Skip to main content

Advertisement

SpringerLink
Log in

Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in lung adenocarcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

Prognosis in patients with lung cancer is poor. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) are proteins involved in the invasion and metastases of cancer. The objective of this study is to determine if there is a relationship between tumor expression of NGAL and MMP-9 in lung adenocarcinoma patients with prognosis and overall survival. Retrospective analysis was made of patients with lung adenocarcinoma treated at Medica Sur Hospital between 2005 and 2013. Tumor tissue was analyzed for NGAL and MMP-9 expression by immunohistochemistry. We identified 41 patients. Mean overexpression in tumoral tissue of NGAL was 70 % and 30 % for MMP-9. Univariate analysis revealed that prognostic factors associated with overall survival (OS) were NGAL expression and stage at diagnosis. Median OS for NGAL expression <70 % was 45.7 months (95 % CI; 15.2–76.2) and for patients with ≥70 % 4.6 months (95 % CI; 0.5–18.8; P < 0.0001), and for stage at diagnosis (stages I and II mean not reached), stage III mean OS 15.57 months (95 % CI; 9.8–21.2) and stage IV 9.6 months (95 % CI; 0.8–18.4. P = 0.002). No differences in OS were found for expression of MMP-9. Multivariate analysis revealed significance for OS in NGAL expression (HR 5.01 [95 % CI; 1.68–14.93] P = 0.004) and stage at diagnosis (HR 2.05 [95 % CI 1.30–3.22] P = 0.002). Tumoral tissue expression of NGAL ≥70 % confers a worse prognosis compared to those who did not. NGAL is an independent prognostic factor of stage at diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

NGAL:

Neutrophil gelatinase-associated lipocalin

MMP-9:

Matrix metalloproteinase–9

References

  1. GLOBOCAN. International Agency for Research on Cancer. Cancer incidence and mortality worldwide in 2012. Globocan cancer fact sheets: lung cancer 2014. http://globocan.iarc.fr/. Accessed 17 June 2012.

  2. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol Off Publ Int Assoc Stud Lung Cancer. 2007;2(8):706–14. doi:10.1097/JTO.0b013e31812f3c1a.

    Google Scholar 

  3. National Comprehensive Cancer Network. Occult primary (version 1.2015). 2014. http://www.nccn.org/professionals/physician_gls/pdf/occult.pdf. Accessed 28 Oct 2014.

  4. Nesbitt JC, Putnam Jr JB, Walsh GL, Roth JA, Mountain CF. Survival in early-stage non-small cell lung cancer. Ann Thorac Surg. 1995;60(2):466–72.

    Article  CAS  PubMed  Google Scholar 

  5. Wenners AS, Mehta K, Loibl S, Park H, Mueller B, Arnold N, et al. Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer. PLoS One. 2012;7(10):e45826. doi:10.1371/journal.pone.0045826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kaur S, Chakraborty S, Baine MJ, Mallya K, Smith LM, Sasson A, et al. Potentials of plasma NGAL and MIC-1 as biomarker(s) in the diagnosis of lethal pancreatic cancer. PLoS One. 2013;8(2):e55171. doi:10.1371/journal.pone.0055171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barresi V, Reggiani-Bonetti L, Di Gregorio C, Vitarelli E, Ponz De Leon M, Barresi G. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in stage I colorectal carcinoma. Pathol Res Pract. 2011;207(8):479–86. doi:10.1016/j.prp.2011.05.012.

    Article  CAS  PubMed  Google Scholar 

  8. Chakraborty S, Kaur S, Guha S, Batra SK. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta. 2012;1826(1):129–69. doi:10.1016/j.bbcan.2012.03.008.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fernandez CA, Yan L, Louis G, Yang J, Kutok JL, Moses MA. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(15):5390–5. doi:10.1158/1078-0432.CCR-04-2391.

    Article  CAS  Google Scholar 

  10. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7(10):778–90. doi:10.1038/nrc2190.

