TY - JOUR
T1 - Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors
AU - Nakada, Mitsutoshi
AU - Nakamura, Hiroyuki
AU - Ikeda, Eiji
AU - Fujimoto, Noboru
AU - Yamashita, Junkoh
AU - Sato, Hiroshi
AU - Seiki, Motoharu
AU - Okada, Yasunori
N1 - Funding Information:
Supported by a grant-in-aid for Cancer Research ( 10152255 ) from the Ministry of Education, Science, and Culture of Japan and Health Sciences Research Grants from the Ministry of Health and Welfare of Japan (to Y. Okada).
PY - 1999/2
Y1 - 1999/2
N2 - 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.
AB - 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.
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U2 - 10.1016/S0002-9440(10)65288-1
DO - 10.1016/S0002-9440(10)65288-1
M3 - Article
C2 - 10027400
AN - SCOPUS:0032959030
SN - 0002-9440
VL - 154
SP - 417
EP - 428
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -
