Document Type : Original Research


Pathology Department, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Background & Objective:  Matrix metalloproteinases-9 (MMP-9) is one of the most important enzymes to breakdown extracellular matrix which plays a major role in tumor invasion and metastasis. This study aimed to determine tumor MMP-9 expression in non-small-cell lung carcinoma (NSCLC) and whether it is associated with histopathologic factors and has prognostic value to affect overall survival (OS).
Methods:  The specimens of 92 patients with NSCLC diagnosis were included. Tumor sections were stained by immunohistochemistry method. Using scores for the percentage of cells positively stained and the intensity of staining, MMP-9 expression total score was classified as low-score (scores of 0 to 2), moderate-score (scores of 3 to 5), or high-score (scores of 6 or 7). OS was defined as the time interval since the diagnosis of NSCLC to the status at the last follow-up (dead or alive). The follow up period was up to 70 months.  
Results:  About 74% of undifferentiated specimens (grade III tumors) showed high scores for MMP-9 expression which was significantly higher than moderately differentiated tumors (25% had high scores for MMP-9 expression) and well differentiated ones which did not have high scores (p <0.001). A total of 74 patients (80.4%) died during the follow-up period. Of this, 36% had high scores for MMP-9 expression. In contrast, none of the patients who were alive at the last follow-up had high scores for MMP-9 expression (p <0.001). Median OS was significantly lower in high score group (6 months) compared to moderate score (9 months) and high score group (15 months) (p <0.001).
Conclusion:  MMP-9 expression may serve as a significant prognostic factor for mortality and overall survival in NSCLC. Undifferentiated tumors significantly express higher MMP-9 immunohistochemically.


