The combined use of EphA2/MMP‑2 expression and MRI findings contributes to the determination of cerebral glioma grade

Suo,Fangfang; Zhong,Binfeng; Lu,Fangfang; Dong,Zhihui

doi:10.3892/ol.2019.10912

The combined use of EphA2/MMP‑2 expression and MRI findings contributes to the determination of cerebral glioma grade

Authors:
- Fangfang Suo
- Binfeng Zhong
- Fangfang Lu
- Zhihui Dong
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Affiliations: Department of Radiology, Luoyang Central Hospital, Luoyang, Henan 471000, P.R. China, Department of Neurosurgery, Luoyang Central Hospital, Luoyang, Henan 471000, P.R. China
Published online on: September 24, 2019 https://doi.org/10.3892/ol.2019.10912
Pages: 5607-5613

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Abstract

Glioma is the most aggressive brain tumor and is associated with a high mortality rate. The aim of the present study was to explore the association between matrix metalloproteinase 2 (MMP‑2) and ephrin type‑A receptor 2 (EphA2) expression in glioma cells, and to investigate the contribution of magnetic resonance imaging (MRI) in glioma classification. A total of 43 patients with pathologically confirmed glioma were divided into two groups as follows: Low‑grade (grades I and II; n=21) and high‑grade (grades IV and IV; n=22). Subsequently, immunohistochemistry staining was performed to detect the expression levels of MMP‑2 and EphA2 in the low‑ and high‑grade groups. MRI routine and enhanced scans were used to measure the peritumoral edema index (EI), tumor enhancement percentage (EP) and maximum tumor diameter. The results demonstrated that the proportion of MMP‑2‑positive patients in the high‑grade group was 86.36% (19/22), which was significantly higher than that of the low‑grade group (57.14%; 12/21) (P<0.05). Furthermore, the proportion of EphA2‑positive patients in the high‑grade group was 90.91% (20/22), significantly higher than that in the low‑grade group (4.76%; 1/21) (P<0.01). In addition, the MRI results indicated that the EI, EP and maximum tumor diameter were significantly higher in the high‑grade group compared with the low‑grade group (P<0.01, P<0.01 and P<0.05, respectively). Finally, the expression levels of MMP‑2 and EphA2 were significantly associated with the EI, EP and maximum tumor diameter (all P<0.05). In conclusion, the expression levels of MMP‑2 and EphA2 were positively correlated with glioma invasion. The correlation between these expression levels and MRI assessment of the EI, EP and maximum tumor diameter indicated that the combination of these two methods may be used for the evaluation of the tumor grade and for further clinical treatment applications.

