Skip to main content
Top
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Relevance of matrix metalloproteases in non-small cell lung cancer diagnosis

Authors: Sonia Blanco-Prieto, Leticia Barcia-Castro, María Páez de la Cadena, Francisco Javier Rodríguez-Berrocal, Lorena Vázquez-Iglesias, María Isabel Botana-Rial, Alberto Fernández-Villar, Loretta De Chiara

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

The need for novel biomarkers that could aid in non-small cell lung cancer (NSCLC) detection, together with the relevance of Matrix Metalloproteases (MMPs) -1, -2, -7, -9 and -10 in lung tumorigenesis, prompted us to assess the diagnostic usefulness of these MMPs and the Tissue Inhibitor of Metalloproteinase (TIMP) -1 in NSCLC patients.

Methods

Markers were evaluated in an initial study cohort (19 NSCLC cases and 19 healthy controls). Those that better performed were analyzed in a larger sample including patients with benign lung diseases. Serum MMPs and TIMP-1 were determined by multiplexed immunoassays. Logistic regression was employed for multivariate analysis of biomarker combinations.

Results

MMPs and TIMP-1 were elevated in the serum of NSCLC patients compared to healthy controls. MMP-1, -7 and -9 performed at best and were further evaluated in the sample including benign pathologies, corroborating the superiority of MMP-9 in NSCLC discrimination, also at early-stage NSCLC. The optimal diagnostic value was obtained with the model including MMP-9, gender, age and smoking history, that demonstrated an AUC of 0.787, 85.54% sensitivity and 64.89% specificity.

