Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors

Mitsutoshi Nakada, Hiroyuki Nakamura, Eiji Ikeda, Noboru Fujimoto, Junkoh Yamashita, Hiroshi Sato, Motoharu Seiki, Yasunori Okada

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

Three different membrane-type matrix metalloproteinases (MT1-, MT2-, and MT3-MMPs) are known to activate in vitro the zymogen of MMP-2 (pro-MMP-2, progelatinase A), which is one of the key MMPs in invasion and metastasis of various cancers. In the present study, we have examined production and activation of pro-MMP-2, expression of MT1-, MT2-, and MT3-MMPs and their correlation with pro-MMP-2 activation, and localization of MMP-2, MT1-MMP, and MT2-MMP in human astrocytic tumors. The sandwich enzyme immunoassay demonstrates that the production levels of pro-MMP-2 in the anaplastic astrocytomas and glioblastomas are significantly higher than that in the low- grade astrocytomas (P < 0.05 and P < 0.01, respectively), metastatic brain tumors (P < 0.05), or normal brains (P < 0.01). Gelatin zymography indicates that the pro-MMP,2 activation ratio is significantly higher in the glioblastomas than in other astrocytic tumors (P < 0.01), metastatic brain tumors (P < 0.01), and normal brains (P < 0.01). The quantitative reverse transcription polymerase chain reaction analyses demonstrate that MT1-MMP and MT2-MMP are expressed predominantly in glioblastoma tissues (17/17 and 12/17 cases, respectively), and their expression levels increase significantly as tumor grade increases. MT3-MMP is detectable in both astrocytic tumor and normal brain tissues, but the mean expression level is approximately 50-fold lower compared with that of MT1-MMP and MT2-MMP in the glioblastomas. The activation ratio of pro-MMP-2 correlates directly with the expression levels of MT1-MMP and MT2-MMP but not MT3-MMP. In situ hybridization indicates that neoplastic astrocytes express MT1-MMP and MT2-MMP in the glioblastoma tissues (5/5 cases and 5/5 cases, respectively). Immunohistochemically, MT1-MMP and MT2-MMP are localized to the neoplastic astrocytes in glioblastoma samples (17/17 cases and 12/17 cases, respectively), which are also positive for MMP- 2. In situ zymography shows gelatinolytic activity in the glioblastoma tissues but not in the normal brain tissues. These results suggest that both MT1-MMP and MT2-MMP play a key role in the activation of pro-MMP-2 in the human malignant astrocytic tumors and that the gelatinolytic activity is involved in the astrocytic tumor invasion.

Original languageEnglish
Pages (from-to)417-428
Number of pages12
JournalAmerican Journal of Pathology
Volume154
Issue number2
DOIs
Publication statusPublished - 1999 Feb

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors'. Together they form a unique fingerprint.

  • Cite this

    Nakada, M., Nakamura, H., Ikeda, E., Fujimoto, N., Yamashita, J., Sato, H., Seiki, M., & Okada, Y. (1999). Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. American Journal of Pathology, 154(2), 417-428. https://doi.org/10.1016/S0002-9440(10)65288-1