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1	Appin CL and Brat DJ: Molecular genetics of gliomas. Cancer J. 20:66–72. 2014. View Article : Google Scholar : PubMed/NCBI
2	Goodenberger ML and Jenkins RB: Genetics of adult glioma. Cancer Genet. 205:613–621. 2012. View Article : Google Scholar : PubMed/NCBI
3	Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 15 (Suppl 2):ii1–ii56. 2013. View Article : Google Scholar : PubMed/NCBI
4	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
5	Wu W, Lamborn KR, Buckner JC, Novotny PJ, Chang SM, O'Fallon JR, Jaeckle KA and Prados MD: Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma. Neuro Oncol. 12:164–172. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bauvois B: New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: Outside-in signaling and relationship to tumor progression. Biochim Biophys Acta. 1825:29–36. 2012.PubMed/NCBI
7	Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R and Kaur G: Matrix metalloproteinases and cancer-roles in threat and therapy. Asian Pac J Cancer Prev. 15:1085–1091. 2014. View Article : Google Scholar : PubMed/NCBI
8	Fingleton B: Matrix metalloproteinases: Roles in cancer and metastasis. Front Biosci. 11:479–491. 2006. View Article : Google Scholar : PubMed/NCBI
9	Martin MD and Matrisian LM: The other side of MMPs: Protective roles in tumor progression. Cancer Metast Rev. 26:717–724. 2007. View Article : Google Scholar
10	Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI
11	Cho HJ, Park JH, Nam JH, Chang YC, Park B and Hoe HS: Ascochlorin Suppresses MMP-2-Mediated Migration and Invasion by targeting FAK and JAK-STAT signaling cascades. J Cell Biochem. 119:300–313. 2018. View Article : Google Scholar : PubMed/NCBI
12	Farina P, Tabouret E, Lehmann P, Barrie M, Petrirena G, Campello C, Boucard C, Graillon T, Girard N and Chinot O: Relationship between magnetic resonance imaging characteristics and plasmatic levels of MMP2 and MMP9 in patients with recurrent high-grade gliomas treated by Bevacizumab and Irinotecan. J Neurooncol. 132:433–437. 2017. View Article : Google Scholar : PubMed/NCBI
13	Ou Y, Wu Q, Wu C, Liu X, Song Y and Zhan Q: Migfilin promotes migration and invasion in glioma by driving EGFR and MMP-2 signalings: A positive feedback loop regulation. J Genet Genomics. 44:557–565. 2017. View Article : Google Scholar : PubMed/NCBI
14	van der Geer P, Hunter T and Lindberg RA: Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol. 10:251–337. 1994. View Article : Google Scholar : PubMed/NCBI
15	Miao H and Wang B: Eph/ephrin signaling in epithelial development and homeostasis. Int J Biochem Cell Biol. 41:762–770. 2009. View Article : Google Scholar : PubMed/NCBI
16	Kullander K and Klein R: Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol. 3:475–486. 2002. View Article : Google Scholar : PubMed/NCBI
17	Nakamoto M and Bergemann AD: Diverse roles for the Eph family of receptor tyrosine kinases in carcinogenesis. Microsc Res Tech. 59:58–67. 2002. View Article : Google Scholar : PubMed/NCBI
18	Pasquale EB: Eph-ephrin bidirectional signaling in physiology and disease. Cell. 133:38–52. 2008. View Article : Google Scholar : PubMed/NCBI
19	Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, et al: EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 16:9–20. 2009. View Article : Google Scholar : PubMed/NCBI
20	Ireton RC and Chen J: EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets. 5:149–157. 2005. View Article : Google Scholar : PubMed/NCBI
21	Zeng G, Hu Z, Kinch MS, Pan CX, Flockhart DA, Kao C, Gardner TA, Zhang S, Li L, Baldridge LA, et al: High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol. 163:2271–2276. 2003. View Article : Google Scholar : PubMed/NCBI
22	Miao H, Gale NW, Guo H, Qian J, Petty A, Kaspar J, Murphy AJ, Valenzuela DM, Yancopoulos G, Hambardzumyan D, et al: EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties. Oncogene. 34:558–567. 2015. View Article : Google Scholar : PubMed/NCBI
23	Cheng N, Brantley DM, Liu H, Lin Q, Enriquez M, Gale N, Yancopoulos G, Cerretti DP, Daniel TO and Chen J: Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res. 1:2–11. 2002. View Article : Google Scholar : PubMed/NCBI
24	Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL and Pasquale EB: The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene. 19:6043–6052. 2000. View Article : Google Scholar : PubMed/NCBI
25	Khurshid SJ and Hussain AM: Nuclear magnetic resonance imaging (MRI). J Pak Med Assoc. 41:259–264. 1991.PubMed/NCBI
26	Cavezian R, Cabanis EA, Pasquet G, Iba-Zizen MT, Le Bihan D, Tamraz J and Roger B: Magnetic resonance imaging. Physical principles, current biomedical applications, maxillofacial perspectives. Actual Odontostomatol (Paris). 40:219–232. 1986.(In French). PubMed/NCBI
27	Guy RL, Benn JJ, Ayers AB, Bingham JB, Lowy C, Cox TC and Sonksen PH: A comparison of CT and MRI in the assessment of the pituitary and parasellar region. Clin Radiol. 43:156–161. 1991. View Article : Google Scholar : PubMed/NCBI
