Skip to content
naulon

No retraction, correction or concern found when last checked on Oct 31, 2026.

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

P A Forsyth, H Wong, T D Laing and 8 more

British Journal of Cancer · 1999

doi:10.1038/sj.bjc.6690291

Abstract

Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis.

References 52

  1. 1.

    Apodaca G., Rutka J. T., Bouhana K., Berens M. E., Giblin J. R., Rosenblum M. L., McKerrow J. H., Banda M. J. Expression of metalloproteinases and metalloproteinase inhibitors by fetal astrocytes and glioma cells. Cancer Res. 1990;50(8):2322-2329.

    Not in our library

  2. 2.

    Aznavoorian S., Murphy A. N., Stetler-Stevenson W. G., Liotta L. A. Molecular aspects of tumor cell invasion and metastasis. Cancer. 1993;71(4):1368-1383.

    Not in our library10.1002/1097-0142(19930215)71:4<1368::aid-cncr2820710432>3.0.co;2-l

  3. 3.

    Azzam H. S., Arand G., Lippman M. E., Thompson E. W. Association of MMP-2 activation potential with metastatic progression in human breast cancer cell lines independent of MMP-2 production. J Natl Cancer Inst. 1993;85(21):1758-1764.

    Not in our library10.1093/jnci/85.21.1758

  4. 4.

    Bendeck M. P., Irvin C., Reidy M. A. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res. 1996;78(1):38-43.

    Not in our library10.1161/01.res.78.1.38

  5. 5.

    Bernhard E. J., Gruber S. B., Muschel R. J. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci U S A. 1994;91(10):4293-4297.

    Not in our library10.1073/pnas.91.10.4293

  6. 6.

    Brown P. D., Bloxidge R. E., Stuart N. S., Gatter K. C., Carmichael J. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma. J Natl Cancer Inst. 1993;85(7):574-578.

    Not in our library10.1093/jnci/85.7.574

  7. 7.

    Burger P. C., Dubois P. J., Schold S. C., Smith K. R., Odom G. L., Crafts D. C., Giangaspero F. Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg. 1983;58(2):159-169.

    Not in our library10.3171/jns.1983.58.2.0159

  8. 8.

    Butler G. S., Will H., Atkinson S. J., Murphy G. Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. Eur J Biochem. 1997;244(2):653-657.

    Not in our library10.1111/j.1432-1033.1997.t01-1-00653.x

  9. 9.

    Cornelius L. A., Nehring L. C., Roby J. D., Parks W. C., Welgus H. G. Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. J Invest Dermatol. 1995;105(2):170-176.

    Not in our library10.1111/1523-1747.ep12317080

  10. 10.

    Costello P. C., Del Maestro R. F., Stetler-Stevenson W. G. Gelatinase A expression in human malignant gliomas. Ann N Y Acad Sci. 1994;732:450-452.

    Not in our library10.1111/j.1749-6632.1994.tb24782.x

  11. 11.

    Davies B., Waxman J., Wasan H., Abel P., Williams G., Krausz T., Neal D., Thomas D., Hanby A., Balkwill F. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res. 1993;53(22):5365-5369.

    Not in our library

  12. 12.

    Edwards D. R., Beaudry P. P., Laing T. D., Kowal V., Leco K. J., Leco P. A., Lim M. S. The roles of tissue inhibitors of metalloproteinases in tissue remodelling and cell growth. Int J Obes Relat Metab Disord. 1996;20(Suppl 3):S9-15.

    Not in our library

  13. 13.

    Foda H. D., George S., Conner C., Drews M., Tompkins D. C., Zucker S. Activation of human umbilical vein endothelial cell progelatinase A by phorbol myristate acetate: a protein kinase C-dependent mechanism involving a membrane-type matrix metalloproteinase. Lab Invest. 1996;74(2):538-545.

    Not in our library

  14. 14.

    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186.

    Not in our library10.1056/nejm197111182852108

  15. 15.

    Forsyth P. A., Laing T. D., Gibson A. W., Rewcastle N. B., Brasher P., Sutherland G., Johnston R. N., Edwards D. R. High levels of gelatinase-B and active gelatinase-A in metastatic glioblastoma. J Neurooncol. 1998;36(1):21-29.

    Not in our library10.1023/a:1005879027267

  16. 16.

    Giese A., Westphal M. Glioma invasion in the central nervous system. Neurosurgery. 1996;39(2):235-252.

    Not in our library10.1097/00006123-199608000-00001

  17. 17.

