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Departments of Neurosurgery [M. Y., S. M., R. S., Z. L. G., J. S. R.], Pathology [G. N. F.], and Tumor Biology [G. L. N.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920, Japan [M. S. H. S.]; and Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892 [L. A. L.]
In this study, we investigated the expression of activated gelatinase A and membrane-type metalloproteinase (MT-MMP) induced by concanavalin A (ConA) in four highly invasive glioma cell lines (UWR2, UWR3, U251MG, and SNB-19). We also examined gelatinase A and MT-MMP expression in human brain tumor tissues in vivo. Gelatin zymography showed that all four cell lines expressed latent progelatinase A (Mr 66,000). Activated gelatinase A (Mr 62,000) was induced by ConA in only UWR2 or UWR3 cells. MT-MMP mRNA was present in all four cell lines prior to ConA treatment, and the relative hybridization signals were 1, 0.80, 0.25, and 0.15 in UWR2, UWR3, U251MG, and SNB-19 cells, respectively. These mRNA signals were dramatically increased (2.8-, 5.4-, and 2.2-fold in UWR2, UWR3, and U251MG cells, respectively) following ConA treatment; however, MT-MMP mRNA expression was unchanged in SNB-19 cells. MT-MMP protein was detected in various amounts in the four cell lines, but only after ConA pretreatment. The amount of MT-MMP mRNA was unchanged in SNB-19 after ConA treatment, and the MT-MMP mRNA level in ConA-treated U251MG was lower than in UWR2 and UWR3 without ConA treatment. MT-MMP protein was detected in SNB-19 and U251 cell lines only after ConA treatment. Gelatin zymography of human brain tumor tissues revealed that almost all samples examined contained a latent form of gelatinase A, whereas the activated form of gelatinase A was only seen in metastatic lung adenocarcinomas and malignant astrocytomas, and especially in glioblastomas. MT-MMP mRNA levels were significantly higher in malignant astrocytomas than in low-grade gliomas and normal brain tissues. These results were confirmed by PCR analysis, which showed that MT-MMP mRNA was absent or barely detectable in normal brain white matter but was easily detectable in malignant astrocytomas. Immunohistochemistry of MT-MMP in frozen sections showed that MT-MMP was localized in neoplastic astrocytes of malignant astrocytomas but was undetectable in normal white brain matter. The data indicate that MT-MMP is present in malignant human glial tumors and that MT-MMP expression correlates with expression and activation of gelatinase A during malignant progression in vivo. A direct correlation between the levels of MT-MMP protein and its transcripts was not found in vitro, suggesting that MT-MMP expression in glioma cell lines might be regulated either at the level of transcription message stability or at posttranscription. Altered MT-MMP expression might contribute, in part, to gelatinase A activation, which in turn facilitates invasion of these tumors.
1 Supported, in part, by Physicians Referral Service funds of the University of Texas M. D. Anderson Cancer Center (Houston, TX), National Cancer Institute Grant CA 56792, and ACS Grant EDT-91 (to J. S. R.).
2 To whom requests for reprints should be addressed, at Department of Neurosurgery, Box 064, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
Received 7/31/95. Accepted 11/ 2/95.
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