    Article  CAS  PubMed  Google Scholar 

  11. Villalba Caloca J, Martínez Heredero R. Frecuencia del carcinoma broncopulmonar en pacientes fumadores y no fumadores diagnosticados en el Instituto Nacional de Enfermedades Respiratorias en el año 2001. Rev Inst Nac Enferm Respiratorias. 2004;17:27–34.

    Google Scholar 

  12. Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg. 1995;109(1):120–9.

    Article  CAS  PubMed  Google Scholar 

  13. Postoperative T1 N0 non-small cell lung cancer. Squamous versus nonsquamous recurrences. The Lung Cancer Study Group. J Thorac Cardiovasc Surg. 1987;94(3):349–54.

  14. Harpole Jr DH, Herndon 2nd JE, Young Jr WG, Wolfe WG, Sabiston Jr DC. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer. 1995;76(5):787–96.

    Article  PubMed  Google Scholar 

  15. Lipford 3rd EH, Eggleston JC, Lillemoe KD, Sears DL, Moore GW, Baker RR. Prognostic factors in surgically resected limited-stage, nonsmall cell carcinoma of the lung. Am J Surg Pathol. 1984;8(5):357–65.

    Article  PubMed  Google Scholar 

  16. Ruffini E, Asioli S, Filosso PL, Buffoni L, Bruna MC, Mossetti C, et al. Significance of the presence of microscopic vascular invasion after complete resection of Stage I-II pT1-T2N0 non-small cell lung cancer and its relation with T-size categories: did the 2009 7th edition of the TNM staging system miss something? J Thorac Oncol Off Publ Int Assoc Stud Lung Cancer. 2011;6(2):319–26. doi:10.1097/JTO.0b013e3182011f70.

    Google Scholar 

  17. Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics. 1997;45(1):17–23. doi:10.1006/geno.1997.4896.

    Article  CAS  PubMed  Google Scholar 

  18. Bratt T. Lipocalins and cancer. Biochim Biophys Acta. 2000;1482(1–2):318–26.

    Article  CAS  PubMed  Google Scholar 

  19. Flower DR. The lipocalin protein family: structure and function. Biochem J. 1996;318(Pt 1):1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goetz DH, Willie ST, Armen RS, Bratt T, Borregaard N, Strong RK. Ligand preference inferred from the structure of neutrophil gelatinase associated lipocalin. Biochemistry. 2000;39(8):1935–41.

    Article  CAS  PubMed  Google Scholar 

  21. Zhao H, Konishi A, Fujita Y, Yagi M, Ohata K, Aoshi T, et al. Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism. Cell Host Microbe. 2012;12(5):705–16. doi:10.1016/j.chom.2012.10.010.

    Article  CAS  PubMed  Google Scholar 

  22. Bauer M, Eickhoff JC, Gould MN, Mundhenke C, Maass N, Friedl A. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat. 2008;108(3):389–97. doi:10.1007/s10549-007-9619-3.

    Article  CAS  PubMed  Google Scholar 

  23. Shinriki S, Jono H, Ueda M, Obayashi K, Nakamura T, Ota K, et al. Stromal expression of neutrophil gelatinase-associated lipocalin correlates with poor differentiation and adverse prognosis in oral squamous cell carcinoma. Histopathology. 2014;64(3):356–64. doi:10.1111/his.12293.

    Article  PubMed  Google Scholar 

  24. Candido S, Maestro R, Polesel J, Catania A, Maira F, Signorelli SS, et al. Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer. Oncotarget. 2014;5(6):1576–94.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol. 2005;169(4):681–91. doi:10.1083/jcb.200409115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bolignano D, Donato V, Lacquaniti A, Fazio MR, Bono C, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Lett. 2010;288(1):10–6. doi:10.1016/j.canlet.2009.05.027.