Conclusion

Our results suggest that MMP-9 is a potential biomarker for NSCLC diagnosis and its combined measurement with other biomarkers could improve NSCLC detection.
Appendix
Available only for authorised users
Literature
1.
go back to reference Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2013; doi:10.1378/chest.12-2353. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2013; doi:10.​1378/​chest.​12-2353.
2.
go back to reference Francisci S, Minicozzi P, Pierannunzio D, Ardanaz E, Eberle A, Grimsrud TK, et al. Survival patterns in lung and pleural cancer in Europe 1999-2007: results from the EUROCARE-5 study. Eur J Cancer. 2015; doi:10.1016/j.ejca.2015.07.033. Francisci S, Minicozzi P, Pierannunzio D, Ardanaz E, Eberle A, Grimsrud TK, et al. Survival patterns in lung and pleural cancer in Europe 1999-2007: results from the EUROCARE-5 study. Eur J Cancer. 2015; doi:10.​1016/​j.​ejca.​2015.​07.​033.
5.
go back to reference Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002; doi:10.1038/nrc745. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002; doi:10.​1038/​nrc745.
8.
go back to reference Hadler-Olsen E, Winberg JO, Uhlin-Hansen L. Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumor Biol. 2013; doi:10.1007/s13277-013-0842-8. Hadler-Olsen E, Winberg JO, Uhlin-Hansen L. Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumor Biol. 2013; doi:10.​1007/​s13277-013-0842-8.
9.
go back to reference Gueders MM, Foidart JM, Noel A, Cataldo DD. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol. 2006; doi:10.1016/j.ejphar.2005.12.082. Gueders MM, Foidart JM, Noel A, Cataldo DD. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol. 2006; doi:10.​1016/​j.​ejphar.​2005.​12.​082.
10.
go back to reference Foley CJ, Fanjul-Fernández M, Bohm A, Nguyen N, Agarwal A, Austin K, et al. Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis. Oncogene. 2014; doi:10.1038/onc.2013.157. Foley CJ, Fanjul-Fernández M, Bohm A, Nguyen N, Agarwal A, Austin K, et al. Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis. Oncogene. 2014; doi:10.​1038/​onc.​2013.​157.
11.
go back to reference Chetty C, Lakka SS, Bhoopathi P, Rao JS. MMP-2 alters VEGF expression via aVß3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int J Cancer. 2010; doi:10.1002/ijc.25134. Chetty C, Lakka SS, Bhoopathi P, Rao JS. MMP-2 alters VEGF expression via aVß3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int J Cancer. 2010; doi:10.​1002/​ijc.​25134.
12.
go back to reference Kim EJ, Lee SY, Woo MK, Choi SI, Kim TR, Kim MJ, et al. Fibulin-3 promoter methylation alters the invasive behavior of non-small cell lung cancer cell lines via MMP-7 and MMP-2 regulation. Int J Oncol. 2012; doi:10.3892/ijo.2011.1191. Kim EJ, Lee SY, Woo MK, Choi SI, Kim TR, Kim MJ, et al. Fibulin-3 promoter methylation alters the invasive behavior of non-small cell lung cancer cell lines via MMP-7 and MMP-2 regulation. Int J Oncol. 2012; doi:10.​3892/​ijo.​2011.​1191.
13.
go back to reference 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; doi:10.1016/S1535-6108(02)00153-8. 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; doi:10.​1016/​S1535-6108(02)00153-8.​
14.
go back to reference Justilien V, Regala RP, Tseng IC, Walsh MP, Batra J, Radisky ES, et al. Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. PLoS One. 2012; doi:10.1371/journal.pone.0035040. Justilien V, Regala RP, Tseng IC, Walsh MP, Batra J, Radisky ES, et al. Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. PLoS One. 2012; doi:10.​1371/​journal.​pone.​0035040.
16.
go back to reference Löffek S, Schilling O, Franzke CW. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011; doi:10.1183/09031936.00146510. Löffek S, Schilling O, Franzke CW. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011; doi:10.​1183/​09031936.​00146510.
17.
go back to reference Alberts WM; American College of Chest Physicians. Diagnosis and management of lung cancer executive summary. ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007; doi: 10.1378/chest.07-1860. Alberts WM; American College of Chest Physicians. Diagnosis and management of lung cancer executive summary. ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007; doi: 10.​1378/​chest.​07-1860.
19.
go back to reference Shah SA, Spinale FG, Ikonomidis JS, Stroud RE, Chang EI, Reed CE. Differential matrix metalloproteinase levels in adenocarcinoma and squamous cell carcinoma of the lung. J Thorac Cardiovasc Surg. 2010; doi:10.1016/j.jtcvs.2009.12.016. Shah SA, Spinale FG, Ikonomidis JS, Stroud RE, Chang EI, Reed CE. Differential matrix metalloproteinase levels in adenocarcinoma and squamous cell carcinoma of the lung. J Thorac Cardiovasc Surg. 2010; doi:10.​1016/​j.​jtcvs.​2009.​12.​016.
20.
go back to reference Gouyer V, Conti M, Devos P, Zerimech F, Copin MC, Créme E, et al. Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer. 2005; doi:10.1002/cncr.20965. Gouyer V, Conti M, Devos P, Zerimech F, Copin MC, Créme E, et al. Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer. 2005; doi:10.​1002/​cncr.​20965.
21.
go back to reference Leinonen T, Pirinen R, Böhm J, Johansson R, Ropponen K, Kosma VM. Expression of matrix metalloproteinases 7 and 9 in non-small cell lung cancer: relation to clinicopathological factors, ß-catenin and prognosis. Lung Cancer. 2006; doi:10.1016/j.lungcan.2005.11.002. Leinonen T, Pirinen R, Böhm J, Johansson R, Ropponen K, Kosma VM. Expression of matrix metalloproteinases 7 and 9 in non-small cell lung cancer: relation to clinicopathological factors, ß-catenin and prognosis. Lung Cancer. 2006; doi:10.​1016/​j.​lungcan.​2005.​11.​002.
22.
go back to reference doi:Gill JH, Kirwan IG, Seargent JM, Martin SW, Tijani S, Anikin VA, et al. MMP-10 is overexpressed, proteolytically active, and a potential target for therapeutic intervention in human lung carcinomas. Neoplasia. 2004; doi:10.1593/neo.04283. doi:Gill JH, Kirwan IG, Seargent JM, Martin SW, Tijani S, Anikin VA, et al. MMP-10 is overexpressed, proteolytically active, and a potential target for therapeutic intervention in human lung carcinomas. Neoplasia. 2004; doi:10.​1593/​neo.​04283.
23.
go back to reference Kanoh Y, Abe T, Masuda N, Akahoshi T. Progression of non-small cell lung cancer: diagnostic and prognostic utility of matrix metalloproteinase-2, C-reactive protein and serum amyloid a. Oncol Rep. 2013; doi:10.3892/or.2012.2123. Kanoh Y, Abe T, Masuda N, Akahoshi T. Progression of non-small cell lung cancer: diagnostic and prognostic utility of matrix metalloproteinase-2, C-reactive protein and serum amyloid a. Oncol Rep. 2013; doi:10.​3892/​or.​2012.​2123.
24.
go back to reference Zhang X, Zhu S, Luo G, Zheng L, Wei J, Zhu J, et al. Expression of MMP-10 in lung cancer. Anticancer Res. 2007;27:2791–5.PubMed Zhang X, Zhu S, Luo G, Zheng L, Wei J, Zhu J, et al. Expression of MMP-10 in lung cancer. Anticancer Res. 2007;27:2791–5.PubMed
25.
go back to reference Li M, Xiao T, Zhang Y, Feng L, Lin D, Liu Y, et al. Prognostic significance of matrix metalloproteinase-1 levels in peripheral plasma and tumour tissues of lung cancer patients. Lung Cancer. 2010; doi:10.1016/j.lungcan.2009.12.007. Li M, Xiao T, Zhang Y, Feng L, Lin D, Liu Y, et al. Prognostic significance of matrix metalloproteinase-1 levels in peripheral plasma and tumour tissues of lung cancer patients. Lung Cancer. 2010; doi:10.​1016/​j.​lungcan.​2009.​12.​007.
26.
go back to reference Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008; doi:10.1371/journal.pmed.0050093. Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008; doi:10.​1371/​journal.​pmed.​0050093.
27.
go back to reference Ulivi P, Casoni GL, Foschi G, Scarpi E, Tomassetti S, Romagnoli M, et al. MMP-7 and fcDNA serum levels in early NSCLC and idiopathic interstitial pneumonia: preliminary study. Int J Mol Sci. 2013; doi:10.3390/ijms141224097. Ulivi P, Casoni GL, Foschi G, Scarpi E, Tomassetti S, Romagnoli M, et al. MMP-7 and fcDNA serum levels in early NSCLC and idiopathic interstitial pneumonia: preliminary study. Int J Mol Sci. 2013; doi:10.​3390/​ijms141224097.
28.
go back to reference Zhang Y, Wu JZ, Zhang JY, Xue J, Ma R, Cao HX, et al. Detection of circulating vascular endothelial growth factor and matrix metalloproteinase-9 in non-small cell lung cancer using Luminex multiplex technology. Oncol Lett. 2014; doi:10.3892/ol.2013.1718. Zhang Y, Wu JZ, Zhang JY, Xue J, Ma R, Cao HX, et al. Detection of circulating vascular endothelial growth factor and matrix metalloproteinase-9 in non-small cell lung cancer using Luminex multiplex technology. Oncol Lett. 2014; doi:10.​3892/​ol.​2013.​1718.
29.
