Expression and Prognostic Impact of Matrix Metalloproteinase-2 (MMP-2) in Astrocytomas

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Feb 25

PMID 28234925

Citations 37

Authors

Rahimsan K Ramachandran

Mia D Sorensen

Charlotte Aaberg-Jessen

Simon K Hermansen

Bjarne W Kristensen

Affiliations

Soon will be listed here.

Abstract

Astrocytomas are the most frequent primary brain tumors in adults, and despite aggressive treatment patients often experience recurrence. Survival decreases with increasing tumor grade, and especially patients with grade IV glioblastoma have poor prognosis due to the aggressive character of this tumor. Matrix metalloproteinase-2 (MMP-2) is an extracellular matrix degrading enzyme which has been shown to play important roles in different cancers. The aim of this study was to investigate the expression and prognostic potential of MMP-2 in astrocytomas. Tissue samples from 89 patients diagnosed with diffuse astrocytoma, anaplastic astrocytoma and glioblastoma were stained immunohistochemically using a monoclonal MMP-2 antibody. The MMP-2 intensity in cytoplasm/membrane was quantified by a trained software-based classifier using systematic random sampling in 10% of the tumor area. We found MMP-2 expression in tumor cells and blood vessels. Measurements of MMP-2 intensity increased with tumor grade, and MMP-2 expression was found to be significantly higher in glioblastomas compared to normal brain tissue (p<0.001), diffuse astrocytomas (p<0.001) and anaplastic astrocytomas (p<0.05). MMP-2 expression was associated with shorter overall survival in patients with grade II-IV astrocytic tumors (HR 1.60; 95% CI 1.03-2.48; p = 0.036). In glioblastoma, high MMP-2 was associated with poorer prognosis in patients who survived longer than 8.5 months independent of age and gender (HR 2.27; 95% CI 1.07-4.81; p = 0.033). We found a positive correlation between MMP-2 and tissue inhibitor of metalloproteinases-1 (TIMP-1), and combined MMP-2 and TIMP-1 had stronger prognostic value than MMP-2 alone also when adjusting for age and gender (HR 2.78; 95% CI 1.30-5.92; p = 0.008). These findings were validated in bioinformatics databases. In conclusion, this study indicates that MMP-2 is associated with aggressiveness in astrocytomas and may hold an unfavorable prognostic value in patients with glioblastoma.

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References

Hermansen S, Dahlrot R, Nielsen B, Hansen S, Kristensen B . MiR-21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas. J Neurooncol. 2012; 111(1):71-81. DOI: 10.1007/s11060-012-0992-3. View

Gavrielides M, Gallas B, Lenz P, Badano A, Hewitt S . Observer variability in the interpretation of HER2/neu immunohistochemical expression with unaided and computer-aided digital microscopy. Arch Pathol Lab Med. 2011; 135(2):233-42. PMC: 7604903. DOI: 10.5858/135.2.233. View

Habberstad A, Lind-Landstrom T, Sundstrom S, Torp S . Primary human glioblastomas - prognostic value of clinical and histopathological parameters. Clin Neuropathol. 2012; 31(5):361-8. DOI: 10.5414/np300439. View

Dahlrot R, Sorensen M, Rosager A, Hellwege S, Bangso J, Rosenberg T . Novel approaches for quantifying protein biomarkers in gliomas: benefits and pitfalls. CNS Oncol. 2014; 3(4):287-98. PMC: 6124359. DOI: 10.2217/cns.14.30. View

Nakada M, Nakamura H, Ikeda E, Fujimoto N, Yamashita J, Sato H . Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol. 1999; 154(2):417-28. PMC: 1850004. DOI: 10.1016/S0002-9440(10)65288-1. View

Dahlrot R, Kristensen B, Hjelmborg J, Herrstedt J, Hansen S . A population-based study of low-grade gliomas and mutated isocitrate dehydrogenase 1 (IDH1). J Neurooncol. 2013; 114(3):309-17. DOI: 10.1007/s11060-013-1186-3. View

Jaalinoja J, Herva R, Korpela M, Hoyhtya M, Turpeenniemi-Hujanen T . Matrix metalloproteinase 2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms. J Neurooncol. 2000; 46(1):81-90. DOI: 10.1023/a:1006421112839. View

Coniglio S, Eugenin E, Dobrenis K, Stanley E, West B, Symons M . Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med. 2012; 18:519-27. PMC: 3356419. DOI: 10.2119/molmed.2011.00217. View

Dahlrot R, Hansen S, Herrstedt J, Schroder H, Hjelmborg J, Kristensen B . Prognostic value of Musashi-1 in gliomas. J Neurooncol. 2013; 115(3):453-61. DOI: 10.1007/s11060-013-1246-8. View

10.

Petterson S, Dahlrot R, Hermansen S, K A Munthe S, Gundesen M, Wohlleben H . High levels of c-Met is associated with poor prognosis in glioblastoma. J Neurooncol. 2015; 122(3):517-27. DOI: 10.1007/s11060-015-1723-3. View

11.

Shima I, Sasaguri Y, Kusukawa J, Yamana H, Fujita H, Kakegawa T . Production of matrix metalloproteinase-2 and metalloproteinase-3 related to malignant behavior of esophageal carcinoma. A clinicopathologic study. Cancer. 1992; 70(12):2747-53. DOI: 10.1002/1097-0142(19921215)70:12<2747::aid-cncr2820701204>3.0.co;2-5. View

12.

Still K, Robson C, Autzen P, Robinson M, Hamdy F . Localization and quantification of mRNA for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human benign and malignant prostatic tissue. Prostate. 1999; 42(1):18-25. DOI: 10.1002/(sici)1097-0045(20000101)42:1<18::aid-pros3>3.0.co;2-a. View

13.

Jensen S, Meyer M, Petterson S, Halle B, Rosager A, Aaberg-Jessen C . Establishment and Characterization of a Tumor Stem Cell-Based Glioblastoma Invasion Model. PLoS One. 2016; 11(7):e0159746. PMC: 4959755. DOI: 10.1371/journal.pone.0159746. View

14.

Kessler J, Guttler A, Wichmann H, Rot S, Kappler M, Bache M . IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status. Radiother Oncol. 2015; 116(3):381-7. DOI: 10.1016/j.radonc.2015.08.007. View

15.

Dahlrot R, Kristensen B, Hjelmborg J, Herrstedt J, Hansen S . A population-based study of high-grade gliomas and mutated isocitrate dehydrogenase 1. Int J Clin Exp Pathol. 2012; 6(1):31-40. PMC: 3515987. View

16.

Talvensaari-Mattila A, Paakko P, Hoyhtya M, Turpeenniemi-Hujanen T . Matrix metalloproteinase-2 immunoreactive protein: a marker of aggressiveness in breast carcinoma. Cancer. 1998; 83(6):1153-62. DOI: 10.1002/(sici)1097-0142(19980915)83:6<1153::aid-cncr14>3.0.co;2-4. View

17.

Shi S, Liu C, Pootrakul L, Tang L, Young A, Chen R . Evaluation of the value of frozen tissue section used as "gold standard" for immunohistochemistry. Am J Clin Pathol. 2008; 129(3):358-66. DOI: 10.1309/7CXUYXT23E5AL8KQ. View

18.

Phillips H, Kharbanda S, Chen R, Forrest W, Soriano R, Wu T . Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006; 9(3):157-73. DOI: 10.1016/j.ccr.2006.02.019. View

19.

Malmstrom A, Gronberg B, Marosi C, Stupp R, Frappaz D, Schultz H . Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012; 13(9):916-26. DOI: 10.1016/S1470-2045(12)70265-6. View

20.

Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio P . Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003; 3(4):347-61. DOI: 10.1016/s1535-6108(03)00085-0. View