title: Expression and prognostic impact of matrix metalloproteinase-2 (MMP-2) in astrocytomas.
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.
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Rahimsan K
authors.initials: RK
authors.lastname: Ramachandran
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Mia D
authors.identifier: http://orcid.org/0000-0002-0105-2940
authors.initials: MD
authors.lastname: Sørensen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Aaberg-Jessen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Hermansen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Bjarne W
authors.initials: BW
authors.lastname: Kristensen
mesh_terms: D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000175:diagnosis / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D012984:Software; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D007521:Isocitrate Dehydrogenase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2