    Haddad S. F., Moore S. A., Schelper R. L., Goeken J. A. Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme. J Neuropathol Exp Neurol. 1992;51(5):488-492.

    Not in our library10.1097/00005072-199209000-00002

  18. 18.

    Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353-364.

    Not in our library10.1016/s0092-8674(00)80108-7

  19. 19.

    Hanemaaijer R., Koolwijk P., le Clercq L., de Vree W. J., van Hinsbergh V. W. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. Biochem J. 1993;296(Pt 3):803-809.

    Not in our library10.1042/bj2960803

  20. 20.

    Heppner K. J., Matrisian L. M., Jensen R. A., Rodgers W. H. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996;149(1):273-282.

    Not in our library

  21. 21.

    Hirschi K. K., D'Amore P. A. Pericytes in the microvasculature. Cardiovasc Res. 1996;32(4):687-698.

    Not in our library

  22. 22.

    Johnson M. D., Kim H. R., Chesler L., Tsao-Wu G., Bouck N., Polverini P. J. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol. 1994;160(1):194-202.

    Not in our library10.1002/jcp.1041600122

  23. 23.

    Kelly P. J., Daumas-Duport C., Scheithauer B. W., Kall B. A., Kispert D. B. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc. 1987;62(6):450-459.

    Not in our library10.1016/s0025-6196(12)65470-6

  24. 24.

    Leco K. J., Apte S. S., Taniguchi G. T., Hawkes S. P., Khokha R., Schultz G. A., Edwards D. R. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett. 1997;401(2-3):213-217.

    Not in our library10.1016/s0014-5793(96)01474-3

  25. 25.

    Lewalle J. M., Munaut C., Pichot B., Cataldo D., Baramova E., Foidart J. M. Plasma membrane-dependent activation of gelatinase A in human vascular endothelial cells. J Cell Physiol. 1995;165(3):475-483.

    Not in our library10.1002/jcp.1041650305

  26. 26.

    Mignatti P., Rifkin D. B. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 1993;73(1):161-195.

    Not in our library10.1152/physrev.1993.73.1.161

  27. 27.

    Murphy G., Knäuper V. Relating matrix metalloproteinase structure to function: why the "hemopexin" domain? Matrix Biol. 1997;15(8-9):511-518.

    Not in our library10.1016/s0945-053x(97)90025-1

  28. 28.

    Nakagawa T., Kubota T., Kabuto M., Fujimoto N., Okada Y. Secretion of matrix metalloproteinase-2 (72 kD gelatinase/type IV collagenase = gelatinase A) by malignant human glioma cell lines: implications for the growth and cellular invasion of the extracellular matrix. J Neurooncol. 1996;28(1):13-24.

    Not in our library10.1007/bf00300442

  29. 29.

    Nakagawa T., Kubota T., Kabuto M., Sato K., Kawano H., Hayakawa T., Okada Y. Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors. J Neurosurg. 1994;81(1):69-77.

    Not in our library10.3171/jns.1994.81.1.0069

  30. 30.

    Nakano A., Tani E., Miyazaki K., Furuyama J., Matsumoto T. Expressions of matrilysin and stromelysin in human glioma cells. Biochem Biophys Res Commun. 1993;192(3):999-1003.

    Not in our library10.1006/bbrc.1993.1515

  31. 31.

    Nakano A., Tani E., Miyazaki K., Yamamoto Y., Furuyama J. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. J Neurosurg. 1995;83(2):298-307.

    Not in our library10.3171/jns.1995.83.2.0298

  32. 32.

    Pendás A. M., Knäuper V., Puente X. S., Llano E., Mattei M. G., Apte S., Murphy G., López-Otín C. Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J Biol Chem. 1997;272(7):4281-4286.

    Not in our library10.1074/jbc.272.7.4281

  33. 33.

    Poulsom R., Hanby A. M., Pignatelli M., Jeffery R. E., Longcroft J. M., Rogers L., Stamp G. W. Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin. J Clin Pathol. 1993;46(5):429-436.

    Not in our library10.1136/jcp.46.5.429

  34. 34.

    Puente X. S., Pendás A. M., Llano E., Velasco G., López-Otín C. Molecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma. Cancer Res. 1996;56(5):944-949.

    Not in our library

  35. 35.

    Pyke C., Ralfkiaer E., Tryggvason K., Danø K. Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am J Pathol. 1993;142(2):359-365.

    Not in our library

  36. 36.