Main Subjects

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63(1):11-30. [DOI:10.3322/caac.21166] [PMID]
  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-90. [DOI:10.3322/caac.20107] [PMID]
  3. Cooke DT, Nguyen DV, Yang Y, Chen SL, Yu C, Calhoun RF. Survival comparison of adenosquamous, squamous cell, and adenocarcinoma of the lung after lobectomy. Ann Thorac Surg 2010;90(3):943-8. [DOI:10.1016/j.athoracsur.2010.05.025] [PMID]
  4. Hubbard MO, Fu P, Margevicius S, Dowlati A, Linden PA. Five-year survival does not equal cure in non-small cell lung cancer: a Surveillance, Epidemiology, and End Results-based analysis of variables affecting 10- to 18-year survival. J Thorac Cardiovasc Surg 2012;143(6):1307-13. [DOI:10.1016/j.jtcvs.2012.01.078] [PMID]
  5. Han JY, Kim HS, Lee SH, Park WS, Lee JY, Yoo NJ. Immunohistochemical expression of integrins and extracellular matrix proteins in non-small cell lung cancer: correlation with lymph node metastasis. Lung Cancer 2003;41(1):65-70. [DOI:10.1016/S0169-5002(03)00146-6]
  6. Cox G, Jones JL, O'Byrne KJ. Matrix metalloproteinase 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer. Clin Cancer Res 2000;6(6):2349-55.
  7. Willumsen N, Bager CL, Leeming DJ, Smith V, Christiansen C, Karsdal MA, et al. Serum biomarkers reflecting specific tumor tissue remodeling processes are valuable diagnostic tools for lung cancer. Cancer Med 2014;3(5):1136-45. [DOI:10.1002/cam4.303] [PMID] [PMCID]
  8. Wen YL, Li L. Correlation between matrix metalloproteinase-9 and vascular endothelial growth factor expression in lung adenocarcinoma. Genet Mol Res 2015;14(4):19342-8. [DOI:10.4238/2015.December.29.44] [PMID]
  9. Gong L, Wu D, Zou J, Chen J, Chen L, Chen Y, et al. Prognostic impact of serum and tissue MMP-9 in non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016;7(14):18458-68. [DOI:10.18632/oncotarget.7607] [PMID] [PMCID]
  10. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2002;2(4):289-300. [DOI:10.1016/S1535-6108(02)00153-8]
  11. Vandooren J, Van den Steen PE, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol 2013;48(3):222-72. [DOI:10.3109/10409238.2013.770819] [PMID]
  12. Shao W, Wang W, Xiong XG, Cao C, Yan TD, Chen G, et al. Prognostic impact of MMP-2 and MMP-9 expression in pathologic stage IA non-small cell lung cancer. J Surg Oncol 2011;104(7):841-6. [DOI:10.1002/jso.22001] [PMID]
  13. Lee CY, Shim HS, Lee S, Lee JG, Kim DJ, Chung KY. Prognostic effect of matrix metalloproteinase-9 in patients with resected Non small cell lung cancer. J Cardiothorac Surg 2015;10:44. [DOI:10.1186/s13019-015-0248-3] [PMID] [PMCID]
  14. Stenvold H, Donnem T, Andersen S, Al-Saad S, Al-Shibli K, Busund LT, et al. Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: correlation with a favorable clinical outcome. Lung Cancer 2012;75(2):235-41. [DOI:10.1016/j.lungcan.2011.06.010] [PMID]
  15. Shi M, Cao M, Song J, Liu Q, Li H, Meng F, et al. PinX1 inhibits the invasion and metastasis of human breast cancer via suppressing NF-kappaB/MMP-9 signaling pathway. Mol Cancer 2015;14:66. [DOI:10.1186/s12943-015-0332-2] [PMID] [PMCID]
  16. Chee-Keong Toh. The Changing Epidemiology of Lung Cancer. 2009. 19: 397-411 [DOI:10.1007/978-1-60327-492-0_19] [PMID]
  17. Wei Dong, Hong Li, Yan Zhang, et al. Matrix metalloproteinase 2 promotes cell growth and invasion in colorectal cancer. Acta Biochim Biophys Sin 2011, 43: 840-848. [DOI:10.1093/abbs/gmr085] [PMID]
  18. Rydlova M, Holubec L, Jr., Ludvikova M, Jr., Kalfert D, Franekova J, Povysil C, et al. Biological activity and clinical implications of the matrix metalloproteinases. Anticancer Res 2008;28(2b):1389-97.
  19. Mehner C, Hockla A, Miller E, Ran S, Radisky DC, Radisky ES. Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget 2014;5(9):2736-49. [DOI:10.18632/oncotarget.1932] [PMID] [PMCID]
  20. Safranek J, Pesta M, Holubec L, Kulda V, Dreslerova J, Vrzalova J, et al. Expression of MMP-7, MMP-9, TIMP-1 and TIMP-2 mRNA in lung tissue of patients with non-small cell lung cancer (NSCLC) and benign pulmonary disease. Anticancer Res 2009;29(7):2513-7.
  21. El-Badrawy MK, Yousef AM, Shaalan D, Elsamanoudy AZ. Matrix metalloproteinase-9 expression in lung cancer patients and its relation to serum mmp-9 activity, pathologic type, and prognosis. J Bronchology Interv Pulmonol 2014;21(4):327-34. [DOI:10.1097/LBR.0000000000000094] [PMID]
  22. Pinto CA, Carvalho PE, Antonangelo L, Garippo A, Da Silva AG, Soares F, et al. Morphometric evaluation of tumor matrix metalloproteinase 9 predicts survival after surgical resection of adenocarcinoma of the lung. Clin Cancer Res 2003;9(8):3098-104.
  23. Zheng S, Chang Y, Hodges KB, Sun Y, Ma X, Xue Y, et al. Expression of KISS1 and MMP-9 in non-small cell lung cancer and their relations to metastasis and survival. Anticancer Res 2010;30(3):713-8.
  24. Sienel W, Hellers J, Morresi-Hauf A, Lichtinghagen R, Mutschler W, Jochum M, et al. Prognostic impact of matrix metalloproteinase-9 in operable non-small cell lung cancer. Int J Cancer 2003;103(5):647-51. [DOI:10.1002/ijc.10841] [PMID]
  25. Grossi F, Spizzo R, Bordo D, Cacitti V, Valent F, Rossetto C, et al. Prognostic stratification of stage IIIA pN2 non-small cell lung cancer by hierarchical clustering analysis of tissue microarray immunostaining data: an Alpe Adria Thoracic Oncology Multidisciplinary Group study (ATOM 014). J Thorac Oncol 2010;5(9):1354-60. [DOI:10.1097/JTO.0b013e3181e77a78] [PMID]
  26. Weiling He , Hui Zhang , Yuefeng Wang , Yanbin Zhou , Yifeng Luo, et al. CTHRC1 induces non-small cell lung cancer (NSCLC) invasion through upregulating MMP-7/MMP-9. BMCCancer(2018)18:400 . [DOI:10.1186/s12885-018-4317-6] [PMID] [PMCID]
  27. Vincenti MP. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol. 2001;151:121-48. [DOI:10.1385/1-59259-046-2:121] [PMID]
  28. A. Churg, R. Wang, X. Wang, P.O. Onnervik, K. Thim, et al. Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodeling in guinea pigs. Thorax 62 (2007) 706-713. [DOI:10.1136/thx.2006.068353] [PMID] [PMCID]
  29. Balla, M., Desai, S., Purwar, P. et al. Differential diagnosis of lung cancer, its metastasis and chronic obstructive pulmonary disease based on serum Vegf, Il-8 and MMP-9. Sci Rep 6, 36065 (2016). [DOI:10.1038/srep36065] [PMID] [PMCID]
  30. Hao Huang, Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances, Sensors 2018, 18(10), 3249 [DOI:10.3390/s18103249] [PMID] [PMCID]