Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases play an important role in tumor invasion, angiogenesis and inflammatory tissue destruction. The 72-kd gelatinase A is the most widely distributed. Along with the 92-kd gelatinase B, it plays an important role in basement membrane turnover. Gelatinase A is secreted as progelatinase A and, when activated, can cause extracellular matrix destruction. The physiologic mechanism of this activation is not well understood. Based on the importance of endothelial cells in inflammation and cancer, we sought in this study to systematically study the PMA-induced activation of endothelial cell progelatinase A. Using HUVEC, we demonstrated that PMA-induced activation of progelatinase A in these vascular endothelial cells (a) was protein kinase C-dependent as it was blocked by H-7; (b) occurred through cell-mediated events as PMA was unable to activate progelatinase A in a cell-free system and that low dose tissue inhibitor of metalloproteinases-2, but not tissue inhibitor of metalloproteinases-1, totally inhibited PMA-induced activation; (c) was accompanied by an increase in the membrane-type matrix metalloproteinase (MT-MMP). We also found that the combination of PMA and the cytokine tumor necrosis factor-alpha increased HUVEC secretion and activation of gelatinase B. In conclusion, our data show that PMA activation of vascular endothelial cell progelatinase A is a cell membrane event that is at least partially mediated through a PKC-dependent mechanism and is accompanied by an increase synthesis of MT-MMP. These data suggest a role for MT-MMP in the activation of progelatinase A in vascular endothelial cells.
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PMID:Activation of human umbilical vein endothelial cell progelatinase A by phorbol myristate acetate: a protein kinase C-dependent mechanism involving a membrane-type matrix metalloproteinase. 878 Jan 71

Gelatinase B is a regulated matrix metalloproteinase with important role in the remodeling of extracellular matrix and many pathological conditions such as tumor invasion and rheumatoid arthritis, physiological processes including embryonic growth and development, migration of blood leukocytes into tissues and tissue remodeling. Elevated levels of certain MMPs are believed to be associated with various pathological states. We cloned the 5'-flanking 600 bp sequence of human gelatinase B gene by PCR, which controls the expression of the gene by ligating it to the chloramphenicol acetyltransferase gene. Four kinds of cell lines were used to transiently transfect. Deletion analysis revealed that 100 bp (-600 to -500 bp) contributed positively to induction by tumour necrosis factor. The 100 bp contains NF-kappa B site, Ap-1 site, PEA3 and Sp-1 site. The expression of the human gelatinase B gene varied in different cells in the presence of TNF.NF-kappa B factor may play an important role in regulating the gene expression. Comparison of the finding with those for the promoter of gelatinase A, collagenase and stromelysin shows that the determinant for the inducibility of the gelatinase B gene is more complex.
Cancer Lett 1996 Sep 10
PMID:Molecular mechanism of transcriptional activation of human gelatinase B by proximal promoter. 884 71

Matrix metalloproteinases (MMPs) have been implicated in tumor progression, but the exact roles that each member of this family may play in contributing to the behavior of malignant tumors are only beginning to be understood. MMP-9 (gelatinase B or the 92-kDa gelatinase/type IV collagenase) expression has been associated with metastasis in a variety of model systems including that of rat sarcomas generated by transformation of rat embryo cells with rasH and myc. To determine the effect that expression of MMP-9 has in this system, we inhibited the expression of MMP-9 using a hammerhead ribozyme. Introduction of an expression vector for a ribozyme directed against the rat MMP-9 mRNA sequence into a metastatic rat embryo cell line transformed by rasH and myc (2.10.10) that constitutively secretes MMP-9 resulted in the absence of detectable MMP-9 mRNA and loss of released 92-kDa gelatinase activity. These cells were no longer metastatic in a lung colonization assay but retained tumorigenicity. Introduction of an expression vector for a control hammerhead ribozyme had no effect. These data document the requirement for MMP-9 expression in metastasis in this system.
Cancer Res 1996 Nov 15
PMID:Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system. 891 69

In situ changes in the repertoire of integrins and proteolytic enzymes have been demonstrated during melanoma metastasis. To investigate whether established human melanoma cell lines, injected into nude mice, could undergo phenotypic changes similar to those observed in in situ lesions, we studied 3 melanoma cell lines of distinct metastatic origin, adherent HT-144 and SK-MEL-2 cells, and non-adherent SK-MEL-1 cells for integrin expression, proteolytic enzyme repertoire and invasive potential after in vitro culture. Heterogeneity in integrin expression, such as elevated levels in alpha(v)beta3 in SK-MEL-1 and SK-MEL-2 cells and low expression in HT-144 cells, correlated with their in vitro invasiveness, since only the adherent HT-144 and SK-MEL-2 cells were able to invade Matrigel, and in addition, secreted a 72-kDa gelatinase. In contrast, no similar correlation could be established in nude mice, as all 3 cell lines, including the non-adherent SK-MEL-1 cells, were tumorigenic when injected s.c., while only HT-144 consistently produced experimental lung metastasis. Immunochemical analysis of the integrin profile in s.c. xenografts revealed over-expression of alpha(v), beta1 and beta3 integrins exclusively in HT-144 cells, as well as increased expression of beta3 in HT-144 cell lung metastases, as confirmed by PCR analysis using species-specific primers, while zymography and Western-blot analysis demonstrated de novo expression of the 92-kDa gelatinase MMP-9 in HT-144 xenografts. Our results highlight a positive correlation between up-regulated beta3 integrin and MMP-9 expression in human HT-144 melanoma cell tumors grown in nude mice.
Int J Cancer 1996 Nov 27
PMID:Up-regulated expression of the beta3 integrin and the 92-kDa gelatinase in human HT-144 melanoma cell tumors grown in nude mice. 893 49

To examine the possible involvement of gelatinase B in human hepatocellular carcinoma (HCC), cellular localization of transcripts and protein of gelatinase B were studied by using in situ hybridization and immunohistochemistry. Transcripts for gelatinase B were observed in tumor cells in 22 cases of 27 HCCs and also in dysplastic nodules. However, there was no significant difference in the expression among histological grades of HCC. The expression was mostly homogeneous, but the intensity varied with the nodules. Of 13 cases with capsular invasion, 12 expressed gelatinase B, whereas 10 of 14 without capsular invasion did (P < 0.05). Gelatinase B transcripts were commonly observed in the sinusoidal cells of the hepatic lobules, in mesenchymal cells both in fibrous capsules and around the necrosis, and also in some undefined cells of the portal tracts of noncancerous liver. Localization of gelatinase B protein was mostly similar to but sometimes different from that of the transcripts in cancer nodules. In conclusion, the expression of gelatinase B appears to be an important characteristic of malignant transformation of hepatocytes. The findings suggest that gelatinase B synthesized by cancer cells plays an important role in the growth and invasion of HCC by degrading surrounding extracellular matrices.
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PMID:Cellular distribution of 92-kd type IV collagenase/gelatinase B in human hepatocellular carcinoma. 895 17

The purpose of this study was to correlate abnormalities in chromosome 14 with the invasive metastatic phenotype of K-1735 murine melanoma cells. Low metastatic K-1735 clone 10 and clone 23 cells were transfected with either basic fibroblast growth factor (bFGF), Kaposi's fibroblast growth factor (kFGF), or c-H-ras gene. A high number of bFGF- and H-ras-transfected cells exhibited chromosome 14 rearrangements. These cells also had increased expression of collagenase IV. The kFGF-transfected cells were highly metastatic but did not have increased expression of collagenase type IV. The kFGF-transfected cells were highly metastatic but did not have increased expression of collagenase type IV, nor abnormalities in chromosome 14. The data imply that karyotypic changes in chromosome 14 are associated with increase expression of collagenase type IV.
Cancer Genet Cytogenet 1996 Nov
PMID:Chromosome 14 alteration is associated with increased collagenase expression and the metastatic potential of murine melanomas. 895 75

During cancer progression, tumor cells interact with stromal cells. As a consequence, matrix metalloproteinases are produced that contribute to the degradation of the extracellular matrix. This study used coculture systems to investigate fibroblast interaction with three colon cancer cell lines isolated from a single patient. Cells from primary colorectal carcinoma, but not from corresponding liver or lymph node metastases, induced gelatinase B expression by fibroblasts of different tissue origin. Remarkably, direct cell-cell contact was required for this induction, which occurred at the pretranslational level (as revealed by Northern blot analysis) and was completely blocked by anti-beta1 integrin monoclonal antibody, but only partially blocked by anti-alpha5 or anti-alpha(v). Induction was also inhibited by cytochalasin D, staurosporine, or dexamethasone, suggesting the need, respectively, for an organized actin cytoskeleton, protein kinase C, and AP-1-driven gene transcription. Our data suggest that direct tumor-stromal cell contact is one inductive event involved in matrix metalloproteinase expression by stromal cells.
Cancer Res 1996 Dec 01
PMID:Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. 896 8

MMP-9 (gelatinase B) and urokinase-type plasminogen activator receptor (u-PAR), which are involved in cancer cell invasion and metastasis, are reported to be predominantly expressed by immune/inflammatory cells in human colorectal cancers. To investigate their significance in cancer progression, we morphometrically analyzed the tissue expression of MMP-9 and u-PAR among different stages of colorectal cancer. The numbers of MMP-9- and u-PAR-positive cells along the invasive margin were significantly smaller in cases with liver metastasis than in cases without liver metastasis, and were also smaller in cases with an infiltrating margin than in cases with an expanding margin. Both variables were larger in colon cancer cases with conspicuous lymphocytic infiltration. These results indicated that the degree of tissue expression of MMP-9 and u-PAR by host cells is inversely associated with liver metastasis and an infiltrating growth pattern in human colorectal cancers. Essentially the same results were obtained for the number of macrophages distributed along the invasive margin. We also found that the expression pattern of MMP-9 was similar to that of MMP-8 (polymorphonuclear leukocyte collagenase). These data are consistent with clinicopathologic studies of host cells. Therefore, our data suggest a dual role of MMP-9 and u-PAR expression in colon cancer tissue; i.e., not only are these proteinases cancer-promoting factors, but also they are related to the host defensive mechanism when they are expressed by host cells.
Jpn J Cancer Res 1997 Jan
PMID:Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect. 904 99

Three stable carcinoma cell lines, designated PLS10, PLS20 and PLS30, have been established from 3,2'-dimethyl-4aminobiphenyl plus testosterone-induced carcinomas in the dorsolateral prostate of male F344 rats. The cells are keratin-positive and grow as typical epithelial monolayers in culture. When injected into intact male nude mice, PLS10 and PLS30 cells form well-differentiated adenocarcinomas with abundant connective tissue stroma, while PLS20 cells give rise to poorly differentiated adenocarcinomas. Growth of all PLS cell lines in nude mice is not affected by castration and the cells are immunohistochemically negative for androgen receptors. Tumor growth rates in nude mice were found to be PLS20 > PLS10 > PLS30, with significant in vitro stimulation by insulin/transferrin, but not epidermal growth factor, dexamethasone or basic fibroblast growth factor. Spontaneous lung metastases were observed in all cases. However, skeletal invasion including bone is essentially observed only with the PLS20 tumors. Gelatin zymography showed predominant secretion of the active form of gelatinase B (Mr 92,000 type IV collagenase) by all the cell lines. Karyotype analysis revealed PLS10, PLS30 and PLS20 to be diploid, hyperdiploid and hypertetraploid, respectively. The results demonstrate that the three PLS cell lines are androgen-independent and metastatic in common, but have different histology, growth potential and invasiveness. They may therefore be useful models for understanding progression and metastasis of human prostatic carcinomas.
Jpn J Cancer Res 1996 Dec
PMID:Establishment and characterization of three androgen-independent, metastatic carcinoma cell lines from 3,2'-dimethyl-4-aminobiphenyl-induced prostatic tumors in F344 rats. 904 56

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.
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PMID:Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. 906 95


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