go back to reference Fiorelli A, Rizzo A, Messina G, Izzo A, Vicidomini G, Pannone G, et al. Correlation between matrix metalloproteinase 9 and 18F-2-fluoro-2-deoxyglucose-positron emission tomography as diagnostic markers of lung cancer. Eur J Cardiothorac Surg. 2012; doi:10.1093/ejcts/ezr117. Fiorelli A, Rizzo A, Messina G, Izzo A, Vicidomini G, Pannone G, et al. Correlation between matrix metalloproteinase 9 and 18F-2-fluoro-2-deoxyglucose-positron emission tomography as diagnostic markers of lung cancer. Eur J Cardiothorac Surg. 2012; doi:10.​1093/​ejcts/​ezr117.
30.
go back to reference Jumper C, Cobos E, Lox C. Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment. Respir Med. 2004;98:173–7.CrossRefPubMed Jumper C, Cobos E, Lox C. Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment. Respir Med. 2004;98:173–7.CrossRefPubMed
31.
go back to reference Ylisirniö S, Höyhtyä M, Mäkitaro R, Pääakkö P, Risteli J, Kinnula VL, et al. Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin Cancer Res. 2001;7:1633–7.PubMed Ylisirniö S, Höyhtyä M, Mäkitaro R, Pääakkö P, Risteli J, Kinnula VL, et al. Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin Cancer Res. 2001;7:1633–7.PubMed
32.
go back to reference Doseeva V, Colpitts T, Gao G, Woodcock J, Knezevic V. Performance of a multiplexed dual analyte immunoassay for the early detection of non-small cell lung cancer. J Transl Med. 2015; doi:10.1186/s12967-015-0419-y. Doseeva V, Colpitts T, Gao G, Woodcock J, Knezevic V. Performance of a multiplexed dual analyte immunoassay for the early detection of non-small cell lung cancer. J Transl Med. 2015; doi:10.​1186/​s12967-015-0419-y.
33.
go back to reference Blanco-Prieto S, Vázquez-Iglesias L, Rodríguez-Girondo M, Barcia-Castro L, Fernández-Villar A, Botana-Rial MI, et al. Serum calprotectin, CD26 and EGF to establish a panel for the diagnosis of lung cancer. PLoS One. 2015; doi:10.1371/journal.pone.0127318. Blanco-Prieto S, Vázquez-Iglesias L, Rodríguez-Girondo M, Barcia-Castro L, Fernández-Villar A, Botana-Rial MI, et al. Serum calprotectin, CD26 and EGF to establish a panel for the diagnosis of lung cancer. PLoS One. 2015; doi:10.​1371/​journal.​pone.​0127318.
34.
go back to reference Jett JR, Peek LJ, Fredericks L, Jewell W, Pingleton WW, Robertson JF. Audit of the autoantibody test, EarlyCDT®-lung, in 1600 patients: an evaluation of its performance in routine clinical practice. Lung Cancer. 2014; doi:10.1016/j.lungcan.2013.10.008. Jett JR, Peek LJ, Fredericks L, Jewell W, Pingleton WW, Robertson JF. Audit of the autoantibody test, EarlyCDT®-lung, in 1600 patients: an evaluation of its performance in routine clinical practice. Lung Cancer. 2014; doi:10.​1016/​j.​lungcan.​2013.​10.​008.
35.
go back to reference Farlow EC, Vercillo MS, Coon JS, Basu S, Kim AW, Faber LP, et al. A multi-analyte serum test for the detection of non-small cell lung cancer. Br J Cancer. 2010; doi:10.1038/sj.bjc.6605865. Farlow EC, Vercillo MS, Coon JS, Basu S, Kim AW, Faber LP, et al. A multi-analyte serum test for the detection of non-small cell lung cancer. Br J Cancer. 2010; doi:10.​1038/​sj.​bjc.​6605865.
36.
go back to reference Bigbee WL, Gopalakrishnan V, Weissfeld JL, Wilson DO, Dacic S, Lokshin AE, et al. A multiplexed serum biomarker immunoassay panel discriminates clinical lung cancer patients from high-risk individuals found to be cancer-free by CT screening. J Thorac Oncol. 2012; doi:10.1097/JTO.0b013e31824ab6b0. Bigbee WL, Gopalakrishnan V, Weissfeld JL, Wilson DO, Dacic S, Lokshin AE, et al. A multiplexed serum biomarker immunoassay panel discriminates clinical lung cancer patients from high-risk individuals found to be cancer-free by CT screening. J Thorac Oncol. 2012; doi:10.​1097/​JTO.​0b013e31824ab6b0​.
37.
go back to reference Izbicka E, Streeper RT, Michalek JE, Louden CL, Diaz A 3rd, Campos DR. Plasma biomarkers distinguish non-small cell lung cancer from asthma and differ in men and women. Cancer Genomics Proteomics. 2012;9:27–35.PubMed Izbicka E, Streeper RT, Michalek JE, Louden CL, Diaz A 3rd, Campos DR. Plasma biomarkers distinguish non-small cell lung cancer from asthma and differ in men and women. Cancer Genomics Proteomics. 2012;9:27–35.PubMed
Metadata
Title
Relevance of matrix metalloproteases in non-small cell lung cancer diagnosis
Authors
Sonia Blanco-Prieto
Leticia Barcia-Castro
María Páez de la Cadena
Francisco Javier Rodríguez-Berrocal
Lorena Vázquez-Iglesias
María Isabel Botana-Rial
Alberto Fernández-Villar
Loretta De Chiara
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3842-z

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine