Title: Association between C - reactive protein and Matrix metalloproteinase-2 in Non-small cell lung carcinoma

Authors: Asha Sharma, Dr Rati Mathur, Dr Hemant Malhotra

 DOI: https://dx.doi.org/10.18535/jmscr/v8i5.40

Abstract

 

Matrix metalloproteinases (MMPs) are enzymes which are involved in irreversible degradation of ECM (extra cellular matrix). MMP-2 is capable in laminin-5 cleavage which increases endothelial cell migration and in the secretion of VEGF that promote angiogenesis in physiological conditions as well as tumor development also. C-reactive protein (CRP) is an acute-phase protein which is used as marker of systemic inflammation. Increased CRP is associated with an increased risk of all the cancer. In the present study serum levels of MMP-2 and CRP is quantified in the NSCLC patients to establish the clinical signifi­cance of these biomarkers during NSCLC disease progression. This is a cross sectional study which includes 120 NSCLC patients and 60 age and sex matched healthy controls attending the medical oncology OPD of our institute from July, 2017 to March, 2019. Blood Samples were collected from patients and healthy controls. CRP was measured by turbidimetric technique and MMP-2 is measured by ELISA. The independent t-test was used to compare the level of MMP-2 and CRP in healthy controls and NSCLC patients. Pearson’s correlation (r) was used to correlate the MMP-2 level and CRP level in NSCLC patients. Serum MMP-2 level and serum CRP levels were found significantly high in NSCLC patients when compared with healthy controls (p<0.001). Furthermore a significant positive correlation was also observed between MMP-2 level and CRP level in NSCLC patients. Therefore measurement of MMP-2 level and CRP level could be a marker for disease progression of NSCLC and to see the association between inflammation and pathogenesis of NSCLC.

Keywords: Matrix metalloproteinases, C - reactive protein, NSCLC.

