Presence of matrix metalloproteinase–2 and tissue inhibitor matrix metalloproteinase–2 gene polymorphisms and immunohistochemical expressions in intracranial meningiomas

Laboratory investigation

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Object

Meningiomas are benign extraaxial tumors with a slow progression. Some of them, in spite of being benign in nature, may show an aggressive progression pattern. To investigate the behavioral characteristics of meningiomas, researchers have studied matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), interstitial collagens, proteins, vascular endothelial growth factors (VEGF), and tumor necrosis factors.

Methods

In this study, the authors investigated MMP2 and TIMP2 gene polymorphisms in formalin-fixed paraffin-embedded tissue samples obtained from meningioma patients who had previously undergone surgery at the authors' institution. In addition, brain invasion, Ki-67 index, and MMP-2 and TIMP-2 expressions were investigated using immunohistochemical methods. MMP2 (735C>T, 1575G>A, 1306C>T) and TIMP2 (418G>C, 303C>T) gene polymorphisms were investigated from paraffin-embedded tissue sections using the polymerase chain reaction–restriction fragment length polymorphism method.

Results

There were statistically significant differences between genotype (p = 0.001) and allele frequencies (p = 0.001 and OR 7.4 [95% CI 1.5–36.2]) in patient and control groups for MMP2 1306C>T polymorphism. The authors did not find a statistically significant difference for other polymorphisms. GA genotype was found to be more frequent when brain invasion was suspected for MMP2 1575G>A polymorphism (p = 0.006). There was not a statistically significant difference for other MMP2 or TIMP2 gene polymorphisms.

Conclusions

The authors' results support the importance of MMPs and their tissue inhibitors in meningioma pathogenesis. In future studies, these gene polymorphisms, especially MMP2 1306C>T and 1575G>A, should be investigated for meningioma or brain invasion susceptibility in larger study groups.

Abbreviations used in this paper:MMP = matrix metalloproteinase; PCR = polymerase chain reaction; TIMP = tissue inhibitor of MMP.

Abstract

Object

Meningiomas are benign extraaxial tumors with a slow progression. Some of them, in spite of being benign in nature, may show an aggressive progression pattern. To investigate the behavioral characteristics of meningiomas, researchers have studied matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), interstitial collagens, proteins, vascular endothelial growth factors (VEGF), and tumor necrosis factors.

Methods

In this study, the authors investigated MMP2 and TIMP2 gene polymorphisms in formalin-fixed paraffin-embedded tissue samples obtained from meningioma patients who had previously undergone surgery at the authors' institution. In addition, brain invasion, Ki-67 index, and MMP-2 and TIMP-2 expressions were investigated using immunohistochemical methods. MMP2 (735C>T, 1575G>A, 1306C>T) and TIMP2 (418G>C, 303C>T) gene polymorphisms were investigated from paraffin-embedded tissue sections using the polymerase chain reaction–restriction fragment length polymorphism method.

Results

There were statistically significant differences between genotype (p = 0.001) and allele frequencies (p = 0.001 and OR 7.4 [95% CI 1.5–36.2]) in patient and control groups for MMP2 1306C>T polymorphism. The authors did not find a statistically significant difference for other polymorphisms. GA genotype was found to be more frequent when brain invasion was suspected for MMP2 1575G>A polymorphism (p = 0.006). There was not a statistically significant difference for other MMP2 or TIMP2 gene polymorphisms.

Conclusions

The authors' results support the importance of MMPs and their tissue inhibitors in meningioma pathogenesis. In future studies, these gene polymorphisms, especially MMP2 1306C>T and 1575G>A, should be investigated for meningioma or brain invasion susceptibility in larger study groups.

Meningiomas are basically benign extraaxial tumors. There are 2 subsets, namely atypical and anaplastic forms that account for approximately 10% of all meningiomas and show aggressive biological behavior. Meningiomas are the most common benign tumors of the intracranial cavity, constituting 13%–26% of primary brain neoplasms. The principal mode of treatment remains surgery with the aim of total tumor removal. Radiosurgery is being used with increasing frequency for certain groups of patients either as a primary or adjuvant therapy.

The difference in incidences of meningiomas between men and women has led to the idea that sex hormones and their receptors play a role in meningioma pathogenesis. The genes located in sex chromosomes could be causing meningiomas. In the literature, genetic changes such as the loss of chromosome arms 1p, 6q, 9p, 10q, 14q, and 18q and gene amplifications at 1q, 6q, 12q, 17q, and 20q have been reported.18 MADH2, MADH4, AMP-1, and DDC tumor suppressor genes located in chromosome region 18q21 have been reported to play an important role in meningioma pathogenesis.1 Losses in chromosome 14 are the third most frequent genetic change following chromosome 22 and chromosome 1 rearrangements. Loss of 14q has been shown to be a predictive factor in recurrences.26 In addition to known genetic changes in meningioma pathogenesis, HER-2/neu gene amplification has been investigated in tissue samples and concluded to be a risk factor.17

The WHO has classified meningiomas 4 times: in 1979, 1997, 2000, and 2007. In the last classification (WHO 2007), criteria such as recurrence grade, potential of aggressive growth, cell type, clinical findings, and biological activity were evaluated. According to this classification, Grade I meningiomas have a lower recurrence risk with a slow growth rate. Grade II and III meningiomas have a higher recurrence risk and/or aggressive behavior.

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play an important role in the cancer invasion in different ways.6 MMPs are the family of endopeptidases, present in normal healthy tissues. The tumor microenvironment can be regulated by MMPs. MMP expression and activation are increased in almost all human cancers compared with normal tissue.4 Activity of MMPs is also regulated by several factors including TIMPs.23

In previous studies, MMP-2 expression has been investigated in meningiomas and is associated with tumor recurrence and histological type, and might be a potential therapeutic target.15,16,21

MMPs are positive regulators of angiogenesis. They enable penetration of epithelial cells to the stroma by destruction of the extracellular matrix. MMP-2, MMP-9, and MMP-14 play a direct role in angiogenesis. The factors inducing angiogenesis increase MMP production to destroy the basal membrane, which contains Type 4 and Type 5 collagen. After the invading cells cross the basal membrane, cell proliferation and invasion result in new vessel formation or new metastatic forms.11 Morbidity and mortality are dependent on tumor tissue in primary intracranial tumors.13 In benign meningiomas, collagenase activity in tumor tissue has been found to be low, whereas it is high in invaded dural and bone tissue. Cancer formation results in the disturbance of the equilibrium between cell proliferation, differentiation, and death.22

In the current study, we aimed to investigate MMP2 and TIMP2 gene polymorphisms in formalin-fixed paraffin-embedded tissue samples of meningiomas from patients who had previously undergone surgery in the Department of Neurosurgery. In addition, brain invasion, Ki-67 index, and MMP-2 and TIMP-2 expressions have been investigated by immunohistochemistry methods.

Methods

Patients

Fifty patients with a diagnosis of meningioma who had undergone surgery between 2000 and 2009 at Başkent University Ankara Hospital, in the central zone of Anatolia and Turkish ethnicity, were included in the study. Of these patients, 24, 21, and 5 harbored Grade I, II, and III meningiomas, respectively. Three-micrometer-thick paraffin sections from tissue blocks of the tumors were obtained, and immunohistochemical investigation of MMP-2 and TIMP-2 expression, brain invasion, and Ki-67 index was performed in the Department of Pathology, Başkent University. The control group comprised 100 healthy age- and sex-matched subjects from the central Anatolian region who did not have meningioma or other benign or malign tumors or a family history of one of these tumors. Peripheral blood samples were obtained from these control subjects.

Microscopic Investigation

The tissues used in this study were 50 formaldehydefixed and paraffin-embedded meningioma specimens. In each case, the histopathological diagnosis of meningioma was established by standard light-microscope evaluation of sections stained with H & E. We reevaluated sections of each sample using the WHO 2007 criteria for brain tumor classification. According to this system, an atypical meningioma exhibits increased mitotic activity (4 or more mitotic figures per 10 hpf) or 3 or more of the following features: increased cellularity, small cells with a high nucleus/cytoplasm ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and foci of “spontaneous” or “geographic necrosis.” An anaplastic meningioma exhibits obviously malignant cytology or a high mitotic index (20 or more mitotic figures per 10 hpf) in addition to the features of atypical meningioma. The 50 specimens were grouped according to tumor grade (I, II, or III). In each case, brain invasion was noted as a separate parameter and was defined as irregular projections of the tumor into adjacent CNS parenchyma without an intervening layer of leptomeninges. According to the latest WHO classification, brain invasive meningiomas were labeled as Grade II.

Immunohistochemical Analysis

Formaldehyde-fixed and paraffin-embedded tumor tissues were sectioned. After deparaffinization and rehydration, each section was immunostained using monoclonal antibodies for Ki-67 (MIB-1 clone, rabbit polyclonal, Neomarkers), MMP-2 (Ab-3, monoclonal mouse, clone: 42–5D11, Oncogene) and TIMP-2 (Ab-2, monoclonal mouse, clone: 67–4H11, Oncogene). Immunohistochemistry procedures were carried out using the streptavidinbiotin 3-step indirect methods. For MMP-2 and TIMP-2 staining, antigen retrieval was performed in a microwave oven in 10 mm citrate buffer (pH 6.0) at 700 W for 15 minutes. Endogenous peroxidase activity was then blocked with 0.3% H2O2 for 15 minutes. After incubation for 10 minutes with 5% bovine serum albumin in Tris-buffered saline (50 mm Tris-HCl, 150 mm NaCl [pH 7.4]) for blocking of nonspecific binding, sections were incubated with primary antibodies. Sections were then incubated with peroxidase-labeled polymer for 30 minutes, followed by prepared diaminobenzidine substrate-chromogen solution. The slides were counterstained with hematoxylin and then coverslipped. Between steps, the slides were washed twice in Tris-buffered saline.

For negative controls, the primary antibodies were omitted and nonimmune serum was used instead. For positive controls, we stained sections of tissues that were considered suitable according to the manufacturer's protocol.

For Ki-67 evaluation, immunoreactivity was defined as intense, diffuse, or granular nuclear staining. The level of Ki-67 immunoreactivity in each section was assessed by counting the stained nuclei in approximately 1000 cells in the regions of maximal staining using ocular micrometry. The Ki-67 index was calculated as a percentage based on the number of positive cells per total cells counted.

The extent and intensity of expression for MMP-2 and TIMP-2 were semiquantitatively evaluated. Scoring was classified into the following four groups: 0, no expression; 1, low expression; 2, moderate expression; and 3, high expression.

Genotyping

MMP2 (735C>T, 1575G>A, 1306C>T) and TIMP2 (418G>C, 303C>T) gene polymorphisms were investigated from paraffin-embedded tissue sections using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. DNA was extracted from tissue and blood samples using commercially available kits. Concentrations of genomic DNA samples obtained from tissue sections of patients and peripheral blood samples of the control group were spectrophotometrically measured, and approximately 250 ng of DNA was used for each reaction. The PCR products were electrophoresed on 2% agarose gels at 90 V for 50 minutes. PCR products were quantified for restriction enzyme reactions depending on the band brightness (5–20 μl), and, accordingly, PCR products were incubated with 5 U of restriction enzymes. Then, products were checked by electrophoresing on 2% high-resolution agarose gels at 90 V for 2 hours.

Statistical Analysis

The SPSS (Statistical Package for the Social Sciences) package program was used for statistical analysis of data. Descriptive statistics were expressed as mean ± standard deviation for continuous data, and the number of observations and percentage for categorical data. Odds ratios, 95% confidence intervals, and significance levels were calculated using the chi-square test for determining allele frequencies; p < 0.05 was considered statistically significant.

Results

There were statistically significant differences between genotype (p = 0.001) and allele frequencies (p = 0.001 and OR 7.4 [1.5–36.2]) of patient and control groups for MMP2 1306C>T polymorphism. We did not find statistically significant differences for the other polymorphisms.

GA genotype was found to be more frequent when brain invasion was suspected for MMP2 1575G>A polymorphism (p = 0.006). There was not a statistically significant difference for other MMP2 or TIMP2 gene polymorphisms.

According to ANOVA analysis, the mean Ki-67 index was statistically different between types of meningiomas.

Discussion

Although the vast majority of intracranial meningiomas are benign and amenable to surgery, there is still a subset of tumors designated as Grade II and Grade III by WHO classification that behave in an aggressive manner with frequent recurrences and an unfavorable prognosis. Intensive research in different fields of medicine and related sciences is helping researchers to gain a better understanding of meningioma pathogenesis and is also helping them to develop reliable predictors of meningioma behavior, which may result in more effective methods of treatment. Contents and structure of intra- and extracellular matrix components and protein structure and functions have been examined by electron microscopy, molecular biology, and immunohistochemistry methods.

MMPs are proteolytic enzymes that can destroy the basal membrane and connective tissues. These enzymes are important for tissue breakdown in the process of invasive growth and metastasis.7,24 The inhibition of MMPs can be an alternative treatment for preventing brain invasion. Angiostatin, which is a product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. It has also been shown that human MMPs generate biologically functional angiostatin from plasminogen. MMP-12 was the most efficient angiostatin-producing MMP.2 Downregulation of MMP activity has been demonstrated to have a striking effect on local invasion and partial suppression of hematogenous metastasis.3 Miyake et al. have studied the balance between MMP-2 and TIMP-2 in the progression of renal cell carcinoma.10 Their results suggested that the MMP-2/TIMP-2 expression ratio is an important factor. In the majority of schwannomas, meningiomas, and pilocytic meningiomas, TIMP-2 expression has been demonstrated. TIMP expression revealed a correlation with tumor grade.5,12

Nordqvist et al. analyzed the expression of MMP-2 and MMP-9 in meningiomas associated with different degrees of brain invasion and edema.14 They found that the expression of MMP-9 mRNA was identified in 14 of 16 tumors and thus a distinct correlation with increasing tumor invasion into the brain was observed while no such correlation was found with MMP-2. Okada et al. found that MMP-2 and MMP-9 expressions are prognostic factors predicting meningioma recurrence regardless of proliferative potential.15

There are studies about the possible relationship between the Ki-67 index and meningioma recurrence, metastasis, and invasion. The Ki-67 index was found to be higher in recurrent meningiomas than in nonrecurrent ones.25 In contrast to this finding, Maes et al. found Ki-67 to be a good marker of the cell proliferation status of the tumors but found no correlation with recurrence.9 They observed that human telomerase catalytic subunit (hTERT) alone seemed to be a potential predictor of recurrence. In our study, the statistical results showed that the Ki-67 labeling index was highly correlated with meningioma grading but not with brain invasion.

To our knowledge, this is the first time MMP2 and TIMP2 gene polymorphism in meningioma patients has been studied. These polymorphisms have been studied before in several cancer types.20 We showed a statistically significant difference between the patient and control groups' genotype disturbance and allele frequencies for MMP2 1306C>T polymorphism in the entire study cohort. In a meta-analysis, MMP2 1306 TT and CT genotype carriers were less susceptible to lung, head and neck, and gastric and esophageal cancer.18 In contrast, our results suggested that CT genotype and T allele frequencies are more frequent in patient groups. In previous studies, another intracranial tumor like meningioma, glioblastoma multiforme, was studied, and variant T allele for MMP2 1306C>T polymorphism was not significantly associated with susceptibility for this tumor.8,20 These adverse findings between previous and present studies can be explained either by different ethnic variations in the study groups or distinct pathophysiological patterns of different cancer types.13

As mentioned before, the inhibition of MMPs can be a treatment alternative for preventing brain invasion. We suspected a statistically significant difference in patients for MMP2 1575G>A polymorphism with or without brain invasion.

Another finding was an association between all polymorphisms of MMP-2 and TIMP-2, and enhanced immunostaining. It may be concluded that better understanding of polymorphisms of MMP2 and TIMP2 may be beneficial for understanding the genetic mechanisms of meningioma pathogenesis.

Conclusions

Our results support the importance of MMPs and their tissue inhibitors in meningioma pathogenesis. In future studies, these gene polymorphisms, especially MMP2 1306C>T and 1575G>A, should be investigated for meningioma or brain invasion susceptibility in larger study groups.

Disclosure

This study was supported by the Başkent University Research Fund. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Coven, Şahin, Altinors. Analysis and interpretation of data: Coven, Ozer, Ozen, Şahin, Altinors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Coven. Statistical analysis: Ozer, Şahin. Administrative/technical/material support: Ozen, Altinors. Study supervision: Coven, Ozen, Şahin, Altinors.

References

  • 1

    Büschges RBoström JWolter MBlaschke BWeber RGLichter P: Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18. Int J Cancer 92:5515542001

  • 2

    Cornelius LANehring LCHarding EBolanowski MWelgus HGKobayashi DK: Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 161:684568521998

  • 3

    DeClerck YAPerez NShimada HBoone TCLangley KETaylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52:7017081992

  • 4

    Egeblad MWerb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:1611742002

  • 5

    Kachra ZBeaulieu EDelbecchi LMousseau NBerthelet FMoumdjian R: Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17:5555661999

  • 6

    Kohn ECLiotta LA: Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res 55:185618621995

  • 7

    Kugler A: Matrix metalloproteinases and their inhibitors. Anticancer Res 19:2C158915921999

  • 8

    Kumar RMalik NTungaria AKawal P: Matrix metalloproteinase-2 gene polymorphism is not associated with increased glioblastoma multiforme susceptibility: an Indian institutional experience. Neurol India 59:2362402011

  • 9

    Maes LLippens EKalala JPOde Ridder L: The hTERT-protein and Ki-67 labelling index in recurrent and non-recurrent meningiomas. Cell Prolif 38:3122005

  • 10

    Miyake HHara IGohji KYamanaka KHara SArakawa S: Relative expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in mouse renal cell carcinoma cells regulates their metastatic potential. Clin Cancer Res 5:282428291999

  • 11

    Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15:1801891997

  • 12

    Nakagawa TKubota TKabuto MSato KKawano HHayakawa T: Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors. J Neurosurg 81:69771994

  • 13

    Nakasu SHirano AShimura TLlena JF: Incidental meningiomas in autopsy study. Surg Neurol 27:3193221987

  • 14

    Nordqvist ACSmurawa HMathiesen T: Expression of matrix metalloproteinases 2 and 9 in meningiomas associated with different degrees of brain invasiveness and edema. J Neurosurg 95:8398442001

  • 15

    Okada MMiyake KMatsumoto YKawai NKunishio KNagao S: Matrix metalloproteinase-2 and matrix metalloproteinase-9 expressions correlate with the recurrence of intracranial meningiomas. J Neurooncol 66:29372004

  • 16

    Ozen ODemirhan BAltinörs N: Correlation between histological grade and MIB-1 and p53 immunoreactivity in meningiomas. Clin Neuropathol 24:2192242005

  • 17

    Ozer OSahin FIAydemir FOzen OYilmaz ZAltinörs N: Her-2/neu gene amplification in paraffin-embedded tissue sections of meningioma patients. Turk Neurosurg 19:1351382009

  • 18

    Peng BCao LMa XWang WWang DYu L: Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk. Mutagenesis 25:3713792010

  • 19

    Riemenschneider MJPerry AReifenberger G: Histological classification and molecular genetics of meningiomas. Lancet Neurol 5:104510542006. (Erratum in Lancet Neurol 6:

  • 20

    Rooprai HKVan Meter TRucklidge GJHudson LEverall IPPilkington GJ: Comparative analysis of matrix metalloproteinases by immunocytochemistry, immunohistochemistry and zymography in human primary brain tumors. Int J Oncol 13:115311571998

  • 21

    Rooprai HKvan Meter TERobinson SDKing ARucklidge GJPilkington GJ: Expression of MMP-2 and -9 in short-term cultures of meningioma: influence of histological subtype. Int J Mol Med 12:9779812003

  • 22

    Siddique KYanamandra NGujrati MDinh DRao JSOlivero W: Expression of matrix metalloproteinases, their inhibitors, and urokinase plasminogen activator in human meningiomas. Int J Oncol 22:2892942003

  • 23

    Stetler-Stevenson WG: The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev 27:57662008

  • 24

    Stetler-Stevenson WGLiotta LAKleiner DE Jr: Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7:143414411993

  • 25

    Uzüm NAtaoğlu GA: Histopathological parameters with Ki-67 and bcl-2 in the prognosis of meningiomas according to WHO 2000 classification. Tumori 94:3893972008

  • 26

    Zang KD: Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases. Cytogenet Cell Genet 93:2072202001

Article Information

Address correspondence to: İlker Coven, M.D., Başkent University Faculty of Medicine, Department of Neurosurgery, Hoca Cihan Mah. Saray Cad. No: 1 Selçuklu, Konya 04280, Turkey. email: covenilker@yahoo.com.

Please include this information when citing this paper: published online September 26, 2014; DOI: 10.3171/2014.8.JNS13515.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Büschges RBoström JWolter MBlaschke BWeber RGLichter P: Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18. Int J Cancer 92:5515542001

2

Cornelius LANehring LCHarding EBolanowski MWelgus HGKobayashi DK: Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 161:684568521998

3

DeClerck YAPerez NShimada HBoone TCLangley KETaylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52:7017081992

4

Egeblad MWerb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:1611742002

5

Kachra ZBeaulieu EDelbecchi LMousseau NBerthelet FMoumdjian R: Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17:5555661999

6

Kohn ECLiotta LA: Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res 55:185618621995

7

Kugler A: Matrix metalloproteinases and their inhibitors. Anticancer Res 19:2C158915921999

8

Kumar RMalik NTungaria AKawal P: Matrix metalloproteinase-2 gene polymorphism is not associated with increased glioblastoma multiforme susceptibility: an Indian institutional experience. Neurol India 59:2362402011

9

Maes LLippens EKalala JPOde Ridder L: The hTERT-protein and Ki-67 labelling index in recurrent and non-recurrent meningiomas. Cell Prolif 38:3122005

10

Miyake HHara IGohji KYamanaka KHara SArakawa S: Relative expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in mouse renal cell carcinoma cells regulates their metastatic potential. Clin Cancer Res 5:282428291999

11

Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15:1801891997

12

Nakagawa TKubota TKabuto MSato KKawano HHayakawa T: Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors. J Neurosurg 81:69771994

13

Nakasu SHirano AShimura TLlena JF: Incidental meningiomas in autopsy study. Surg Neurol 27:3193221987

14

Nordqvist ACSmurawa HMathiesen T: Expression of matrix metalloproteinases 2 and 9 in meningiomas associated with different degrees of brain invasiveness and edema. J Neurosurg 95:8398442001

15

Okada MMiyake KMatsumoto YKawai NKunishio KNagao S: Matrix metalloproteinase-2 and matrix metalloproteinase-9 expressions correlate with the recurrence of intracranial meningiomas. J Neurooncol 66:29372004

16

Ozen ODemirhan BAltinörs N: Correlation between histological grade and MIB-1 and p53 immunoreactivity in meningiomas. Clin Neuropathol 24:2192242005

17

Ozer OSahin FIAydemir FOzen OYilmaz ZAltinörs N: Her-2/neu gene amplification in paraffin-embedded tissue sections of meningioma patients. Turk Neurosurg 19:1351382009

18

Peng BCao LMa XWang WWang DYu L: Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk. Mutagenesis 25:3713792010

19

Riemenschneider MJPerry AReifenberger G: Histological classification and molecular genetics of meningiomas. Lancet Neurol 5:104510542006. (Erratum in Lancet Neurol 6:

20

Rooprai HKVan Meter TRucklidge GJHudson LEverall IPPilkington GJ: Comparative analysis of matrix metalloproteinases by immunocytochemistry, immunohistochemistry and zymography in human primary brain tumors. Int J Oncol 13:115311571998

21

Rooprai HKvan Meter TERobinson SDKing ARucklidge GJPilkington GJ: Expression of MMP-2 and -9 in short-term cultures of meningioma: influence of histological subtype. Int J Mol Med 12:9779812003

22

Siddique KYanamandra NGujrati MDinh DRao JSOlivero W: Expression of matrix metalloproteinases, their inhibitors, and urokinase plasminogen activator in human meningiomas. Int J Oncol 22:2892942003

23

Stetler-Stevenson WG: The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev 27:57662008

24

Stetler-Stevenson WGLiotta LAKleiner DE Jr: Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7:143414411993

25

Uzüm NAtaoğlu GA: Histopathological parameters with Ki-67 and bcl-2 in the prognosis of meningiomas according to WHO 2000 classification. Tumori 94:3893972008

26

Zang KD: Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases. Cytogenet Cell Genet 93:2072202001

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