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The expression of matrix metalloproteinase-2 and-9 in human gliomas of different pathological grades

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Abstract

Matrix metalloproteinases (MMPs) have been implicated to play a critical role in glioma invasiveness. In this study, we aimed to investigate, the expression of MMP-2 and MMP-9 in human gliomas of different degrees of malignancy, and evaluated the correlation between MMP-2 and MMP-9 expression in gliomas. The samples from 65 cases of glioma were divided into four groups according to the WHO classification: there were 16 cases of grade I, 17 cases of grade II, 20 cases of grade III, and 12 cases of grade IV. Normal brain samples served as the control group, and biopsy specimens were obtained from 8 glioma patients with a needle placed into the adjacent brain 1 cm from the margin after tumor resection. All the samples were stained with hematoxylin and eosin and immunohistochemistry. A computer-aided image-analysis system was employed to measure the integral optical density (IOD) of positive slides. No positive staining was found in the control group. The positive staining was localized in the cytoplasm of glioma cells, the extracellular matrix (ECM), the basement membrane (BM), and the endothelial cells of blood vessels. Positive staining rates increased significantly when the degree of malignancy of gliomas was elevated. The IOD value of MMP-2 and MMP-9 also indicated that the intensity of MMP-2 and MMP-9 expression was elevated significantly with the degree of malignancy of the gliomas. There was a positive correlation between MMP-2 and MMP-9 expression in gliomas. Glioma invasion and angiogenesis were particularly seen in the biopsied tissues, and MMP-9 immunostaining seemed to be much more intense and extensive than MMP-2 immunostaining in these samples. These results suggest that MMP-2 and MMP-9 staining in gliomas is localized in the cytoplasm of tumor cells, BM, and endothelial cells, and that MMP-2 and MMP-9 together play an important role in the invasiveness of gliomas, mediating the degradation of the ECM and angiogenesis. MMP-2 and MMP-9 could be molecular targets in the treatment of malignant glioma.

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References

  1. Yoshida D, Piepmeier JM, Bergenheim T, et al (1998) Suppression of metalloproteinase-2 mediated cell invasion in U87MG, human glioma cells by anti-microtubule agent: in vitro study. Br J Cancer 77:21–25

    PubMed  CAS  Google Scholar 

  2. Choe GY, Park JK, Lisa JS, et al (2002) Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype. Clin Cancer Res 8:2894–2901

    PubMed  CAS  Google Scholar 

  3. Presto MS (1999) Epidemiology. In: Berger MS, Wilson CB (eds) The gliomas. W.B. Saunders Co., Philadelphia, pp 2–11

    Google Scholar 

  4. Yoshida D, Watanabe K, Noha M, et al (2002) Suppression of matrix metalloproteinase activity by SI-27: detection by a new activity assay with s-24444, a specific chromogenic peptide. J Neurooncol 58:1–11

    Article  PubMed  Google Scholar 

  5. Yoshida D, Watanabe K, Noha M, et al (2003) Anti-invasive effect of an anti-matrix metalloproteinase agent in a murine brain slice model using the serial monitoring of green fluorescent protein-labeled glioma cells. Neurosurgery 52:187–197

    Article  PubMed  Google Scholar 

  6. Kachra Z, Beaulieu E, Delvecchi L, et al (1999) Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17:555–566

    Article  PubMed  CAS  Google Scholar 

  7. Lampert K, Machein U, Machein MR, et al (1998) Expression of matrix metalloproteinases and their tissure inhibitors in human brain tumor. Am J Pathol 153:429–437

    PubMed  CAS  Google Scholar 

  8. Yamamoto M, Mohanam S, Sawaya R, et al (1996) Differential expression of membrane-type matrix metalloproteinase and its correlation with gelatinase. A activation in human malignant brain tumors in vivo and in vitro. Cancer Res 56:384–392

    PubMed  CAS  Google Scholar 

  9. Kondraganti S, Mohanam S, Chintala SK, et al (2000) Selective suppression of matrix metalloproteinase-9 in glioblastoma cells by antisense gene transfer impairs glioblastoma cell invasion. Cancer Res 60:6851–6855

    PubMed  CAS  Google Scholar 

  10. Deryugina EI, Bourdon MA, Luo GX, et al (1997) Matrix metalloproteinase-2 activation modulates glioma cell migration. J Cell Sci 110:2473–2482

    PubMed  CAS  Google Scholar 

  11. Rooprai HK, Rucklidge GJ, Panou C, et al (2000) The effect of exogenous growth factors on matrix metalloproteinase secretion by human brain tumour cells. Br J Cancer 82:52–55

    Article  PubMed  CAS  Google Scholar 

  12. Sawaya RE, Yamamoto M, Gokaslan ZL, et al (1996) Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis 14:35–42

    Article  PubMed  CAS  Google Scholar 

  13. Forsyth PA, Wong H, Liang TD, et al (1999) Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer Res 79:1828–1835

    Article  CAS  Google Scholar 

  14. Cox G, Jones JL, O'Byne KJ, (2000) Matrix metalloproteinase 9 and the epidermal growth factor signal pathway in operable nonsmall cell lung cancer. Clin Cancer Res 6:2349–2355

    PubMed  CAS  Google Scholar 

  15. Matrisian LM (1992) The matrix-degrading metalloproteinases. Bioessays 14:455–463

    Article  PubMed  CAS  Google Scholar 

  16. Giannelli G, Falk-Marzillier J, Schiraldi O, et al (1997) Induction of cell migration by matrix metalloproteinase-2 cleavage of laminin-5. Science 277:225–228

    Article  PubMed  CAS  Google Scholar 

  17. Rao JS, Steck PA, Mohanam S, et al (1993) Elevated levels of M 9200 type IV collagenase in human brain tumor. Cancer Res 53:2208–2211

    PubMed  CAS  Google Scholar 

  18. Reith A, Rucklidge GJ (1992) Invasion of brain tissue by primary glioma: evidence for the involvement of urokinase-type plasminogen activator as an activator of type IV collagenase. Biochem Biophys Res Commun 186:348–354

    Article  PubMed  CAS  Google Scholar 

  19. Yasuo S, Hiroyuki S, Robert CS, et al (1998) Matrix metalloproteinases-2 and-9 are expressed in human neuroblastoma: contribution to their production and correlation with metastasis. Cancer Res 58:2209–2216

    Google Scholar 

  20. Sallinen P, Hapasalo H, Kerttula T, et al (1994) Sources of variation in the assessment of cell proliferation using proliferating cell nuclear antigen immunohistochemistry. Anak Qyant Cytik Histol 16:261–268

    CAS  Google Scholar 

  21. Nakagawa T, Kuboto T, Kubota M (1996) Secretion of matrix metalloproteinase-2 (72 KD gelatinase/type IV collagnase-gelatinase A) by malignant human glioma cell lines: implication for the growth and cellular invasion of the extracellular matrix. J Neurooncol 28:16–24

    Article  Google Scholar 

  22. Bergers G, Brekken R, McMahon G, et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  PubMed  CAS  Google Scholar 

  23. Deryugina EI, Lao GX, Reisteld RA, et al (1997) Tumor cell invasion through matrigel is regulated by activated matrix metalloproteinases-2. Anticancer Res 17:3201–3210

    PubMed  CAS  Google Scholar 

  24. Lamperl K, Maechein MR, Conea W (1998) Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. Am J Pathol 153:429–437

    Google Scholar 

  25. Wang M, Fudage K, Rhim JS, et al (1996) Cytokine regulation of the matrix metalloproteinases-1 promoter via functional interaction of AP-1 and Ets-1 transcription factors. J Oncol Res 8:303–315

    CAS  Google Scholar 

  26. Raymond S, Yoshinori G, Athanassios PK, et al (1998) Elevated levels of Mr 92,000 type IV, collagenase during tumor growth in vivo. Biochem Biophys Res 251:632–636

    Article  Google Scholar 

  27. Esteve PO, Tremblay M, St-Pierre R (1998) In vitro expression of MMP-2 and MMP-9 in glioma cells following exposure to inflammatory mediators. Biochem Biophys Acta 1403:885–896

    Google Scholar 

  28. Nakada M, Nakamura H, Ikeda E, et al (1991) Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol 154:417–428

    Google Scholar 

  29. Rooprai HK, Van Meter T, Rucklidge GJ, et al (1998) Comparative analysis of matrix metalloproteinases by immunocytochemistry, immunohistochemistry and zymography in human primary brain tumors. Int J Oncol 13:1153–1157

    PubMed  CAS  Google Scholar 

  30. Wild-Bode C, Weller M, Wick W (2001) Molecular determinants of glioma cell migration and invasion. J Neurosurg 94:978–984

    Article  PubMed  CAS  Google Scholar 

  31. Lakka SS, Jasti SL, Kyritsis AP, et al (2000) Regulation of MMP-9 (type IV collagenase) production and invasiveness in gliomas by the extracellular signal-regulated kinase and jun amino-terminal kinase signaling cascades. Clin Exp Metastasis 18:245–252

    Article  PubMed  CAS  Google Scholar 

  32. Vince GH, Wagner S, Pietsch T, et al (1999) Heterogeneous regional expression patterns of matrix metalloproteinases in human malignant gliomas. Int J Dev Neurosci 17:437–445

    Article  PubMed  CAS  Google Scholar 

  33. Zucker S, Mirza H, Conner C, et al (1998) Vascular endothelial growth factor induces factor and matrix metalloproteinase in endothelial dothelial cell: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer 75:780–786

    Article  PubMed  CAS  Google Scholar 

  34. Yoshida D, Noha M, Watanabe K, et al (2001) Novel approach to analysis of in vitro tumor angiogenesis with a variable-pressure scanning electron microscope: suppression by matrix metalloproteinase inhibitor SI-27. Brain Tumor Pathol 18:89–100

    Article  PubMed  CAS  Google Scholar 

  35. Lund E, Spang-Thomsen M, Skovgard-Poulsen H (1998) Tumor angiogenesis—a new therapeutic target in gliomas. Acta Neurol Scand 97:52–62

    Article  PubMed  CAS  Google Scholar 

  36. Muller D, Breathnach R, Engelmann A (1991) Expression of collagenase-related metalloproteinase genes in human lung of head and neck tumors. Int J Cancer 48:550–556

    Article  PubMed  CAS  Google Scholar 

  37. Muller D, Wolf C, Abecassis J, et al (1993) Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas. Cancer Res 53:165–169

    PubMed  CAS  Google Scholar 

  38. Venstrom KA, Reichardt LE (1993) Extracellular matrix: role of extracellular matrix molecules and their receptors in the nervous system. FASEB J 7:996–1003

    PubMed  CAS  Google Scholar 

  39. Mohanam S, Wang WW, Rayford A, et al (1995) Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo. Clin Exp Metastasis 13:57–62

    Article  PubMed  CAS  Google Scholar 

  40. Noha M, Yoshida D, Watanabe K, et al (2000) Suppression of cell invasion on human malignant glioma cell lines by a novel matrix metalloproteinase inhibitor SI-27: in vitro study. J Neurooncol 48:217–223

    Article  PubMed  CAS  Google Scholar 

  41. Watanabe K, Yoshida D, Noha M, et al (2001) Suppression of matrix metalloproteinase-2 and-9 mediated invasiveness by a novel matrix metalloproteinase inhibitor, BE16627B. J Neurooncol 52:1–9

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. Maode Wang

    Present address: Department of Neurosugery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, 113-8603, Tokyo, Japan

Authors and Affiliations

  1. Department of Neurosugery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, 113-8603, Tokyo, Japan

    Daizo Yoshida & Akira Teramoto

  2. Department of Neurosurgery, the First Hospital, Xi'an Jaotong University, No. 1 Jiankang Road, 710061, Xi'an, China

    Maode Wang, Tuo Wang & Shuoxun Liu

Authors
  1. Maode Wang
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  2. Tuo Wang
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  3. Shuoxun Liu
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  4. Daizo Yoshida
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  5. Akira Teramoto
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Correspondence to Maode Wang.

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Wang, M., Wang, T., Liu, S. et al. The expression of matrix metalloproteinase-2 and-9 in human gliomas of different pathological grades. Brain Tumor Pathol 20, 65–72 (2003). https://doi.org/10.1007/BF02483449

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  • DOI: https://doi.org/10.1007/BF02483449

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