Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The significance of plasminogen activators and matrix metalloproteases for clinical outcome, growth and metastatic behavior of head and neck squamous cell carcinoma (SCC) is still controversial. The majority of studies has been based on either immunohistological stainings, which provide only limited quantitative information, or in vitro experiments. We analyzed 44 head and neck SCC and 11 mucosa tissue samples for the expression of gelatinolytic or fibrinolytic proteases by quantitative zymographic analysis and compared lytic activities to clinical and histopathological data. We calculated activation ratios for matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) by separate evaluations of inactive and activated MMP forms. Increased gelatinolytic and fibrinolytic activity was found in head and neck SCC when compared to mucosa. Increased values were caused by MMP-9 and urokinase type plasminogen activator, respectively. No statistically significant correlations of either protease lytic activity or activation ratio could be related to T-stage, metastasis, tissue necrosis or the differentiation stage of tumors. The data recorded are compared with previously published reports.
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PMID:Proteolytic patterns of head and neck squamous cell carcinoma. 1047 28

Proteolysis occurs when proteinase activity exceeds inhibitor activity. Proteolysis is normally tightly regulated and is involved in cancer invasion and metastasis. The aim of this study was to compare proteolysis in breast and colorectal cancer. Proteinase and inhibitor expression were analysed in paired tumour and normal tissue samples from 43 breast and 24 colorectal cancer patients using substrate zymography, Western blotting and quenched fluorescence substrate hydrolysis. The expression of the latent forms of matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-9, urokinase plasminogen activator (uPA), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression were observed in both tumour and normal tissue samples from breast and colorectal tissue; however, expression was greater in the tumour tissue. Expression of active MMP-2 and MMP-9 and the total MMP activity were greater in tumour compared to normal samples in both tissues (P < 0.05). The expression of all proteinases and total MMP activity was greater in colorectal tissue than breast tissue samples. Breast and colorectal cancer demonstrated different proteinase profiles, however proteolysis in both tissues was greater in tumour tissue than normal tissue.
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PMID:Proteolysis in human breast and colorectal cancer. 1049 54

Many studies have highlighted the role played by matrix metalloproteinases MMP-2 and -9, by serine proteases uPA and plasmin in tumor cell invasion. This study investigates the impact of the MMP-inhibitor Batimastat and/or the serine protease inhibitor Aprotinin on the in vitro proteolytic activity and in vivo invasive behavior the of esophageal (OC1) and ovarian (OVCAR-3) carcinoma cells. In presence and absence of inhibitors, proteolytic activity of the tumor cells was determined by caseinolytic and collagenolytic in vitro assays and tumor cell invasion by intraperitoneal inoculation of the tumor cells into nude mice. In vitro, Aprotinin, tested alone or in combination with Batimastat, efficiently inhibited degradation of collagen IV and casein by the tumor cells. Batimastat alone had no effect on caseinolytic activities and only partially blocked collagen-type-IV-degradation by the tumor cells. In vivo, Aprotinin tested alone or in combination with Batimastat did not prevent tumor cell invasion. Treatment of tumor bearing mice with Batimastat significantly inhibited tumor growth but promoted tumor cell invasion into the liver. Our findings demonstrate that the inhibition pattern of cellular proteolytic activity achieved in vitro by a serine protease and an MMP inhibitor may lead to predictions that are not necessarily verified in vivo and may even have adverse effects.
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PMID:Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo. 1062 17

Our previous clinicopathologic study revealed an inverse association of liver metastasis of colorectal cancer and stromal expression of matrix metalloproteinase-9 (MMP-9) or urokinase receptor (uPAR). This suggests that host cells, particularly macrophages, expressing matrix-degrading enzymes/factors could be protective for the host against hematogenous metastasis. However, our previous study was unable to differentiate whether our results were causes or effects of widely spread cancer. To solve this point, we designed the present study on colorectal cancers that developed hematogenous metastasis after operation, ie., metachronous hematogenous metastasis. These cancers, being solely micrometastasized at the time of operation, allowed us to eliminate possible systemic effects by widely spread cancer. Sixty-two primary tumors with metachronous metastasis showed a decreased number of MMP-9+ stromal cells and CD68+ macrophages along the invasive margin with unchanged uPAR+ stromal area as compared with those in 72 control cases, which were free from tumor metastasis or recurrence for more than 5 years. Therefore, we judged the decrease of MMP-9+ host cells or macrophages in the primary site is irrelevant of effects of widely spread metastasis but probably related to causes of metastasis. Our data also characterized the metachronous metastasis group by uPAR expression in fibroblasts. The number of uPAR+ cancer cells, although small in number, were also larger in the metachronous metastasis group. Our data revealed that macrophages, a major source of uPAR and one of the sources of MMP-9, could be inhibitory to hematogenous metastasis, while uPAR+ fibroblasts and cancer cells, in turn, facilitate hematogenous metastasis. This suggests the functional multiplicity of matrix degradation processes in cancer tissue.
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PMID:Clinicopathologic significance of urokinase receptor- and MMP-9-positive stromal cells in human colorectal cancer: functional multiplicity of matrix degradation on hematogenous metastasis. 1072 90

