Roles of membrane type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinases 2 in invasion and dissemination of human malignant glioma.

Abstract

OBJECT:

Acquisition of invasive and metastatic potentials through proteinase expression is an essential event in tumor progression. Among proteinases, matrix metalloproteinases (MMPs) are thought to play a key role in tumor progression through the degradation of the extracellular matrix. In the present study, the authors examined the role of MMP-2 (gelatinase A) and membrane type 1 MMP (MT1-MMP), an activator of the zymogen of MMP-2, proMMP-2, together with tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in the invasion of astrocytic tumors in humans.

METHODS:

Analyses performed using sandwich enzyme immunoassays demonstrated that the production levels of pro-MMP-2 and TIMP-1, but not TIMP-2, are significantly higher in glioblastomas multiforme than in other grades of astrocytic tumors. Quantitative reverse transcription-polymerase chain reaction indicated that MT1-MMP is expressed predominantly in glioblastoma tissues, and its expression levels are significantly enhanced as tumor grade increases. In addition, the expression levels and proMMP-2 activation ratio were remarkably higher in glioblastomas associated with cerebrospinal fluid (CSF) dissemination than in those not associated with CSF dissemination. In contrast, an examination of TIMP-2 levels showed a reverse correlation. Like MT1-MMP, TIMP-1 and TIMP-2 were immunolocalized to neoplastic cells in glioblastoma samples. To study the roles of these molecules in the invasion of astrocytic tumors more fully, stable transfectants expressing the MT1-MMP gene were developed in a U251 human glioblastoma cell line. The MT1-MMP transfectants displayed prominent activation of proMMP-2 and invasive growth in three-dimensional collagen gel; however, mock transfectants and parental cells displayed noninvasive growth without the activation. The invasion and gelatinolytic activity of the transfectants were completely inhibited by addition of recombinant TIMP-2, but not recombinant TIMP-1.

CONCLUSIONS:

These results indicate that MT1-MMP may contribute to tumor invasion and CSF dissemination of glioblastoma cells on the basis of an imbalance of TIMP-2.

• Authors: M Nakada, D Kita, K Futami, J Yamashita, N Fujimoto, H Sato, Y Okada
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 94 Issue 3 Pg. 464-73 (Mar 2001) ISSN: 0022-3085 [Print] United States
• PMID: 11235952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Precursors
• Gels
• RNA, Messenger
• Tissue Inhibitor of Metalloproteinase-1
• Tissue Inhibitor of Metalloproteinase-2
• Gelatin
• Collagen
• Gelatinases
• Metalloendopeptidases
• progelatinase
• Matrix Metalloproteinase 1

Topics

• Astrocytoma (enzymology, pathology)
• Brain Neoplasms (enzymology, pathology)
• Cell Division
• Collagen
• Enzyme Precursors (analysis, metabolism)
• Gelatin (metabolism)
• Gelatinases (analysis, metabolism)
• Gels
• Gene Expression Regulation, Enzymologic
• Humans
• Immunoenzyme Techniques
• Immunohistochemistry
• Matrix Metalloproteinase 1 (analysis, genetics, metabolism)
• Metalloendopeptidases (analysis, metabolism)
• Neoplasm Invasiveness (pathology)
• RNA, Messenger (analysis)
• Tissue Inhibitor of Metalloproteinase-1 (analysis, metabolism)
• Tissue Inhibitor of Metalloproteinase-2 (analysis, metabolism)
• Transfection
• Tumor Cells, Cultured