References

  1. Nagase H, Woessner Jr JF. Matrix metalloproteinases. J Biol Chem 1999;274 (31):21491 4.
  2. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014;15(12):786–801.
  3. Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 2000; 14(17):2123–33.
  4. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674.
  5. B. Pepys, G.M. Hirschfield, C-reactive protein: a critical update, J. Clin. Invest. 111 (2003) 1805–1812.
  6. Hans C. Ablij, Arend E. Meinders, C-reactive protein: history and revival, Eur. J. Intern. Med. 13 (7) (2002) 412–422.
  7. P. Smith, B.J. Lipworth, C-reactive protein in simple community-acquired pneumonia, Chest 107 (1995) 1028–1031.
  8. Guo et al, Association between C - reactive protein and risk of cancer: a meta-analysis of prospective cohort studies, Asian Pacific J. Cancer Prev. 14 (1) (2013) 243–248.
  9. A. Mahmoud, N.I. Rivera, The role of C-reactive protein as a prognostic indicator in advanced cancer, Curr. Oncol. Rep. 4 (2002) 250–255.
  10. E. Postmus, E. Brambilla, K. Chansky, J. Crowley, P.Goldstraw, E.F. Patz Jr., et al, The IASLC lung cancer staging project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer, J. Thorac. Oncol. 2 (2007) 686–693.
  11. Søyseth, J.S. Benth, K. Stavem, The association between hospitalization for pneumonia and the diagnosis of lung cancer, Lung cancer 57 (2007) 152–158.
  12. Arbeláez LF, Bergmann U, Tuuttila A, Shanbhag VP and Stigbrand T: Interaction of matrix metalloproteinases-2 and -9 with pregnancy zone protein and α2-macroglobulin. Arch Biochem Biophys 347: 62-68, 1997.
  13. Beekman B, Drijfhout JW, Ronday HK and Tekoppele JM: Fluorogenic MMP activity assay for plasma including MMPs complexed to α2-macroglobulin. Ann NY Acad Sci 878: 150-156, 1999.
  14. Chen WT and Wang JY: Specialized surface protrusions of invasive cells, invadopodia and lamellipodia, have differential MT1-MMP, MMP-2 and TIMP-2 localization. Ann NY Acad Sci 878: 361-370, 1999.
  15. Ding S, Zhang M, Zhao Y, Chen W, Yao G, Zhang C, Zhang P and Zhang Y: The role of carotid plaque vulnerability and inflammation in the pathogenesis of acute ischemic stroke. Am J Med Sci 336: 27-31, 2008.
  16. Alvarez B, Ruiz C, Chacon P, Alvarez-Sabin J and Matas M: Serum values of metalloproteinase-2 and metalloproteinase-9 as related to unstable plaque and inflammatory cells in patients with greater than 70% carotid artery stenosis. J Vasc Surg 40: 469-475, 2004.
  17. Yap SH, Moshage HJ, Hazenberg BP, Roelofs MH, Bijizet J, Limburg PC, Aarden LA and van Rijiswijk MH: Tumor necrosis factor (TNF) inhibits interleukin (IL)-1 and/or IL-6 stimulated synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes. Biochim Biophys Acta 1091: 405-408, 1991.
  18. Smith JW and McDonald TL: Production of serum amyloid A and C-reactive protein by HepG2 cells stimulated with combina­tions of cytokines or monocyte conditioned media: the effects of prednisolone. Clin Exp Immunol 90: 293-299, 1992.
  19. Matsuda T, Hirano T, Nagasawa S and Kishimoto T: Identification of α2 macroglobulin as a carrier protein for IL-6. J Immunol 142: 148-152, 1989.
  20. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual [eds.] 7th edition. Springer, New York, 2010.
  21. Suzuki M, Lizasa T, Fujisawa T, Baba M, Yamaguchi Y, Kimura H, Suzuki H: Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in non-small cell lung cancer. Invasion Metastasis 1999;18:134–141.
  22. Schütz A, Schneidenbach D, Aust G, Tannapfel A,Steinert M, Wittekind C: Differential expression and activity status of MMP-1, MMP-2 and MMP-9 in tumor and stromal cells of squamous cell carcinomas of the lung. Tumour Biol 2002;23:179–184.
  23. Thomas P, Khokha R, Shepherd FA, Feld R, Tsao MS: Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J Pathol 2000;190:150–156.
  24. Atkinson JM, Pennington CJ, Martin SW, Anikin VA, Mearns AJ, Loadman PM,Edwards DR, Gill JH: Membrane type matrix metalloproteinases (MMPs) show differential expression in non-small cell lung cancer (NSCLC) compared to normal lung: correlation of MMP-14 mRNA expression and proteolytic activity. Eur J Cancer 2007;43:1764–1771.
  25. Z. Guo, L. Pan, C.J. Du, D.Q. Ren, X.M. Xie, Association between C-reactive protein and risk of cancer: a meta-analysis of prospective cohort studies, Asian Pac. J. Cancer Prev. 14(1) (2013) 243–248.
  26. S. Wang, C.F. Sun, C-reactive protein and malignancy: clinico-pathological association and therapeutic implication, Chang Gung Med. J. 32 (5) (2009) 471–482.
  27. Basso, C. Fabris, A. Meani, et al, C reactive protein in pancreatic cancer and chronic pancreatitis, Ann. Clin. Res. 20 (1988) 414–416.
  28. M. O’Hanlon, J. Lynch, M. Cormican, H.F. Given, The acute phase response in breast carcinoma, Anticancer Res. 22 (2002) 1289–1293.
  29. G. Alexandrakis, F.H. Passam, I.A. Moschandrea, et al,Levels of serum cytokines and acute phase proteins in patients with essential and cancer-related thrombocytosis, Am. J. Clin. Oncol. 26 (2003) 135–140.
  30. Balkwill, A. Mantovani, Inflammation and cancer: back toVirchow?, Lancet 357 (2001) 539–545.
  31. D. Blann, G.J. Byrne, A.D. Baildam, Increased soluble intercellular adhesion molecule-1, breast cancer and the acute phase response, Blood Coagul. Fibrinolysis 13 (2002)165–168.
  32. Chung HW, Kim JW, Lee JH, Song Sy, Chung JB, Kwon OH, et al. Comparison of the validity of three biomarkers for gastric cancer screening: carcinoembryonic antigen, pepsinogens, and high sensitive C-reactive protein. J Clin Gastroenterol. 2009;43(1):19-26.
  33. Domagala-Kulawik J.The role of the immune system in non-small cell lung carcinoma and potential for therapeutic intervention. Transl Lung Cancer Res. 2015;4(2):177– 190.
  34. Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006; 4(4):221–233. PubMed
  35. Tarrant JM Blood cytokines as biomarkers of in vivo toxicity in preclinical safety assessment: considerations for their use. Toxicol Sci. 2010;117(1):4–16. PubMed
  36. Cobos C, Figueroa JA, Mirandola L, Colombo M, Summers G, et al.The role of human papilloma virus (HPV) infection in non-anogenital cancer and the promise of immunotherapy: a review. Int Rev Immunol. 2014; 33 (5):383–401. PubMed
  37. Vacchelli E, Aranda F, Bloy N, Buque A, Cremer I, et al., Trial Watch-Immunostimulation with cytokines in cancer therapy. Oncoimmunology. 2016; 5(2): PubMed e1115942.
  38. Yuhsaku Kanoh, Tadashi Abe, Noriyuki Masuda and Tohru Akahoshi. Progression of non-small cell lung cancer: Diagnostic and prognostic utility of matrix metalloproteinase-2, C-reactive protein and serum amyloid A: Oncology Reports 29: 469-473, 2013.

Corresponding Author

Dr Rati Mathur

Sr. Professor, Department of Biochemistry, SMS Medical College, Jaipur, India