Primary varicose veins are functionally characterized by venous back-flow and blood stagnation in the upright position. Dilatation and tortuosity provide evidence for progressive venous wall remodelling, with disturbance of smooth muscle cell/extracellular matrix organization. Affected areas are not uniformly distributed, some areas being hypertrophic, whereas others are atrophic or unaffected. In 12 varicose veins and ten control veins, the proteolytic enzyme/inhibitor balance which may participate in the remodelling of the venous wall was investigated. For this purpose, the presence and enzymatic activity of matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitors of MMPs (TIMP-1, TIMP-2), urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PAs), and plasminogen activator inhibitor-1 (PAI-1) were quantified by western blot and gelatin or plasminogen-casein zymography. In addition, MMP-2, TIMP-1, TIMP-2, and PAI-1 levels were measured by ELISA. A high TIMP-1 level and a low MMP-2 level/activity were found in varicose veins (p<0.005), resulting in a three-fold increase in the TIMP-1/MMP-2 ratio in varicose versus control veins. Levels of PAs (uPA and tPA) as well as PAI-1 were both lower in varicose veins (p<0.005), with minimal change in the PAI/PA ratio. These results demonstrate that varicose veins are characterized by a higher than normal TIMP/MMP ratio, which may facilitate extracellular matrix accumulation in the diseased venous wall.
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PMID:Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. 1095 7

During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.
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PMID:Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. 1102 65

We established and characterized a new mammary tumor cell line, LM2, derived from M2 mammary adenocarcinoma which spontaneously appeared in a BALB/c female mouse. The LM2 cell line has been maintained in culture for more than 40 passages and grows as poorly differentiated elongated cells. Ultrastructural and immunocytochemistry analysis revealed characteristic features of adenocarcinoma. Cytogenetic studies showed that LM2 cells are fundamentally hypotetraploid. They express metalloproteinases (MMP) and show high levels of plasminogen activator type urokinase (uPA). They were sensitive to nitric oxide (NO)-mediated cytotoxicity when NO derived from an exogenous donor. In vivo, although LM2 cells were able to grow in the lungs, they could not metastasize to the same target organ from s.c. primary tumors. The LM2 mouse mammary adenocarcinoma cell line is a suitable model to examine different aspects of tumor biology, in particular those related to the different pathways involved in the metastatic cascade and in the cytotoxicity mediated by NO.
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PMID:Characterization of a fibroblastoid mammary carcinoma cell line (LM2) originated from a mouse adenocarcinoma. 1107 14

The ets-1 proto-oncogene is a member of the transcriptional factor family and was identified by homology to the v-ets oncogene. It was recently demonstrated that Ets-1 protein interacts with the promoter region of the genes coding for proteinases, including matrix metalloproteinase-1 (MMP-1), MMP-3, and urokinase-type plasminogen activator, suggesting that it may play an important role in the regulation of MMP expression. The role of the ets-1 proto-oncogene in advanced glomerular diseases, where extracellular matrix accumulation is observed, remains undefined. In this study, the expression of ets-1 mRNA and protein during the progression of rat crescentic glomerulonephritis was examined using immunohistochemical analysis, reverse transcription-PCR, and in situ hybridization. Passive accelerated anti-glomerular basement membrane-induced nephritis was induced in rats by intravenous injection of nephrotoxic serum. Rats were euthanized on day 7, 14, 21, 28, or 42. Immunohistochemical analysis demonstrated significant upregulation of Ets-1 protein expression in glomeruli and the interstitium in anti-glomerular basement membrane-induced nephritis. The numbers of Ets-1-positive cells were increased 8.8-fold on day 21 in glomeruli (1.2+/-0.1 cells/glomerular cross-section, P<0.001) and sixfold on day 28 in the interstitium (21+/-1.3 cells/mm(2), P<0.001), compared with control samples. Ets-1 protein was predominantly localized in glomerular epithelial cells, endothelial cells, and interstitial cells. A small number of vascular endothelial cells, macrophages, and T cells also expressed Ets-1 protein. MMP-3 deposition was upregulated and positive cells in the interstitium often coexpressed Ets-1, whereas only a few glomerular cells were positive for both MMP-3 and Ets-1 protein. The expression of ets-1 mRNA was also markedly increased in diseased kidneys. The distribution of ets-1 mRNA was similar to that of the protein. These results indicate that overexpression of the ets-1 proto-oncogene by phenotypically altered renal cells might be associated with the pathogenesis of rat crescentic glomerulonephritis.
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PMID:Renal expression of the Ets-1 proto-oncogene during progression of rat crescentic glomerulonephritis. 1109 47

