Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the factors related to lymph node metastasis of testicular germ cell tumors, we first established a seminoma orthotopic model with lymph node metastasis in SCID mice by inoculating small fragments from subcutaneous xenografts. Second, we compared the expression patterns of metastasis-related genes of the seminoma xenografts and of the TCam-2 cells which were established as a seminoma cell line from a primary testicular seminoma. Third, we immunohistochemically analyzed human germ cell tumors (25 seminomas, 17 nonseminomas) using monoclonal antibodies to CD34, VEGF, VEGF-C, Flt-4, MMP-2 and E-cadherin. Testicular seminoma xenografts grew in 32/32 (100%) of the inoculated mice, of which 15 (47%) developed macroscopic metastasis to the renal hilar lymph node. Circulating tumor cells were detectable by using a PCR assay for the human beta-globin gene in 25/32 (78%) mice, although metastatic foci were not histologically evident in the visceral organs, including lungs, liver, kidneys and spleen. This may reflect the lymphophilic characteristics of the seminoma cells used. Regarding mRNA expression of metastasis-related genes, an increased expression of MMP-2 and VEGF compared with that in the s.c. xenografts was demonstrated by RT-PCR assay in the testicular seminoma xenografts. In addition, uPAR, MMP-1, MMP-2, MT1-MMP and MT3-MMP showed a a stronger expression and PAI-2 a weaker expression in the seminoma xenografts than did TCam-2 cells. These results suggest a higher metastatic potential of the seminoma xenografts, especially testicular xenografts, as compared with TCam-2 cells. In the immunohistochemical study, a significant correlation was found between MMP-2 expression and lymph node metastasis, which is compatible with the results for the metastasis-related gene expression from the seminoma xenografts.
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PMID:[Correlation between expression of metastasis-related genes and lymph node metastasis in testicular cancer]. 1121 9

In order to determine key MMPs for invasion and metastasis in various human cancers, we examined the expression of ten MMPs (MMP-1, 2, 3, 7, 8, 9, 13 and MT1, 2, 3-MMPs) and tissue inhibitors of metalloproteinases (TIMP-1 and 2) in breast carcinomas, thyroid papillary carcinomas, endometrial carcinomas, ovarian carcinomas, gastric adenocarcinomas, oral squamous cell carcinomas and gliomas. Of the MMPs examined, the activation of proMMP-2 by MT1-MMP (membrane type 1-MMP) was commonly important for the invasion and metastasis of these cancers except for endometrial carcinomas. The MMP-2 and MT1-MMP were localized to the carcinoma cells and gelatinolytic activity was demonstrated within the carcinoma cell nests by in situ zymography. In endometrial carcinomas, production and activation of proMMP-7 were a key determinant of the lymph node metastasis. The activation of proMMP-2 in gliomas involved MT2-MMP as well as MT1-MMP, and a combination of decreased TIMP-2 production and enhanced MT1-MMP expression was important in the subarachnoidal dissemination of glioblastoma cells. Brevican, a major adult brain proteoglycan, was degraded with MMP-1, 2, 3, 7, 10 and ADAMTS4 (aggrecanase-1) by being cleaved at the MMP site (the Ala360-Phe361 bond) with the MMPs and ADAM site (the Glu395-Ser396 bond) with ADAMTS4. Since activated MMP-2 and ADAMTS4 are present in human glioma tissues, they may play a key role in the invasion of glioma cells through the brevican degradation. The data in the present study suggest that the extracellular matrix-degrading metalloproteinases acting probably on the cell membranes of cancer cells are essential to the invasion and metastasis of human cancers.
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PMID:Tumor cell-matrix interaction: pericellular matrix degradation and metastasis. 1121 46

Structure activity relationships are described for a series of succinyl hydroxamic acids 4a-o as potent and selective inhibitors of matrix metalloprotease-3 (stromelysin-1). Optimisation of P1' and P3' groups gave compound 4j (MMP-3 IC50=5.9nM) which was >140-fold less potent against MMP-1 (IC50=51,000nM), MMP-2 (IC50=1790nM), MMP-9 (IC50=840nM) and MMP-14 (IC50=1900nM).
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PMID:Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1). 1122 74

We measured the production levels of seven different matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9 and 13) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in the homogenates of human oral squamous cell carcinomas and control normal squamous epithelia by the corresponding sandwich enzyme immunoassay systems. The levels of MMP-1, 2, 3, 8, 9, 13 and TIMP-1 were significantly higher in the carcinoma samples than in the control. Among them, only the production level of MMP-2 was significantly higher in the carcinomas with cervical lymph node metastasis than in those without metastasis (P < 0.05). Gelatin zymography demonstrated that activation ratio of the zymogen of MMP-2 (proMMP-2) is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or normal control (P < 0.01). Quantitative RT-PCR for membrane-types 1, 2 and 3 MMPs (MT1, 2 and 3-MMPs), which activate proMMP-2 in vitro, demonstrated that MT1-MMP is predominantly expressed in the carcinoma tissues, and the expression level is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or the control samples (P < 0.05). Although MT2-MMP and MT3-MMP were detected in approximately 30% of the carcinoma cases, their expression levels were extremely lower compared with that of MT1-MMP. There was a direct correlation between the MT1-MMP expression level and proMMP-2 activation ratio (r = 0.62, P < 0.01). In situ hybridization and immunohistochemistry indicated that carcinoma cells and stromal cells adjacent to carcinoma cell nests express MT1-MMP transcripts and protein. MMP-2 and TIMP-2 were also immunolocalized to the carcinoma cells in the carcinoma samples. By in situ zymography, gelatinolytic activity was demonstrated in the carcinoma cell nests and abolished by the treatment with an MMP inhibitor, BB94. These results suggest that among seven different MMPs, the production of proMMP-2 and its activation mediated by MT1-MMP play an important role in the cervical lymph node metastasis of the human oral squamous cell carcinomas.
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PMID:Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human oral squamous cell carcinomas: implications for lymph node metastasis. 1123 94

EA.hy 926 cells, a derivative of human umbilical vein endothelial cells, in the presence of fibroblasts show the phenomena of angiogenesis, express the proteoglycan decorin and escape apoptosis, when they are maintained in collagen lattices, while fibroblast-free cultures do not show these changes. Virus-mediated decorin expression can substitute for the presence of fibroblasts. Since the expression of matrix metalloproteinases (MMPs) is an essential step in the formation of capillaries, several MMPs and tissue inhibitors of metalloproteinases (TIMPs) were investigated. MMP-1, MMP-2, MMP-9, and the cell-associated MMP-14 were augmented on the protein level in the presence of fibroblasts. No effect was seen with respect to MMP-3, TIMP-1, and TIMP-2. Semiquantitative RT-PCRs of endothelial cells in co-culture revealed a 7-, 19-, and 11-fold increase for mRNAs of MMP-1, MMP-2, and MMP-14 after six days, respectively. Virus-mediated decorin expression also was accompanied by an up-regulation of these MMPs. The expression of MMP-1 mRNAs increased 5-fold after 2 days and gradually declined thereafter. In contrast, MMP-2 and MMP-14 showed a 7-fold and a 14-fold increase on day two which returned to basal levels within 24 h, indicating that the expression of MMP-1 is differentially regulated from MMP-2 and MMP-14. In spite of the upregulation of the proteases, an enhanced degradation of decorin was not observed. These results indicate that the expression of decorin is a sufficient signal in EA.hy 926 cells for a finely tuned induction of selected MMPs which are involved in angiogenesis whereas the up-regulation of MMPs does not lead to the degradation of the responsible proteoglycan.
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PMID:Matrix metalloproteinase expression by endothelial cells in collagen lattices changes during co-culture with fibroblasts and upon induction of decorin expression. 1124 47

Type I collagen stimulation of pro-matrix metalloproteinase (pro-MMP)-2 activation by ovarian cancer cells involves beta(1) integrin receptor clustering; however, the specific cellular and biochemical events that accompany MMP processing are not well characterized. Collagenolysis is not required for stimulation of pro-MMP-2 activation, and denatured collagen does not elicit an MMP-2 activation response. Similarly, DOV13 cells bind to intact collagen utilizing both alpha(2)beta(1) and alpha(3)beta(1) integrins but interact poorly with collagenase-treated or thermally denatured collagen. Antibody-induced clustering of alpha(3)beta(1) strongly promotes activation of pro-MMP-2, whereas alpha(2)beta(1) integrin clustering has only marginal effects. Membrane-type 1 (MT1)-MMP is present on the DOV13 cell surface as both an active 55-kDa TIMP-2-binding species and a stable catalytically inactive 43-kDa form. Integrin clustering stimulates cell surface expression of MT1-MMP and co-localization of the proteinase to aggregated integrin complexes. Furthermore, cell surface proteolysis of the 55-kDa MT1-MMP species occurs in the absence of active MMP-2, suggesting MT1-MMP autolysis. Cellular invasion of type I collagen matrices requires collagenase activity, is blocked by tissue inhibitor of metalloproteinases-2 (TIMP-2) and collagenase-resistant collagen, is unaffected by TIMP-1, and is accompanied by pro-MMP-2 activation. Together, these data indicate that integrin stimulation of MT1-MMP activity is a rate-limiting step for type I collagen invasion and provide a mechanism by which this activity can be down-regulated following collagen clearance.
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PMID:Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. 1133 Dec 72

To investigate the distribution and potential participation of microglia, the resident defense cells of the central nervous system, in the optic nerve head (ONH) in glaucoma, histological paraffin sections of optic nerves from normal and glaucoma patients with mild to advanced nerve damage were studied using double labeling immunohistofluorescence. A monoclonal antibody for HLA-DR, indicating activated microglia, was colocalized with antibodies for functional proteins. In normal ONHs, microglia do not contain TGF-beta2, COX-2, or TNF-alpha and are not positive for PCNA; however, in glaucomatous ONHs, microglia contain abundant TGF-beta2, TNF-alpha, and PCNA. In glaucomatous eyes, a few microglia are usually positive for COX-2. In normal ONHs, there are rarely microglia containing TGF-beta1, NOS-2, TSP, TIMP-2, and CD68, but, in glaucomatous tissue, a few microglia are positive from the prelaminar to the postlaminar regions. MMP-1, MMP-2, MMP-3, and MMP-14 are constitutively present in the perivascular microglia in normal ONHs and appear to be more abundant in glaucomatous tissue. COX-1, TNF-R1, TIMP-1, and c-fms are constitutively present in normal tissues and appear to be increased in microglia in the glaucomatous ONHs. HSP27 is not present in microglia. In glaucomatous ONHs, microglia become activated and phagocytic and produce cytokines, mediators, and enzymes that can alter the extracellular matrix. Our findings suggest that activated microglia may participate in stabilizing the tissue early in the disease process, but, as the severity of the glaucomatous damage increases, the activities of microglia may have detrimental consequences for the pathological course of glaucomatous optic neuropathy.
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PMID:Activated microglia in the human glaucomatous optic nerve head. 1139 7

The activity of matrix metalloproteinases (MMPs) specifies the ability of the trophoblast cell to degrade extracellular matrix (ECM) substrates. Usually the process of normal human placentation involves a coordinated interaction between the fetal-derived trophoblast cells and their microenvironment in the uterus. In this study, the effects of ECM proteins on the expression of MMP-2, -9, and -14 (membrane-type MMP-1); and the production of tissue inhibitors of metalloproteinase (TIMP) types -1, -2, and -3 have been investigated. Cytotrophoblast cells at 9 or 10 wk of gestation were cultured on various ECM coated dishes under serum-free conditions. Gelatin zymography analysis showed that cells grown on fibronectin (FN), laminin (LN), and vitronectin (VN) secreted more MMP-9 (about 1.5- to 3-fold more) than cells cultured on collagen I (Col I), whereas the secretion of MMP-9 by cells cultured on collagen IV (Col IV) was only half that by the cells on Col I. Northern Blot analysis gave the same results as zymography, indicating that expression of the MMP-9 gene in cytotrophoblast cells can be affected by matrix proteins. There was no significant difference in the expression of MMP-2 either at protein or mRNA levels among the cells cultured on the different matrix substrates. The expression of MMP-14 was regulated in a manner similar to that of MMP-2. Using ELISA, we detected higher levels of TIMP-1 in the culture medium of cells grown on VN, LN, and FN compared with that grown on Col I. But the expression of TIMP-3 mRNA was remarkably inhibited by VN, and ECM proteins had no effect on TIMP-1 and TIMP-2 mRNA expression. It was also observed that cultured cytotrophoblast cells expressed the corresponding receptors for the tested matrix proteins, such as integrins alpha(1), alpha(5), alpha(6), beta(1), and beta(4). Furthermore, the adhesiveness of cytotrophoblast cells on Col I, Col IV, FN, and LN was increased by 62%, 45%, 21%, and 22%, respectively, when compared with adhesiveness on VN. Isolated cytotrophoblast cells remained stationary when cultured on dishes coated with Col I and Col IV, but they assumed a more motile morphology and aggregated into a network when cultured on LN and VN. These data indicate that human trophoblast cells interact with their microenvironment to control their behavior and function.
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PMID:Effects of matrix proteins on the expression of matrix metalloproteinase-2, -9, and -14 and tissue inhibitors of metalloproteinases in human cytotrophoblast cells during the first trimester. 1142 Feb 45

Matrix metalloproteinase-2 (MMP2) is a key enzyme in the process of extracellular matrix remodeling involved in tumor invasion and metastasis. The activation of MMP2 involves interplay with the membrane type-matrix metalloproteinase-1 (MT1-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP2). In vitro, activated hepatic stellate cells are a main source of MMP2 and collagen I induces MMP2 activation. The steady-state mRNA levels of MMP2, MT1-MMP, TIMP2, collagen I, collagen IV, and laminin gamma1 were compared with MMP2 activity in 55 hepatocellular carcinomas, 47 matching nontumor biopsies and 19 histologically normal livers. In hepatocellular carcinomas, increased collagen I mRNA levels were strongly associated with those of MMP2 (Spearman R =.74, P <.001), MT1-MMP (R =.65, P <.001) and TIMP2 (R = 0.61, P <.001). MMP2 activity was correlated with the mRNA expression of collagen I (R =.45 P <.01), collagen IV (R =.40, P <.01) and laminin gamma1 (R =.33, P <.05). Unlike collagen IV and laminin gamma1 mRNAs, MMP2, MT1-MMP, TIMP2, collagen I mRNA levels were increased in nonencapsulated compared with encapsulated tumors (P <.05). In addition, MMP2 activity was fourfold higher (P <.01) in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers. Moreover, tumor recurrence was associated with 4.6- and 2.8-fold (P <.05) higher collagen I and MMP2 mRNA levels, respectively, in hepatocellular carcinomas arising in cirrhotic livers. Thus, a high extracellular matrix remodeling favors tumor progression in hepatocellular carcinomas.
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PMID:Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. 1143 37

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by blood-brain barrier (BBB) breakdown. Disruptions of BBB continuity result in an influx of activated T cells and monocytes, and could contribute to lesion formation in the CNS. Matrix metalloproteinases (MMP) are enzymes implicated in BBB disruption, and in degradation of extracellular matrix proteins and myelin components. An imbalance in levels of MMP and tissue inhibitors of MMP (TIMP) has been implicated in the pathogenesis of MS. Since monocytes form a major cell population in acute MS lesions and may facilitate their entrance into the CNS by secretion of MMP, knowledge on MMP expression by blood monocytes could be useful to improve our understanding of the pathogenesis of MS. In the present study, we examined the expression of MMP-1, -3, -7, -9, -14 and TIMP-1 mRNA by blood monocytes in patients with MS using in situ hybridization. Levels of MMP-1, -3, -7, -9 and of TIMP-1 mRNA expressing monocytes were elevated in MS compared to controls, while those of MMP-14 did not differ. We therefore conclude that MS is associated with elevated levels of MMP and TIMP expressing blood monocytes that may contribute to MS pathogenesis.
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PMID:Multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes. 1143 95


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