughton, K., Waloszek, J.M., Woods, M.J., Trinder, J. & Allen, N.B. (2013). Acute phase protein and cytokine levels in serum and saliva: A comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain Behav Immun, 34, 164-75. DOI

  3. Gilbertson-White, S., Aouizerat, B.E. & Miaskowski, C. (2011). Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms. Biol Res Nurs, 13, 15-24. DOI

  4. Khan, A. (2012). Detection and quantitation of forty-eight cytokines, chemokines, growth factors and nine acute phase proteins in healthy human plasma, saliva and urine. J Proteom, 75, 4802-4819. DOI

  5. Fernandez-Botran, R., Miller, J.J., Burns, V.E. & Newton, T.L. (2011). Correlations among inflammatory markers in plasma, saliva and oral mucosal transudate in postmenopausal women with past intimate partner violence. Brain Behav Immun, 25, 314-321. DOI

  6. Williamson, S., Munro, C., Pickler, R., Grap, M.J. & Elswick, R.K. (2012). Comparison of biomarkers in blood and saliva in healthy adults. Nurs Res Pract, Article ID 246178, DOI

  7. Cullen, T., Thomas, A.W., Webb, R. & Hughes, M.G. (2015). The relationship between interleukin-6 in saliva, venous and capillary plasma, at rest and in response to exercise. Cytokine, 71(2), 397-400. DOI

  8. Ouellet-Morin, I., Danese, A., Williams, B. & Arseneault, L. (2011). Validation of a high-sensitivity assay for C-reactive protein in human saliva. Brain Behav Immun, 25, 640-646. DOI

  9. Mirzaii-Dizgah, I., Riahi, E. & Miri, R. (2012). Serum and saliva levels of high-sensitivity C-reactive protein in acute myocardial infarction. J Mol Biomark Diagn, 3(4). DOI

  10. Pfaffe, T., Cooper-White, J., Beyerlein, P., Kostner, K. & Punyadeera, C. (2011). Diagnostic potential of saliva. Current state and future applications. Clin Chem, 57, 675-687. DOI

  11. Javaid, M.A., Ahmed, A.S., Durand, R. & Tran, S.D. (2016). Saliva as a diagnostic tool for oral and systemic diseases. J Oral Biol Craniofac Res, 6(1), 67-76. DOI

  12. Suzuki, T., Omata, K., Satoh, T., Miyasaka, T., Arai, C., Maeda, M., Matsuno, T. & Miyamura, T. (2005). Quantitative detection of hepatitis C virus (HCV) RNA in saliva and gingival crevicular fluid of HCV-infected patients. J Clin Microbiol, 43, 4413-4417. DOI

  13. Shipper, R.G., Silletti, E. & Vingerhoeds, M.H. (2007). Saliva as research material: Biochemical, physicochemical and practical aspects. Arch Oral Biol, 52, 1114-1135. DOI

  14. Papacosta, E. & Nassis, G.P. (2011). Saliva as a tool for monitoring steroid, peptide and immune markers in sport and exercise science. J Sci Med Sport, 14, 424-234. DOI

  15. Granger, D.A., Kivlighan, K.T., Fortunato, C., Harmon, A.G., Hibel, L.C., Schwartz, E.B. & Whembolua, G-L. (2007). Integration of salivary biomarkers into developmental and behaviorally-oriented research: problems and solutions for collecting specimens. Physiol Behav, 92, 583-590. DOI

  16. Isaza-Guzmán, D.M., Cardona-Vélez, N., Gaviria-Correa, D.E., Martínez-Pabón, M.C., Castano-Granada, M.C. & Tabón-Arroyave, S.I. (2015). Association study between salivary levels of interferon (IFN)-gamma, interleukin (IL)-17, IL-21, and IL-22 with chronic periodontitis. Arch Oral Biol, 60, 91-99. DOI

  17. Dafar, A., Rico, P., Işik, A., Jontell, M. & Cevik-Aras, H. (2014). Quantitative detection of epidermal growth factor and interleukin-8 in whole saliva of healthy individuals. J Immunol Methods, 408: 46-51. DOI

  18. Aleynikov, A.S., Gayduk, I.V., Panin, A.M., Babkina, I.V. & Kushlinsky, N.E. (2014). Proinflammatory cytokines in saliva of patients with chronic sialodochitis. TSU Bulletin, 19(6), 1909-1914.

  19. Rhodus, N.L., Ho, V., Miller, C.S., Myers, S. & Ondrey, F. (2005). NF-kB dependent cytokine levels in saliva of patients with oral preneoplastics lesions and oral squamous cell carcinoma. Cancer Detect Prev, 29, 42-45. DOI

  20. Schapher, M., Wendler, O. & Gröschl, M. (2011). Salivary cytokines in cell proliferation and cancer. Clin Chim Acta, 412, 1740-1748. DOI

  21. Russo, N., Bellile, E., Murdoch-Kinch, C.A., Liu, M., Eisbruch, A., Wolf, G.T. & D’Silva, N.J. (2016). Cytokines in saliva increase in head and neck cancer patients after treatment. Oral Surg Oral Med Oral Pathol Oral Radiol, 122(4): 483-490. DOI

  22. Osman, T.A., Costea, D.E. & Johannessen, A.C. (2012). The use of salivary cytokines as a screening tool for oral squamous cell carcinoma: A review of the literature. J Oral Maxillofac Pathol, 16(2), 256-261. DOI

  23. Jacobs, R., Tshehla, E., Malherbe, S., Kriel, M., Loxton, A.G., Stanley, K., van der Spuy, G., Walzl, G. & Chegou, N.N. (2016). Host biomarkers detected in saliva show promise as markers for the diagnosis of pulmonary tuberculosis disease and monitoring of the response to tuberculosis treatment. Cytokine, 81, 50-56. DOI

