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)

A comparison of the production of tissue-type plasminogen activator (t-PA) and gelatinases A and B was made at the mRNA and protein levels in human Bowes melanoma cells treated with phorbol myristate acetate (PMA). Immunocytochemical analysis confirmed previous quantitative data on PMA-mediated induction of t-PA. It also showed that t-PA immunoreactivity can be restrained to the local environment of the producing cell, most probably by interaction with extracellular matrix components. Zymographical analysis showed that gelatinase B protein was induced by PMA, whereas gelatinase A remained at the constitutive level. Protein kinase C (PKC) appeared to be involved in this regulation since, after PMA treatment (1) the PKC activity was found to be translocated from the cytosol to the particulate fraction of the cells and (2) addition of staurosporine and H-7 blocked the gelatinase B increase. Northern-blot hybridization showed a transient rise in t-PA and gelatinase B mRNA levels whereas gelatinase A mRNA levels remained unchanged. When c-fos and c-jun mRNAs were investigated, only that of c-fos was affected by PMA. Activation by PMA can be kinetically ordered as follows: translocation of PKC to the membrane fraction, transcription of the c-fos gene and eclipsing of gelatinase B mRNA, increase in steady-state mRNA levels of t-PA and gelatinase B and, finally, secretion of t-PA and gelatinase B glycoproteins. Our data also suggest that various proteases that are known to cooperate in the remodeling of the extracellular matrix can be differently regulated in one tumor-cell type.
Int J Cancer 1993 Feb 01
PMID:Differential regulation of gelatinase B and tissue-type plasminogen activator expression in human Bowes melanoma cells. 842 93

When human MG-63 osteosarcoma cells are triggered with IL-1 beta, they produce, among various other cytokines, also monocyte chemotactic proteins (MCPs). Homogeneous MCP-1, MCP-2 and MCP-3 were found to induce production of gelatinase B and chemotaxis of monocytes. Based on the almost complete amino acid sequence of natural MCP-3, two sets of degenerated oligonucleotides were used for the amplification of MCP-3 cDNA. Total RNA from stimulated MG-63 cells was reverse transcribed and PCRs done on the mRNA:cDNA duplex. Using the PCR-product, several cDNAs were isolated from a cDNA library of IL-1-stimulated MG-63 cells. From the cDNA sequence the complete primary structure of the protein was deduced: MCP-3 shows 71% and 58% amino acid homology with MCP-1 and MCP-2, respectively. Our study establishes MCP-3 as an inflammatory cytokine that regulates macrophage functions. Because MCP-3 is often produced by tumor cell lines and regulates protease secretion by macrophages, its production might also contribute to invasion and metastasis of cancer cells.
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PMID:Human monocyte chemotactic protein-3 (MCP-3): molecular cloning of the cDNA and comparison with other chemokines. 846 Oct 11

We demonstrated that four human oesophageal squamous cell carcinoma cell lines (TE8, TE9, TE10 and TE11) produced matrix metalloproteinase-1 (proMMP-1/tissue collagenase), 2 (ProMMP-2/'type IV collagenase'), 3 (proMMP-3/stromelysin), and 9 (proMMP-9/92-kDa gelatinase) as members of a matrix metalloproteinase (MMP) family, which degrades extracellular matrix macromolecules. Under normal culture conditions, in immunoblot analysis, proMMP-1 of M(r) = 53,00 was detected in one cell line (TE8), proMMP-2 of M(r) = 72,000 in three cell lines (TE9, TE10, and TE11), and proMMP-3 of M(r) = 57,000 in all four cell lines. In addition to these enzymes, in enzymography, a gelatinolytic activity around M(r) = 92-kDa, likely to be proMMP-9, was detected in only one cell line (TE10) under normal culture conditions. When these cell lines were treated with epidermal growth factor (EGF), however, the agent stimulated three cell lines (TE8, TE10 and TE11) to produce proMMP-9 in a dose-dose dependent manner. Oesophageal carcinoma-conditioned medium stimulated oesophageal fibroblasts to produce proMMP-1, -2, and -3, suggesting that the interaction between oesophageal carcinoma and stromal fibroblasts also plays a role in the production of MMPs by the latter. Our present study illustrates that oesophageal squamous cell carcinoma produces a variety of MMPs including proMMP-1, -2, -3, and -9 in vitro, suggesting that the ability of MMP production of the tumour may play an important role in its malignant behaviour and that the production of proMMP-9 may be regulated by EGF via overexpression of EGF receptors.
Br J Cancer 1993 Apr
PMID:Production of matrix metalloproteinase 9 (92-kDa gelatinase) by human oesophageal squamous cell carcinoma in response to epidermal growth factor. 847 29

Degradation of the extracellular matrix during cancer invasion is accomplished by the concerted action of several proteolytic enzymes, including matrix metalloproteinases (MMPs). We have studied the immunohistochemical localization of one of these enzymes, 92-kDa type IV collagenase (MMP-9), in short-term fixed specimens of 19 colon adenocarcinomas and 2 biopsies of adjacent normal colon. Staining was confined to neutrophils and macrophages, as identified by double staining. All neutrophils were positive in all cases. Some positively stained tumor-infiltrating macrophages were seen in 6 (32%) of the tumors, located adjacent to invasive tumor glands. No cancer cells were stained in any of the cases. In normal colon tissue, staining was only seen of scattered neutrophils in vessels and of macrophages in Peyer's patches. Routinely processed specimens from 7 of the 19 carcinomas were analyzed by in situ hybridization. In agreement with previous results, a MMP-9 mRNA signal was in all cases seen in a subpopulation of tissue macrophages surrounding invasive tumor glands, while no MMP-9 mRNA was detected in any other cell types, including neutrophils and cancer cells. Our results indicate that in this type of cancer all neutrophils contain MMP-9, which has been produced before they infiltrate the tumors; that a subpopulation of the tumor-infiltrating macrophages most likely in all cases produces MMP-9 but that the content of this protein is low due to a rapid turnover and that malignant epithelial cells do not produce or contain detectable amounts of MMP-9. These findings extend previous results indicating that stromal cells are actively involved in the generation and regulation of extracellular proteolysis during cancer invasion.
Int J Cancer 1996 Jan 03
PMID:92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. 854 96

We have previously shown that a 78-kDa "invasion stimulating factor" (ISF) triggers collagenase IV (MMP-2) secretion and the invasive behavior of metastatic PC-3 ML subclones in modified Boyden chamber assays [Stearns, M. E.; Stearns, M. Autocrine factors, type IV collagenase secretion and prostatic cancer cell invasion. Cancer Metastasis Rev. 12:39-52; 1993. Wang, M.; Stearns, M.; Stearns, M. E. Identification of the receptor for a novel M(r) 78,000 "invasion stimulating factor" from metastatic human prostatic PC-3 ML clones. Cancer Res. 54:2492-2495; 1994.]. Recently, we have shown that interleukin 10 (IL-10) preferentially stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) production in these cells [Wang, M.; Stearns, M. E. Characterization of a novel TIMP-1 enhancer element. J. Biol. Chem., submitted.]. In this paper, we report that IL-10 (20-40 ng) can inhibit the invasion stimulatory effects of ISF (30-60 ng) on PC-3 ML cells. "Checkerboard analysis" with modified Boyden chambers (precoated with 10 and 100 micrograms collagen IV) shows that IL-10 inhibits the stimulatory effects of ISF on both cell motility and chemoinvasion processes. In support of these data, exogenously supplied TIMP-1 (10 micrograms/ml) and collagenase antibodies (1:200 dilution) both completely blocked invasion. Quantitative ELISAs comparing the molar ratios of TIMP-1:MMP-2 and TIMP-2:MMP-2 further demonstrate that IL-10 (10-40 ng) preferentially activates TIMP-1 secretion to increase the molar ratio of TIMP-1:MMP-2 in the presence of increasing amounts of ISF (0-60 ng). IL-10 did not elevate TIMP-2 secretion or influence the molar ratio of TIMP-2:MMP-2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-10 blocks collagen IV invasion by "invasion stimulating factor" activated PC-3 ML cells: upregulation of TIMP-1 expression. 855 49

Human gelatinase B was produced from peripheral blood neutrophils and purified by affinity chromatography on gelatin sepharose. This material was used as an antigen to prepare mouse monoclonal antibodies (mAb). The resulting hybridomas were selected on the basis of binding to biotinylated antigen and by a sandwich ELISA using gelatinase-B-specific polyclonal rabbit antiserum and pure natural antigen. Five of these mAb were selected for further characterization. They all displayed variable epitope specificity, binding capacity and inhibitory activity. Whereas mAb REGA-2D9 and REGA-3G12 showed the strongest binding to biotinylated gelatinase B and natural gelatinase B, respectively, mAb REGA-2F9 did not bind biotinylated antigen. None of the mAb displayed cross-reactivity to gelatinase A in a direct ELISA. The mAb REGA-1G8 was found to cross-react with human serum albumin. The binding capacity of the other four mAb with leukocyte gelatinase B was compared and a sensitive sandwich ELISA was developed with the antibodies REGA-3G12 and REGA-2D9 (detection limit 0.5 ng/ml). The mAb REGA-3G12 was unique in that it inhibited catalysis by gelatinase B. This was shown by assaying the degradation of nasal septum type II gelatin in the presence and absence of each of the five mAb. Furthermore, mAb REGA-3G12 inhibited the degradation of biotinylated gelatin in a microtiterplate solution assay. In addition to the potential use of the inhibitory mAb REGA-3G12 in the treatment of diseases with excessive gelatinase B production, several of the described mAb are useful as diagnostic probes to detect gelatinase B in body fluids and tissue samples of patients with multiple sclerosis, rheumatoid arthritis and cancer.
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PMID:Monoclonal antibodies specific for natural human neutrophil gelatinase B used for affinity purification, quantitation by two-site ELISA and inhibition of enzymatic activity. 857 32

