This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choe, G. Articles by Mischel, P. S. Search for Related Content PubMed PubMed Citation Articles by Choe, G. Articles by Mischel, P. S.

Active Matrix Metalloproteinase 9 Expression Is Associated with Primary Glioblastoma Subtype¹

Departments of Pathology and Laboratory Medicine [G. C., J. K. P., L. J-S., H. V. V., P. S. M.] and Neurosurgery [T. J. K., L. M. L.] and the Henry E. Singleton Brain Tumor Program [T. J. K., L. M. L., T. F. C., P. S. M.], University of California Los Angeles, Los Angeles, California 90095-1732; Miami Dade Medical Examiners Office, Miami, Florida [L. J-S.]; and Department of Pathology, Seoul National University College of Medicine, Seoul 110-744, Korea [G. C.]

Purpose: Glioblastoma multiforme (GBM) is an aggressive cancer characterized by extensive brain invasion. Matrix metalloproteinase (MMP)-9 plays a major role in this process. GBMs can be divided into two subtypes based on distinct clinical and molecular features. Primary GBMs arise de novo and frequently overexpress the epidermal growth factor receptor (EGFR) and its ligand-independent variant, EGFR variant III (EGFRvIII); secondary GBMs progress from a lower grade glioma and commonly harbor p53 mutations. Because EGFR signaling promotes MMP-9 expression and activation in other cancer cell types, we analyzed whether MMP-9 was associated with primary GBM subtype.

Experimental Design: Autopsies were performed on 20 GBM patients, and MMP expression was assessed by gelatin zymography in the tumor and the adjacent normal brain. EGFR, EGFRvIII, p53, and activated mitogen-activated protein kinase/extracellular signal-regulated kinase were assessed by immunohistochemistry, and associations between molecular phenotype and MMP-9 expression were analyzed.

Results: Latent MMP-9 was detected in 90% of tumors, and active MMP-9 was found in 50% of tumors. MMP-9 was not detected in any of the normal brain samples (P < 0.001). More importantly, primary GBMs were significantly more likely than secondary GBMs to contain active MMP-9 (69% of primary and 14% of secondary GBMs contained active MMP-9; P = 0.027). Active MMP-9 was observed in 73% of EGFR-overexpressing/wild-type p53-staining tumors but in only 20% of EGFR-negative/aberrant p53-staining tumors (P = 0.072). Active MMP-9 expression was even more strongly correlated with EGFRvIII expression, occurring in 83% of the EGFRvIII-immunopositive tumors but in none of the EGFRvIII-negative tumors (P = 0.0004). Extracellular signal-regulated kinase activation was also strongly correlated with EGFRvIII expression (P < 0.0001) and with MMP-9 activation (P = 0.003).

Conclusions: These results identify a novel association between MMP-9 activation and primary GBM subtype and suggest that primary GBM patients, especially those whose tumors express EGFRvIII, may benefit from anti-MMP therapy.

This article has been cited by other articles:

				J. A. Fromm, S. A. S. Johnson, and D. L. Johnson Epidermal Growth Factor Receptor 1 (EGFR1) and Its Variant EGFRvIII Regulate TATA-Binding Protein Expression through Distinct Pathways Mol. Cell. Biol., October 15, 2008; 28(20): 6483 - 6495. [Abstract] [Full Text] [PDF]

				H. Ohgaki and P. Kleihues Genetic Pathways to Primary and Secondary Glioblastoma Am. J. Pathol., May 1, 2007; 170(5): 1445 - 1453. [Abstract] [Full Text] [PDF]

				C. Grommes, G. E. Landreth, M. Sastre, M. Beck, D. L. Feinstein, A. H. Jacobs, U. Schlegel, and M. T. Heneka Inhibition of in Vivo Glioma Growth and Invasion by Peroxisome Proliferator-Activated Receptor {gamma} Agonist Treatment Mol. Pharmacol., November 1, 2006; 70(5): 1524 - 1533. [Abstract] [Full Text] [PDF]

				D. B. Ramnarain, S. Park, D. Y. Lee, K. J. Hatanpaa, S. O. Scoggin, H. Otu, T. A. Libermann, J. M. Raisanen, R. Ashfaq, E. T. Wong, et al. Differential Gene Expression Analysis Reveals Generation of an Autocrine Loop by a Mutant Epidermal Growth Factor Receptor in Glioma Cells Cancer Res., January 15, 2006; 66(2): 867 - 874. [Abstract] [Full Text] [PDF]

				M. Aghi, P. Gaviani, J. W. Henson, T. T. Batchelor, D. N. Louis, and F. G. Barker II Magnetic Resonance Imaging Characteristics Predict Epidermal Growth Factor Receptor Amplification Status in Glioblastoma Clin. Cancer Res., December 15, 2005; 11(24): 8600 - 8605. [Abstract] [Full Text] [PDF]

				L. J. Kaufman, C. P. Brangwynne, K. E. Kasza, E. Filippidi, V. D. Gordon, T. S. Deisboeck, and D. A. Weitz Glioma Expansion in Collagen I Matrices: Analyzing Collagen Concentration-Dependent Growth and Motility Patterns Biophys. J., July 1, 2005; 89(1): 635 - 650. [Abstract] [Full Text] [PDF]

				S. S. Lakka, C. S. Gondi, D. H. Dinh, W. C. Olivero, M. Gujrati, V. H. Rao, C. Sioka, and J. S. Rao Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas J. Biol. Chem., June 10, 2005; 280(23): 21882 - 21892. [Abstract] [Full Text] [PDF]

				O. Ozen, B. Krebs, B. Hemmerlein, A. Pekrun, H. Kretzschmar, and J. Herms Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance Clin. Cancer Res., July 15, 2004; 10(14): 4746 - 4753. [Abstract] [Full Text] [PDF]

				Y. Okada, E. E. Hurwitz, J. M. Esposito, M. A. Brower, C. L. Nutt, and D. N. Louis Selection Pressures of TP53 Mutation and Microenvironmental Location Influence Epidermal Growth Factor Receptor Gene Amplification in Human Glioblastomas Cancer Res., January 15, 2003; 63(2): 413 - 416. [Abstract] [Full Text] [PDF]