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

Am J Pathol. 1999 Feb;154(2):417-28. doi: 10.1016/S0002-9440(10)65288-1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / secondary
  • Astrocytoma / enzymology*
  • Astrocytoma / pathology
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / secondary
  • Collagenases / genetics
  • Collagenases / metabolism*
  • DNA Primers / chemistry
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Gelatinases / genetics
  • Gelatinases / metabolism*
  • Glioblastoma / enzymology*
  • Glioblastoma / pathology
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization
  • Lung Neoplasms / pathology
  • Matrix Metalloproteinase 1
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / metabolism*
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • RNA, Messenger / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DNA Primers
  • Enzyme Precursors
  • RNA, Messenger
  • Collagenases
  • Gelatinases
  • Metalloendopeptidases
  • progelatinase
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 1