    Article  CAS  PubMed  Google Scholar 

  27. Krysan K, Cui X, Gardner BK, Reckamp KL, Wang X, Hong L, et al. Elevated neutrophil gelatinase-associated lipocalin contributes to erlotinib resistance in non-small cell lung cancer. Am J Transl Res. 2013;5(5):481–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Provatopoulou X, Gounaris A, Kalogera E, Zagouri F, Flessas I, Goussetis E, et al. Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease. BMC Cancer. 2009;9:390. doi:10.1186/1471-2407-9-390.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dic A. Evaluation of neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP-9) and their complex MMP-9/NGAL in sera and urine of patients with kidney tumors. Oncol Lett. 2013;5(5):1677–81. doi:10.3892/ol.2013.1252.

    Google Scholar 

  30. Tong Z, Kunnumakkara AB, Wang H, Matsuo Y, Diagaradjane P, Harikumar KB, et al. Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res. 2008;68(15):6100–8. doi:10.1158/0008-5472.can-08-0540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yan L, Borregaard N, Kjeldsen L, Moses MA. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem. 2001;276(40):37258–65. doi:10.1074/jbc.M106089200.

    Article  CAS  PubMed  Google Scholar 

  32. Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci. 2009;100(1):9–16. doi:10.1111/j.1349-7006.2008.01001.x.

    Article  CAS  PubMed  Google Scholar 

  33. Cao L, Yang H, Hu C. The expression and its clinical significance of MMP-2 and MMP-9 in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi = Chin J Lung Cancer. 2003;6(6):484–7. doi:10.3779/j.issn. 1009-3419.2003.06.18.

    CAS  Google Scholar 

  34. Iniesta P, Moran A, De Juan C, Gomez A, Hernando F, Garcia-Aranda C, et al. Biological and clinical significance of MMP-2, MMP-9, TIMP-1 and TIMP-2 in non-small cell lung cancer. Oncol Rep. 2007;17(1):217–23.

    CAS  PubMed  Google Scholar 

  35. Liu Z, Xu S, Xiao N, Song C, Zhang H, Li F. Overexpression of IL-8 and MMP-9 confer high malignant phenotype in patients with non-small cell lung cancer. Zhongguo Fei Ai Za Zhi = Chin J Lung Cancer. 2010;13(8):795–802. doi:10.3779/j.issn. 1009-3419.2010.08.09.

    Google Scholar 

  36. Ramanujum R, Lin YL, Liu JK, He S. Regulatory expression of MMP-8/MMP-9 and inhibition of proliferation, migration and invasion in human lung cancer A549 cells in the presence of HGF variants. Kaohsiung J Med Sci. 2013;29(10):530–9. doi:10.1016/j.kjms.2013.01.011.

    Article  PubMed  Google Scholar 

  37. Rollin J, Regina S, Vourc'h P, Iochmann S, Blechet C, Reverdiau P, et al. Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer. Lung Cancer. 2007;56(2):273–80. doi:10.1016/j.lungcan.2006.11.021.

    Article  PubMed  Google Scholar 

  38. Roomi MW, Monterrey JC, Kalinovsky T, Niedzwiecki A, Rath M. Modulation of MMP-2 and MMP-9 by cytokines, mitogens and inhibitors in lung cancer and malignant mesothelioma cell lines. Oncol Rep. 2009;22(6):1283–91.

    CAS  PubMed  Google Scholar 

  39. Schveigert D, Cicenas S, Bruzas S, Samalavicius NE, Gudleviciene Z, Didziapetriene J. The value of MMP-9 for breast and non-small cell lung cancer patients’ survival. Adv Med Sci. 2013;58(1):73–82. doi:10.2478/v10039-012-0066-y.

    Article  CAS  PubMed  Google Scholar 

  40. Wang JL, Wu DW, Cheng ZZ, Han WZ, Xu SW, Sun NN. Expression of High Mobility Group Box - B1 (HMGB-1) and Matrix Metalloproteinase-9 (MMP-9) in Non-small Cell Lung Cancer (NSCLC). Asian Pac J Cancer Prev APJCP. 2014;15(12):4865–9.

    Article  PubMed  Google Scholar 

  41. 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.

    PubMed  Google Scholar 

  42. O'Sullivan S, Medina C, Ledwidge M, Radomski MW, Gilmer JF. Nitric oxide-matrix metaloproteinase-9 interactions: biological and pharmacological significance—NO and MMP-9 interactions. Biochim Biophys Acta. 2014;1843(3):603–17. doi:10.1016/j.bbamcr.2013.12.006.

    Article  PubMed  Google Scholar 

  43. Chang CK, Hung WC, Chang HC. The Kazal motifs of RECK protein inhibit MMP-9 secretion and activity and reduce metastasis of lung cancer cells in vitro and in vivo. J Cell Mol Med. 2008;12(6B):2781–9. doi:10.1111/j.1582-4934.2008.00215.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng R, Qin X, Li W, Kang J. Effect of Src tyrosine kinase inhibition on secretion of MMP-2 and MMP-9 by non-small cell lung cancer cells. Zhongguo Fei Ai Za Zhi = Chin J Lung Cancer. 2011;14(1):13–7. doi:10.3779/j.issn. 1009-3419.2011.01.03.

    CAS  Google Scholar 

  45. Lee JH, Lin YL, Hsu WH, Chen HY, Chang YC, Yu CJ, et al. Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer. J Thorac Oncol Off Publ Int Assoc Stud Lung Cancer. 2014;9(9):1385–92. doi:10.1097/jto.0000000000000238.

    CAS  Google Scholar 

  46. Zhang XF, Zhang Y, Zhang XH, Zhou SM, Yang GG, Wang OC, et al. Clinical significance of Neutrophil gelatinase-associated lipocalin(NGAL) expression in primary rectal cancer. BMC Cancer. 2009;9:134. doi:10.1186/1471-2407-9-134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hu L, Hittelman W, Lu T, Ji P, Arlinghaus R, Shmulevich I, et al. NGAL decreases E-cadherin-mediated cell-cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells. Lab Investig J Tech Methods Pathol. 2009;89(5):531–48. doi:10.1038/labinvest.2009.17.

    Article  CAS  Google Scholar 

  48. Buss JL, Greene BT, Turner J, Torti FM, Torti SV. Iron chelators in cancer chemotherapy. Curr Top Med Chem. 2004;4(15):1623–35.

    Article  CAS  PubMed  Google Scholar 

  49. Jones DT, Trowbridge IS, Harris AL. Effects of transferrin receptor blockade on cancer cell proliferation and hypoxia-inducible factor function and their differential regulation by ascorbate. Cancer Res. 2006;66(5):2749–56. doi:10.1158/0008-5472.can-05-3857.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflicts of interest

None

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional committee. For this type of study, formal consent is not required.

Author information

Authors and Affiliations

  1. Oncology Center, Medica Sur Hospital, Puente de Piedra 150, Col. Toriello Guerra. Deleg Tlalpan, Mexico City, Mexico

    José Manuel Ruiz-Morales & Daniel Motola-Kuba

  2. Anatomical Pathology Department, Medica Sur Hospital, Mexico City, Mexico

    Rita Dorantes-Heredia

  3. Lung Cancer Unit, National Cancer Institute, Mexico City, Mexico

    Oscar Arrieta & Norberto C. Chávez-Tapia

  4. Gastroenterology Clinic, Medica Sur Hospital, Mexico City, Mexico

    Daniel Motola-Kuba

Authors
  1. José Manuel Ruiz-Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Dorantes-Heredia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oscar Arrieta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norberto C. Chávez-Tapia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Motola-Kuba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Motola-Kuba.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruiz-Morales, J.M., Dorantes-Heredia, R., Arrieta, O. et al. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in lung adenocarcinoma. Tumor Biol. 36, 3601–3610 (2015). https://doi.org/10.1007/s13277-014-2997-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2997-3

Keywords

Search

Navigation