Wound healing is a complex process involving the interactions of many different cell types, matrix components and biological factors, including proteinases and cytokines. This study compared the levels of proteinases (matrix metalloproteinases and plasminogen activators), proteinase inhibitors (tissue inhibitors of metalloproteinases and plasminogen activator inhibitors), inflammatory cytokines and growth factors in acute wound fluid samples collected from the surgical drains of elective breast (n = 24) and colorectal (n = 26) patients on the first postoperative day. Gelatin zymography was used to determine matrix metalloproteinase-2 and -9 levels, quenched fluorescence substrate hydrolysis was applied for total MMP activity and enzyme-linked immunoassays were used to quantitate other factors. Colorectal wound fluid samples showed significantly (p < 0.05) greater levels of the matrix metalloproteinases (MMP-1, 2, 3, and 9), tissue inhibitor of metalloproteinases-1, urokinase plasminogen activator receptor and the inflammatory cytokines (interleukin-1beta, -6, and tumor necrosis factor-alpha); e.g., matrix metalloproteinase-3 colon; median 275 (range 11-2.530) ng/ml; breast; 530-400. However, tissue plasminogen activator and growth factor levels (epidermal growth factor, platelet-derived growth factor, basic fibroblast growth factor, transforming growth factor-beta1) were significantly greater in breast samples; e.g., epidermal growth factor breast 468 (103-1, 444) pg/ml; colon 57(1-573). There was no difference in the levels of urokinase type plasminogen activator, plasminogen activator inhibitor-1 and -2, tissue inhibitor of metalloproteinases -2 or vascular endothelial growth factor. Acute wound fluid from different surgical wounds showed different profiles of proteinases, proteinase inhibitors, and cytokines. This may lead to differences in the rate of tissue remodeling and therefore healing in these two wounds in vivo.
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PMID:Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. 1111 51

The matrix metalloproteinase (MMP) and fibrinolytic (plasminogen/plasmin) systems cooperate in many (patho)physiological processes requiring extracellular proteolysis. The effect of MMP-3 (stromelysin-1), MMP-7 (matrilysin), MMP-9 (gelatinase B) or MMP-12 (metalloelastase) on cellular fibrinolytic activity was studied with the use of smooth muscle cells (SMC) and fibroblasts derived from mice with specific inactivation of these genes. Activation of cell-bound plasminogen by two-chain urokinase-type plasminogen activator (tcu-PA) was not significantly different with SMC or fibroblasts from the gene-deficient mice (78% to 140% of wild-type). For all cell types, very limited conversion of plasminogen to angiostatin-like kringle-containing fragments was observed (< 3% of the total cell-bound plasminogen). Activation of plasminogen in solution by cell-associated tcu-PA was also comparable for SMC or fibroblasts of the different genotypes (54% to 160% of wild-type). In vitro SMC migration on scrape wounded collagen-coated surfaces was comparable for wild-type, MMP-7(-/-), MMP-9(-/-) and MMP-12(-/-) SMC, but was significantly reduced for MMP-3(-/-) SMC (P < .005 vs. wild-type). Serum-free conditioned medium of MMP-3(-/-) and MMP-7(-/-) SMC or fibroblasts induced similar lysis of fibrin films as wild-type cells. These findings indicate that several interactions that have been described between these MMPs and the plasminogen/plasmin system in a purified system do not significantly affect plasmin-mediated cellular fibrinolytic activity under cell culture conditions.
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PMID:Matrix metalloproteinase deficiencies do not impair cell-associated fibrinolytic activity. 1132 16


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