We examined the production and tissue localization of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in gastric carcinoma tissues. MMP-1 (tissue collagenase), MMP-9 (gelatinase B) and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 (gelatinase A) on tumor cell membranes, whereas no or little immunostaining for MMP-3 (stromelysin-1) and TIMP-1 was seen in carcinoma cells. Stromal cells in carcinoma tissue were also positively stained for these MMPs and TIMPs. MMP-2 immunostaining was observed exclusively on advanced gastric carcinoma cells and correlated with vascular invasion by tumor cells. Sandwich enzyme immunoassays revealed enhanced production of MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1 by carcinoma tissues. Gelatinolytic activities were significantly higher in carcinoma samples than in normal controls. Using gelatin zymography, active forms of MMP-2 and MMP-9 were more frequently detected in carcinoma tissue, and the activation rate of the zymogen of MMP-2 (proMMP-2), but not that of proMMP-9, correlated well with degree of local invasion and lymphatic permeation. Our data indicate an enhanced production of 4 MMPs in gastric carcinoma tissue and suggest that activation of pro-MMP-2 may be a key step for spreading of gastric carcinoma cells.
Int J Cancer 1996 Feb 20
PMID:Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas. 860 68

The matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) have been associated with tumor invasion and metastasis in many human cancers. Immunohistochemical studies were performed on frozen tumor samples from 42 patients with invasive bladder cancer treated by cystectomy with monoclonal antibodies against the Mr 72,000 gelatinase A (MMP-2), Mr 92,000 gelatinase B (MMP-9), and TIMP-2 to evaluate their significance in bladder cancer. Immunoreactivity for the gelatinases was predominantly tumor cell-associated, whereas strong TIMP-2 staining was mostly detected in the stroma. Tumor cells demonstrated moderate to strong reactivity for MMP-2 and MMP-9 in 71 and 71% of cases, respectively, which did not correlate with stage, grade, or outcome. Tumor cells were positive for TIMP-2 in 26 (62%) of 42 cases, and this correlated with a worse outcome (69 versus 25% died of disease; P < 0.05). In 31 (74%) of 42, there was moderate to strong stromal staining for TIMP-2; this also was associated with a poor outcome (65 versus 25% died of cancer; P < 0.05). Tumor basement membrane (BM) status was investigated using an antibody to type IV collagen. In 9 cases, the invasive tumor nests were surrounded by an intact BM; in 7 of these, stromal staining for TIMP-2 was absent. None of these 9 patients (0%) died of tumors compared with 7 (100%) of 7 with complete loss of BM staining (P < 0.001). These results suggest a potential role for TIMP-2 and BM staining as prognostic indicators in invasive bladder cancer.
Cancer Res 1996 Apr 01
PMID:High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. 860 16

Co-cultures of human osteosarcoma Takase (OST) cells with various human fibroblasts derived from surgical specimens stimulated production of gelatinase B (92-kDa type-IV collagenase, MMP-9), tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-2 when compared to cultures of individual cells. The maximum stimulation of gelatinase-B production occurred at a cellular ratio of 1:1. Conditioned media from several fibroblast cultures stimulated OST cells to produce gelatinase B, TIMP-1 and TIMP-2, but not vice versa. Among various recombinant growth factors or cytokines, tumor necrosis factor (TNF)-alpha stimulated gelatinase-B production in cultures of OST cells alone, while recombinant basic fibroblast growth factor (bFGF) stimulated gelatinase-B production in co-cultures of OST cells with skin fibroblasts but not in individual cultures of each cell type. In the co-cultures, gelatinase-B production was inhibited by anti-bFGF monoclonal antibody (MAb), but not by anti TNF-alpha MAb. This co-culture-specific stimulation of gelatinase-B production by bFGF was associated with increased expression of the FGF receptor in the co-culture.
Int J Cancer 1996 Mar 28
PMID:Stimulation of gelatinase B and tissue inhibitors of metalloproteinase (TIMP) production in co-culture of human osteosarcoma cells and human fibroblasts: gelatinase B production was stimulated via up-regulation of fibroblast growth factor (FGF) receptor. 860 72

We established and characterized high- (LuM1) and low-lung-metastatic (NM11) cell lines derived from murine colon adenocarcinoma 26 tumor line. LuM1 cell line was established as a clonal cell line from a cultured cell mixture derived from a lung-metastatic nodule after 7 sequential subcutaneous transplantations of lung-metastatic tumors in the abdominal wall of BALB/c mice. NM11 cell line was established from a cultured cell mixture derived from a subcutaneous transplant of murine colon adenocarcinoma 26 tumor cells. LuM1 cells showed marked spontaneous lung metastases, but NM11 cells rarely did. High invasive potential of LuM1 cells was revealed by in vitro invasion assay using Matrigel reconstituted membranes. Rapid retraction was observed in monolayers of human umbilical vein endothelial cells and bovine aortic endothelial cells when LuM1 cells were added on the monolayers. Gelatin zymography and immunochemical examinations with monoclonal antibodies against gelatinase B (Mr 95,000 type IV collagenase) showed secretion of large amounts of the gelatinase by LuM1 cells.
Jpn J Cancer Res 1996 Jan
PMID:Establishment and characterization of high- and low-lung-metastatic cell lines derived from murine colon adenocarcinoma 26 tumor line. 860 53


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