Main Article Content

Jennifer Shehan Suprit Gupta Ragupathy Vengoji Satyanarayana Rachagani Yan Zhang Kavita Mallya Sukhwinder Kaur Maneesh Jain Matthew White Michele Aizenberg Rodney McComb Lynette Smith Marlene Cohen Surinder Batra Nicole A Shonka


Pseudoprogression and radiation necrosis prevent confident interpretation of magnetic resonance imaging (MRI) results and lead to challenges in the management of glioblastoma (GBM). We examined the utility of matrix metalloproteinase-2 (MMP-2) and neutrophil gelatinase-associated lipocalin (NGAL) in the serum and urine as biomarkers of tumor burden in patients with GBM, with the goal of improving the interpretation of MRI and predicting overall survival (OS) and progression free survival (PFS). Expression of MMP-2 and NGAL was analyzed by immunohistochemistry in GBM and non-tumor epileptic control tissues. Serum and urine samples were collected pre and postoperatively and at each MRI. MMP-2 and NGAL levels in the serum and urine were measured by enzyme-linked immunosorbent assay.  MRI results, tumor volumes, survival, symptoms, and quality of life were assessed using repeated measures and autoregressive models correlation structure. Although the staining intensity of NGAL was indistinguishable, GBM tissues exhibited significantly higher number of NGAL positive cells as compared to control epileptic brain tissue. Serum MMP-2 was significantly higher in GBM patients than control subjects (p=0.0112) and was highest in patients who underwent biopsy compared to maximal resection (p=0.0038). Elevated levels of both NGAL and MMP-2 in the preoperative samples indicated a trend towards shorter PFS and OS, while preoperative urine NGAL levels were marginally predictive of PFS. Trajectory of symptoms and quality of life results were too variable to adequately correlate with the biomarker levels. Although biomarkers did not aid in differentiating between pseudoprogression, radiation necrosis, and tumor growth, preoperative levels correlated with survival. 

Article Details

How to Cite
SHEHAN, Jennifer et al. MMP-2 AND NGAL AS BIOMARKERS IN GLIOBLASTOMA: A PILOT STUDY. Medical Research Archives, [S.l.], v. 7, n. 6, oct. 2019. ISSN 2375-1924. Available at: <>. Date accessed: 14 nov. 2019. doi:
Research Articles


1. American Cancer Soceity, Surveillance Research. 2019.
2. Kim BS, Seol HJ, Nam DH, Park CK, Kim IH, Kim TM, et al. Concurrent Chemoradiotherapy with Temozolomide Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients: A Retrospective Multicenter Observation Study in Korea. Cancer Res Treat. 2017;49:193-203.
3. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008;26:2192-7.
4. Drezner N, Hardy KK, Wells E, Vezina G, Ho CY, Packer RJ, et al. Treatment of pediatric cerebral radiation necrosis: a systematic review. J Neurooncol. 2016;130:141-8.
5. Ellingson BM, Chung C, Pope WB, Boxerman JL, Kaufmann TJ. Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape. J Neurooncol. 2017;134:495-504.
6. Polin RS, Marko NF, Ammerman MD, Shaffrey ME, Huang W, Anderson FA, Jr., et al. Functional outcomes and survival in patients with high-grade gliomas in dominant and nondominant hemispheres. J Neurosurg. 2005;102:276-83.
7. Laws ER, Parney IF, Huang W, Anderson F, Morris AM, Asher A, et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg. 2003;99:467-73
8. Bergo E, Lombardi G, Guglieri I, Capovilla E, Pambuku A, Zagone V. Neurocognitive functions and health-related quality of life in glioblastoma patients: a concise review of the literature. Eur J Cancer Care (Engl). 2019;28:e12410.
9. Nicolaidis S. Biomarkers of glioblastoma multiforme. Metabolism. 2015;64:S22-7.
10. Sonoda Y, Yokosawa M, Saito R, Kanamori M, Yamashita Y, Kumabe T, et al. O(6)-Methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma. Int J Clin Oncol. 2010;15:352-8.
11. Lampert K, Machein U, Machein MR, Conca W, Peter HH, Volk B. Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. Am J Pathol. 1998;153:429-37.
12. Thier M, Roeb E, Breuer B, Bayer TA, Halfter H, Weis J. Expression of matrix metalloproteinase-2 in glial and neuronal tumor cell lines: inverse correlation with proliferation rate. Cancer Lett. 2000;149:163-70.
13. Paek SH, Kim DG, Park CK, Phi JH, Kim YY, Im SY, et al. The role of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase in microcystic meningiomas. Oncol Rep. 2006;16:49-56.
14. Park CM, Park MJ, Kwak HJ, Lee HC, Kim MS, Lee SH, et al. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res. 2006;66:8511-9.
15. Zhao JX, Yang LP, Wang YF, Qin LP, Liu DQ, Bai CX, et al. Gelatinolytic activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 in rat brain after implantation of 9L rat glioma cells. Eur J Neurol. 2007;14:510-6.
16. Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA. Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res. 2008;14:2378-86.
17. Iwamoto FM, Hottinger AF, Karimi S, Riedel E, Dantis J, Jahdi M, et al. Longitudinal prospective study of matrix metalloproteinase-9 as a serum marker in gliomas. J Neurooncol. 2011;105:607-12.
18. Noha M, Yoshida D, Watanabe K, Teramoto A. Suppression of cell invasion on human malignant glioma cell lines by a novel matrix-metalloproteinase inhibitor SI-27: in vitro study. J Neurooncol. 2000;48:217-23.
19. Beliveau R, Delbecchi L, Beaulieu E, Mousseau N, Kachra Z, Berthelet F, et al. Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Ann N Y Acad Sci. 1999;886:236-9.
20. Kunishio K, Okada M, Matsumoto Y, Nagao S. Matrix metalloproteinase-2 and -9 expression in astrocytic tumors. Brain Tumor Pathol. 2003;20:39-45.
21. Chakraborty S, Kaur S, Guha S, Batra SK. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 2012;1826(1):129-69 doi 10.1016/j.bbcan.2012.03.008.
22. Fayers PM, Aaronson, N. K., Bjordal, K., Groenvold, M., Curran, D., Bottomley, A. The EORTC QLQ–C30 scoring manual. 3rd ed. Brussels, Belgium: European Organization for Research and Treatment of Cancer. 2001.
23. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-76.
24. Stoesz SP, Friedl A, Haag JD, Lindstrom MJ, Clark GM, Gould MN. Heterogeneous expression of the lipocalin NGAL in primary breast cancers. Int J Cancer. 1998;79:565-72.
25. Quinten C, Coens C, Mauer M, Comte S, Sprangers MA, Cleeland C, et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data from EORTC clinical trials. Lancet Oncol. 2009;10:865-71.
26. Schuler MK, Trautmann F, Radloff M, Schmadig R, Hentschel L, Eberlein-Gonska M, et al. Implementation of a mobile inpatient quality of life (QoL) assessment for oncology nursing. Support Care Cancer. 2016;24:3391-9.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.