Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma

Johan Ph. Kuyvenhoven; Bart van Hoek; Eric Blom; Wim van Duijn; Roeland Hanemaaijer; Jan H. Verheijen; Cornelis B.H.W. Lamers; Hein W. Verspaget

doi:10.1055/s-0037-1613578

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 89(04): 718-725
DOI: 10.1055/s-0037-1613578

Cellular Proteolysis and Oncology

Schattauer GmbH

Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma

Johan Ph. Kuyvenhoven

¹Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

,

Bart van Hoek

¹Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

,

Eric Blom

¹Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

,

Wim van Duijn

¹Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

,

Roeland Hanemaaijer

²Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

,

Jan H. Verheijen

²Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

,

Cornelis B.H.W. Lamers

¹Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

,

Hein W. Verspaget

¹Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

› Author Affiliations

Abstract

Summary

Matrix metalloproteinases (MMPs) have the ability to degrade basement membranes and may thus play an important role in extracellular matrix turnover in liver fibrosis and carcinogene-sis. Serum levels of MMPs have been suggested as diagnostic markers in these processes.

We measured serum MMP-2 and MMP-9 by ELISA in 91 patients with chronic liver disease, including 25 patients with hepatocellular carcinoma (HCC), and in 60 controls.

MMP-2 was significantly higher in patients with chronic liver disease compared to controls, and increased with Child-Pugh class. There was a significant correlation between MMP-2 and liver function (bilirubin, albumin, and prothrombin time), and a strong opposite correlation between MMP-9 and these parameters.

MMP-2 levels in patients with HCC were significantly higher than in controls, but comparable to patients with chronic liver disease without this malignancy. MMP-9 yielded no significant differences between patients with or without HCC and controls.

Serum MMP-2 and to a lesser extent MMP-9 correlate with the severity of liver disease and may reflect changes in extracellular matrix remodeling. Due to a considerable overlap in patients with chronic liver disease with or without HCC, MMP-2 and MMP-9 can not be used as a diagnostic marker for HCC.

Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

Keywords

Hepatocellular carcinoma - liver disease - matrix metalloproteinases

Full Text

References

References
1 Murphy G, Docherty AJ. The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol 1992; 7: 120-5.
2 Nagase H, Woessner Jr JF. Matrix metalloproteinases. J Biol Chem 1999; 274: 21491-4.
3 Arthur MJ. Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2000; 279: G245-G249.
4 Milani S, Herbst H, Schuppan D, Grappone C, Pellegrini G, Pinzani M. et al. Differential expression of matrix metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol 1994; 144: 528-37.
5 Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 1996; 110: 821-31.
6 Préaux A-M, Mallat A, Tran Van Nhieu J, d’Ortho M-P, Hembry RM, Mavier P. Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions. Hepatology 1999; 30: 944-50.
7 Murawaki Y, Yamada S, Ikuta Y, Kawasaki H. Clinical usefulness of serum matrix metalloproteinase-2 concentration in patients with chronic viral liver disease. J Hepatol 1999; 30: 1090-8.
8 Ebata M, Fukuda Y, Nakano I, Katano Y, Fujimoto N, Hayakawa T. Serum levels of tissue inhibitor of metalloproteinases-2 and of precursor form of matrix metalloproteinase-2 in patients with liver disease. Liver 1997; 17: 293-9.
9 Kasahara A, Hayashi N, Mochizuki K, Oshita M, Katayama K, Kato M. et al. Circulating matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as serum markers of fibrosis in patients with chronic hepatitis C. Relationship to interferon response. J Hepatol 1997; 26: 574-83.
10 Walsh KM, Timms P, Campbell S, MacSween RN, Morris AJ. Plasma levels of matrix metal-loproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis. Dig Dis Sci 1999; 44: 624-30.
11 Musso O, Theret N, Campion JP, Turlin B, Milani S, Grappone C, Clément B. In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepato-cellular carcinoma and in liver metastasis. J Hepatol 1997; 26: 593-605.
12 Theret N, Musso O, L’Helgoualc’h A, Campion JP, Clément B. Differential expression and origin of membrane-type 1 and 2 matrix metalloproteinases (MT-MMPs) in association with MMP2 activation in injured human livers. Am J Pathol 1998; 153: 945-54.
13 Määttä M, Soini Y, Liakka A, Autio-Harmainen H. Differential expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: implications for tumor progression and clinical prognosis. Clin Cancer Res 2000; 6: 2726-34.
14 Theret N, Musso O, Turlin B, Lotrian D, Bioulac-Sage P, Campion JP. et al. Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Hepatology 2001; 34: 82-8.
15 Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L. et al. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 2002; 97: 425-31.
16 Hayasaka A, Suzuki N, Fujimoto N, Iwama S, Fukuyama E, Kanda Y, Saisho H. Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma. Hepatology 1996; 24: 1058-62.
17 Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-9.
18 Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed. The liver and portal hypertension. Philadelphia: Saunders 1964; 50.
19 Gveric D, Hanemaaijer R, Newcombe J, van Lent NA, Sier CFM, Cuzner ML. Plasminogen activators in multiple sclerosis lesions. Implications for the inflammatory response and axonal damage. Brain 2001; 124: 1978-88.
20 Hanemaaijer R, Visser H, Konttinen YT, Koolwijk P, Verheijen JH. A novel and simple immunocapture assay for determination of gelatinase- B (MMP-9) activities in biological fluids: saliva from patients with Sjögren’s syndrome contain increased latent and active gelatinase-B levels. Matrix Biol 1998; 17: 657-65.
21 Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 2001; 21: 373-84.
22 Takahara T, Furui K, Yata Y, Jin B, Zhang LP, Nambu S, Sato H, Seiki M, Watanabe A. Dual expression of matrix metalloproteinase-2 and membrane-type 1- matrix metalloproteinase in fibrotic human livers. Hepatology 1997; 26: 1521-9.
23 Kuo WH, Chou FP, Lu SC, Chu SC, Hsieh YS. Significant differences in serum activities of matrixmetalloproteinase- 2 and -9 between HCV- and HBV-infected patients and carriers. Clin Chim Acta 2000; 294: 157-68.
24 Arthur MJ. Collagenases and liver fibrosis. J Hepatol 1995; 22: 43-8.
25 Winwood PJ, Schuppan D, Iredale JP, Kawser CA, Docherty AJ, Arthur MJ. Kupffer cell-derived 95-kd type IV collagenase/gelatinase B: characterization and expression in cultured cells. Hepatology 1995; 22: 304-15.
26 Kossakowska AE, Edwards DR, Lee SS, Urbanski LS, Stabbler AL, Zhang CL. et al. Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Am J Pathol 1998; 153: 1895-902.
27 Lichtinghagen R, Michels D, Haberkorn I C, Arndt B, Bahr M, Flemming P. et al. Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J Hepatol 2001; 34: 239-47.
28 Lichtinghagen R, Huegel O, Seifert T, Haberkorn I C, Michels D, Flemming P. et al. Expression of matrix metalloproteinase-2 and -9 and their inhibitors in peripheral blood cells of patients with chronic hepatitis C. Clin Chem 2000; 46: 183-92.
29 Brown PD. Matrix metalloproteinases in gastrointestinal cancer. Gut 1998; 43: 161-3.
30 Arii S, Mise M, Harada T, Furutani M, Ishigami S, Niwano M. et al. Overexpression of matrix metalloproteinase 9 gene in hepato-cellular carcinoma with invasive potential. Hepatology 1996; 24: 316-22.