    Rao J. S., Steck P. A., Mohanam S., Stetler-Stevenson W. G., Liotta L. A., Sawaya R. Elevated levels of M(r) 92,000 type IV collagenase in human brain tumors. Cancer Res. 1993;53(10 Suppl):2208-2211.

    Not in our library

  37. 37.

    Rao J. S., Yamamoto M., Mohaman S., Gokaslan Z. L., Fuller G. N., Stetler-Stevenson W. G., Rao V. H., Liotta L. A., Nicolson G. L., Sawaya R. E. Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas. Clin Exp Metastasis. 1996;14(1):12-18.

    Not in our library10.1007/bf00157681

  38. 38.

    Rosenthal R. A., Moses M. A., Shintani Y., Megyesi J. F., Langer R., Folkman J. Purification and characterization of two collagenase inhibitors from mouse sarcoma 180 conditioned medium. J Cell Biochem. 1994;56(1):97-105.

    Not in our library10.1002/jcb.240560114

  39. 39.

    Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994;370(6484):61-65.

    Not in our library10.1038/370061a0

  40. 40.

    Sawaya R. E., Yamamoto M., Gokaslan Z. L., Wang S. W., Mohanam S., Fuller G. N., McCutcheon I. E., Stetler-Stevenson W. G., Nicolson G. L., Rao J. S. Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis. 1996;14(1):35-42.

    Not in our library10.1007/bf00157684

  41. 41.

    Schnaper H. W., Grant D. S., Stetler-Stevenson W. G., Fridman R., D'Orazi G., Murphy A. N., Bird R. E., Hoythya M., Fuerst T. R., French D. L. Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro. J Cell Physiol. 1993;156(2):235-246.

    Not in our library10.1002/jcp.1041560204

  42. 42.

    Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P. D., Giavazzi R. Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst. 1995;87(4):293-298.

    Not in our library10.1093/jnci/87.4.293

  43. 43.

    Thorgeirsson U. P., Yoshiji H., Sinha C. C., Gomez D. E. Breast cancer; tumor neovasculature and the effect of tissue inhibitor of metalloproteinases-1 (TIMP-1) on angiogenesis. In Vivo. 1996;10(2):137-144.

    Not in our library

  44. 44.

    Ueno H., Nakamura H., Inoue M., Imai K., Noguchi M., Sato H., Seiki M., Okada Y. Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas. Cancer Res. 1997;57(10):2055-2060.

    Not in our library

  45. 45.

    Uhm J. H., Dooley N. P., Villemure J. G., Yong V. W. Glioma invasion in vitro: regulation by matrix metalloprotease-2 and protein kinase C. Clin Exp Metastasis. 1996;14(5):421-433.

    Not in our library10.1007/bf00128958

  46. 46.

    Urbanski S. J., Edwards D. R., Maitland A., Leco K. J., Watson A., Kossakowska A. E. Expression of metalloproteinases and their inhibitors in primary pulmonary carcinomas. Br J Cancer. 1992;66(6):1188-1194.

    Not in our library10.1038/bjc.1992.434

  47. 47.

    Wesseling P., Schlingemann R. O., Rietveld F. J., Link M., Burger P. C., Ruiter D. J. Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study. J Neuropathol Exp Neurol. 1995;54(3):304-310.

    Not in our library10.1097/00005072-199505000-00003

  48. 48.

    Woessner J. F. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991;5(8):2145-2154.

    Not in our library

  49. 49.

    Wong H., Anderson W. D., Cheng T., Riabowol K. T. Monitoring mRNA expression by polymerase chain reaction: the "primer-dropping" method. Anal Biochem. 1994;223(2):251-258.

    Not in our library10.1006/abio.1994.1581

  50. 50.

    Yamamoto M., Mohanam S., Sawaya R., Fuller G. N., Seiki M., Sato H., Gokaslan Z. L., Liotta L. A., Nicolson G. L., Rao J. S. 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. 1996;56(2):384-392.

    Not in our library

  51. 51.

    Yong V. W., Krekoski C. A., Forsyth P. A., Bell R., Edwards D. R. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 1998;21(2):75-80.

    Not in our library10.1016/s0166-2236(97)01169-7

  52. 52.

    Zucker S., Conner C., DiMassmo B. I., Ende H., Drews M., Seiki M., Bahou W. F. Thrombin induces the activation of progelatinase A in vascular endothelial cells. Physiologic regulation of angiogenesis. J Biol Chem. 1995;270(40):23730-23738.

    Not in our library10.1074/jbc.270.40.23730

Cited by papers we hold 8

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.