28	Qi S, Yu L, Li H, Ou Y, Qiu X, Ding Y, Han H and Zhang X: Isocitrate dehydrogenase mutation is associated with tumor location and magnetic resonance imaging characteristics in astrocytic neoplasms. Oncol Lett. 7:1895–1902. 2014. View Article : Google Scholar : PubMed/NCBI
29	Puttick S, Bell C, Dowson N, Rose S and Fay M: PET, MRI, and simultaneous PET/MRI in the development of diagnostic and therapeutic strategies for glioma. Drug Discov Today. 20:306–317. 2015. View Article : Google Scholar : PubMed/NCBI
30	Crooks V, Waller S, Smith T and Hahn TJ: The use of the karnofsky performance scale in determining outcomes and risk in geriatric outpatients. J Gerontol. 46:M139–M144. 1991. View Article : Google Scholar : PubMed/NCBI
31	de Haan R, Aaronson N, Limburg M, Hewer RL and Van Crevel H: Measuring quality of life in stroke. Stroke. 24:320–327. 1993. View Article : Google Scholar : PubMed/NCBI
32	Okada A: Roles of matrix metalloproteinases and tissue inhibitor of metalloproteinase (TIMP) in cancer invasion and metastasis. Gan To Kagaku Ryoho. 26:2247–2252. 1999.(In Japanese). PubMed/NCBI
33	Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H and Itohara S: Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58:1048–1051. 1998.PubMed/NCBI
34	Rao JS: Molecular mechanisms of glioma invasiveness: The role of proteases. Nat Rev Cancer. 3:489–501. 2003. View Article : Google Scholar : PubMed/NCBI
35	Yue X, Lan F, Yang W, Yang Y, Han L, Zhang A, Liu J, Zeng H, Jiang T, Pu P and Kang C: Interruption of β-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells. Brain Res. 1366:27–37. 2010. View Article : Google Scholar : PubMed/NCBI
36	Chicoine MR and Silbergeld DL: The in vitro motility of human gliomas increases with increasing grade of malignancy. Cancer. 75:2904–2909. 1995. View Article : Google Scholar : PubMed/NCBI
37	Wykosky J, Gibo DM, Stanton C and Debinski W: EphA2 as a novel molecular marker and target in glioblastoma multiforme. Mol Cancer Res. 3:541–551. 2005. View Article : Google Scholar : PubMed/NCBI
38	Langer A: A systematic review of PET and PET/CT in oncology: A way to personalize cancer treatment in a cost-effective manner? BMC Health Serv Res. 10:2832010. View Article : Google Scholar : PubMed/NCBI
39	Ross R: Advances in the application of imaging methods in applied and clinical physiology. Acta Diabetol. 40 (Suppl 1):S45–S50. 2003. View Article : Google Scholar : PubMed/NCBI
40	Caravan P, Ellison JJ, McMurry TJ and Lauffer RB: Gadolinium(III) chelates as MRI contrast agents: Structure, dynamics, and applications. Chem Rev. 99:2293–2352. 1999. View Article : Google Scholar : PubMed/NCBI
41	Zhou Z and Lu ZR: Gadolinium-based contrast agents for magnetic resonance cancer imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 5:1–18. 2013. View Article : Google Scholar : PubMed/NCBI
42	Ye F, Liu J and Ouyang H: Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and multidetector-row computed tomography for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. Medicine (Baltimore). 94:e11572015. View Article : Google Scholar : PubMed/NCBI
43	Ying SH, Teng XD, Wang ZM, Wang QD, Zhao YL, Chen F and Xiao WB: Gd-EOB-DTPA-enhanced magnetic resonance imaging for bile duct intraductal papillary mucinous neoplasms. World J Gastroenterol. 21:7824–7833. 2015. View Article : Google Scholar : PubMed/NCBI
44	Chung C, Metser U and Menard C: Advances in magnetic resonance imaging and positron emission tomography imaging for grading and molecular characterization of glioma. Semin Radiat Oncol. 25:164–171. 2015. View Article : Google Scholar : PubMed/NCBI
45	Zuo N, Cheng J and Jiang T: Diffusion magnetic resonance imaging for Brainnetome: A critical review. Neurosci Bull. 28:375–388. 2012. View Article : Google Scholar : PubMed/NCBI
46	Jahng GH, Li KL, Ostergaard L and Calamante F: Perfusion magnetic resonance imaging: A comprehensive update on principles and techniques. Korean J Radiol. 15:554–577. 2014. View Article : Google Scholar : PubMed/NCBI
47	Ledezma CJ, Chen W, Sai V, Freitas B, Cloughesy T, Czernin J and Pope W: 18F-FDOPA PET/MRI fusion in patients with primary/recurrent gliomas: Initial experience. Eur J Radiol. 71:242–248. 2009. View Article : Google Scholar : PubMed/NCBI
48	Chen W and Silverman DH: Advances in evaluation of primary brain tumors. Semin Nucl Med. 38:240–250. 2008. View Article : Google Scholar : PubMed/NCBI
49	Costello JF: DNA methylation in brain development and gliomagenesis. Front Biosci. 8 (Suppl):S175–S184. 2003. View Article : Google Scholar : PubMed/NCBI
50	Carlson MR, Pope WB, Horvath S, Braunstein JG, Nghiemphu P, Tso CL, Mellinghoff I, Lai A, Liau LM, Mischel PS, et al: Relationship between survival and edema in malignant gliomas: Role of vascular endothelial growth factor and neuronal pentraxin 2. Clin Cancer Res. 13:2592–2598. 2007. View Article : Google Scholar : PubMed/NCBI
51	Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS and Cloughesy TF: MR imaging correlates of survival in patients with high-grade gliomas. AJNR Am J Neuroradiol. 26:2466–2474. 2005.PubMed/NCBI