  24. Yano, T., Yoshino, L., Yokoyama, H., Fukuyama, Y., Takai, E., Asoh, H. & Ichinose, Y. (1996). The clinical significance of serum soluble interleukin-2 receptors in lung cancer. Lung Cancer, 15, 79-84. DOI

  25. Chi ,X. & Tai, H-H. (2010). Interleukin-4 up-regulates 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in human lung cancer cells. Exp Cell Res, 316, 2251-2259. DOI

  26. Ryan, B.M., Pine, S.R., Chaturvedi, A.K., Caporaso, N. & Harris, C.C. (2014). A combined prognostic serum interleukin-8 and interleukin-6 classifier for stage 1 lung cancer in the prostate, Lung, colorectal, and ovarian cancer screening trial. J Thorac Oncol, 9(10), 1494-1503. DOI

  27. Luppi, F., Longo, A.M., de Boer, W.I., Rabe, K.F. & Hiemstra P.S. (2007). Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer, 56, 25-33. DOI

  28. Rovina, N., Hillas, G., Dima, E., Vlastos, F., Loukides, S., Veldekis, D., Rousso, C., Alhanatis, M. & Bakakos, P. (2011). VEGF and IL-18 in induced sputum of lung cancer patients. Cytokine, 54, 277-281. DOI

  29. O’Dowd, C., McRae, L.A., McMillan, D.C., Kirk, A. & Milroy, R. (2010). Elevated preoperative C-reactive protein predicts poor cancer specific survival in patients undergoing resection for non-small cell lung cancer. J Thorac Oncol, 5(7), 988-992. DOI

  30. Hoseok, I. & Cho, J-Y. (2015). Lung cancer biomarkers. Adv Clin Chem, 72, 107-170. DOI

  31. Shcheglova, M.Yu. (2005). System of cytokines in health and respiratory disease. Bulletin of Physiology and Respiration Pathology, 21, 93-97.

  32. Akdis, M., Aab, A., Altunbulakli, C., Azkur, K., Costa, R.A. & Crameri, R. (2016). Interleukins (from IL-1 to IL-38), interferons, transforming growth factor b, and TNF-a: Receptors, functions, and roles in diseases. J Allergy Clin Immunol, 138(4), 984-1010. DOI

  33. Nelms, K., Keegan, A.D., Zamorano, J., Ryan, J.J. & Paul, W.E. (1999). The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol, 17, 701-738. DOI

  34. Ho, L-J., Luo, S-F. & Lai, J-H. (2015). Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers. Biochem Pharmacol, 97(1), 16-26. DOI

  35. Seike, M., Yanaihara, N. & Bowman, E.D. (2007). Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifie. J Natl Cancer Inst, 99, 1257-1269. DOI

  36. Yatsunami, J., Tsuruta, N., Ogata, K., Wakamatsu, K., Takayama, K., Kawasaki, M., Nakanishi, Y., Hara, N. & Hayashi, S. (1997). Interleukin-8 participates in angiogenesis in non-small cell, but not small cell carcinoma of the lung. Cancer Lett, 120, 101-108. DOI

  37. Pine, S.R., Mechanic, L.E. & Enewold, L. (2011). Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. J Natl Cancer Inst, 103, 1112‑1122. DOI

  38. Crohns, M., Saarelainen, S., Laine, S., Poussa, T., Alho, H. & Kellokumpu-Lehtinen, P. (2010). Cytokines in bronchoalveolar lavage fluid and serum of lung cancer patients during radiotherapy — Association of interleukin-8 and VEGF with survival. Cytokine, 50, 30-36. DOI

  39. Erzutova, M.V., Uspenskaya, I.D., Majanskaya, I.V., Korkotashvili, L.V. & Potekhin, P.P. (2011). Significance of proinflammatory cytokines in a mouth cavity secret in patients with celiac disease. Medical Almanac, 6(19), 179-182.

  40. Black, S., Kushner, I. & Samols, D. (2004). C-reactive protein. J Biol Chem, 279(47), 48487-48490. DOI

  41. Chaturvedi, A.K., Caporaso, N.E. & Katki, H.A. (2010). C-reactive protein and risk of lung cancer. J Clin Oncol, 28, 2719-2726. DOI

  42. Wu, Y., Potempa, L.A., El Kebir, D. & Filep, J.G. (2015). C-reactive protein and inflammation: conformational changes affect function. Biol Chem, 396(11), 1181-1197. DOI

  43. Pastorino, U., Morelli, D., Leuzzi, G., Gisabella, M., Suatoni, P., Taverna, F., Bertocchi, E., Boeri, M., Sozzi, G., Cantarutti, A. & Corrao, G. (2017). Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer. Eur J Cancer, 79, 90-97. DOI

  44. Jin, Y., Sun, Y., Shi, X., Zhao, J., Shi, L. & Yu, X. (2014). Prognostic value of circulating C-reactive protein levels in patients with non-small cell lung cancer: a systematic review with meta-analysis. J Cancer Res Ther, 10, 160-166. DOI

  45. Saeed, A.I., Qeadan, F., Sood, A., VanderJagt, D.J., Mishra, S.I., Hill, D.A., Peikert, T. & Sopori, M.L. (2017). A novel cytokine profile associated with cancer metastasis to mediastinal and hilar lymph nodes identified using fine needle aspiration biopsy – A pilot study. Cytokine, 89, 98-104. DOI

  46. Perlikos, F., Harrington, K.J. & Syrigos, K.N. (2013). Key molecular mechanisms in lung cancer invasion and metastasis: A comprehensive review. Crit Rev Oncol./Hematol, 87, 1-11. DOI
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