In:
Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 94, No. 3 ( 2001-03), p. 464-473
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 proMMP-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.
Type of Medium:
Online Resource
ISSN:
0022-3085
DOI:
10.3171/jns.2001.94.3.0464
Language:
Unknown
Publisher:
Journal of Neurosurgery Publishing Group (JNSPG)
Publication Date:
2001
detail.hit.zdb_id:
2026156-1
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