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)

Results from model tumour systems suggest that either increased levels of certain metalloproteases (MMPs) or decreased levels of their inhibitors correlate with metastatic potential. In this study, levels of two MMPs, i.e. MMP-8 and -9, and their inhibitor tissue inhibitor of metalloprotease type 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in human breast tumours. Levels of MMP-8 and -9 correlated significantly with each other, but neither MMP correlated with urokinase plasminogen activator. Levels of both MMP-8 and -9 were also significantly related to levels of TIMP-1. In contrast, neither MMP correlated with plasminogen activator inhibitor. No relationship was found between MMP-8, MMP-9 or TIMP-1 and either tumour size or metastasis to axillary nodes. MMP-8 and -9 levels were inversely related to levels of oestrogen receptors. MMP-8 but not MMP-9 levels were also inversely correlated with progesterone receptor levels. It is concluded that the assay for MMP-8 and -9 described here will permit the evaluation of these proteases as prognostic markers in cancer.
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PMID:Assay of matrix metalloproteases types 8 and 9 by ELISA in human breast cancer. 773 94

The present study was carried out to characterize the patterns of expression of matrix metalloproteinases or their tissue inhibitor (TIMP-1) in normally healing, acute vs. chronic, skin wounds. In situ hybridization was performed to localize collagenase, stromelysin-1, stromelysin-2, matrilysin, urokinase plasminogen activator (uPA) and TIMP-1 mRNAs in 14 chronic venous ulcers and 10 normally healing wounds, representing different time points after wounding. Surgical wounds, made in piglets harvested at several time points, were studied as controls. Collagenase, stromelysin-1 and -2, as well as uPa, were expressed in keratinocytes in both acute and chronic wounds, while epithelial TIMP-1 mRNA was not detected in any chronic wound biopsies studied. However, TIMP-1 was expressed at the epithelial edges of both acute human and pig wounds. Our results suggest that the balance between metalloenzymes and their inhibitor TIMP-1, is disturbed, in poorly healing wounds.
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PMID:Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. 877 59

Basement membrane transmigration is an important step in tissue recruitment of eosinophils into inflamed tissue. Recent reports showed that this phenomenon is modulated by platelet-activating factor (PAF) in combination with cytokines and proteinases. We investigated the in vitro efficacy of 5-oxo-6,8,11, 14-eicosatetraenoic acid (5-oxo-ETE), a metabolite of arachidonic acid and known as a potent eosinophil chemotactic factor, in promoting the transmigration of blood eosinophils from normal and asthmatic subjects through a Matrigel basement membrane. 5-Oxo-ETE proved to be a more potent (> 10-fold) inducer of eosinophil transmigration than PAF, and this effect was similar in cells from normal and asthmatic subjects (82.0 +/- 3.7% and 88.1 +/- 3.7%, respectively). Moreover, 5-oxo-ETE was active in the absence of interleukin (IL)-5, although this cytokine amplified the effect of 5-oxo-ETE from 61.3 +/- 3.3% to 92.8 +/- 1.8% (p = 0.003). The membrane receptor for urokinase plasminogen activator (CD87), a serine protease, was observed on eosinophils, and its expression was increased by IL-5. The inhibition of both metalloproteinases (MMP) and plasmin/plasminogen complex with inhibitor or monoclonal antibodies decreased cell transmigration by about 50%. Combination of an MMP inhibitor with anti-CD87 antibodies had no additive effect. These data show that 5-oxo-ETE is an efficient promoter of eosinophil transmigration in vitro, and is much more potent in this respect than PAF. The data suggest that 5-oxo-ETE could play an important role in eosinophil recruitment in vivo. Moreover, they demonstrate that in addition to MMP, the plasmin/plasminogen system could be involved in eosinophil transmigration.
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PMID:5-Oxo-6,8,11,14-eicosatetraenoic acid induces important eosinophil transmigration through basement membrane components: comparison of normal and asthmatic eosinophils. 1038 97

Kaposi's sarcoma (KS) cells are considered to be of endothelial origin. KS lesions are characterized by hyperproliferation and an invasive phenotype. We have determined that KS cell cultures constitutively secrete multiple forms of several matrix metalloproteinases (MMPs) and an altered form of urokinase plasminogen activator (uPA) by zymogram and Western analysis of the culture media. MMPs are a family of secreted endoproteinases which degrade components of the extracellular matrix. Their enhanced expression and activity are strongly correlated with cellular processes involving tissue remodeling and invasion. The KS cells secrete increased levels of gelatinase A and B and a high molecular weight uPA in vitro when compared with non-KS endothelial or epithelial cells. Multiple forms of gelatinases A and B were observed on gelatin zymograms. Caseinolytic bands observed were confirmed by Western blot analysis to be due to stromelysin activity, whereas matrilysin was not detected by casein zymography. Western blot analysis also detected secretion of interstitial collagenase and high molecular weight uPA. Gelatinolytic activity with the mobility of gelatinase B was detected on gelatin zymograms, but not by Western analysis. This unusual constitutive expression pattern of MMPs and uPA by KS cells in vitro is characterized by elevated levels of gelatinase A, gelatinase B, interstitial collagenase, stromelysin and a high molecular weight form of uPA, and the lack of expression of matrilysin. These secreted MMPs, taken together, are capable of digesting a broad range of components of the extracellular matrix. This unusual pattern is likely to contribute to the characteristic hyperproliferative and invasive phenotype of KS lesions.
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PMID:Expression of multiple matrix metalloproteinases and urokinase type plasminogen activator in cultured Kaposi sarcoma cells. 1044 93

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

Tumour progression to the metastatic phenotype is mainly dependent on tumour cell invasiveness. Cell migration is a crucial step in this process. Here we investigate the effect of hepatocyte growth factor (HGF) on the induction of in vitro invasiveness of poorly aggressive Caco-2 colonic cancer epithelial cells. Invasion assays through a Matrigel barrier were performed. Proteases were assessed by zymography, reverse transcription-polymerase chain reaction and immunoblotting. Caco-2 cells were found to express HGF receptor but not HGF and to secrete several proteases, namely matrix metalloproteinase-1 (MMP-1), MMP-2, possibly MMP-9 and urokinase plasminogen activator (uPA). Exogenous HGF promoted invasiveness of Caco-2 cells through an artificial basement membrane matrix and enhanced their production of proteases. In addition, analyses of media at the end of invasion assays indicated that anti-HGF antibody inhibited protease production in parallel with cell invasion. The involvement of proteases in the HGF-induced invasion process was further investigated using either a synthetic general MMP inhibitor or neutralizing antibodies against MMPs or uPA. All components significantly inhibited HGF-promoted cell invasion. Moreover, specific inhibitors of PKCalpha/beta1 and PI3 kinase also decreased both HGF-promoted cell invasion and protease expression in invasion assay media. Thus, our findings provide evidence that the process of HGF-activated invasiveness of Caco-2 cells involves PI3 kinase and PKC and results from close association of two events, stimulation of cell motile activity and concomitant overproduction of proteases, which permits cell migration through a degraded extracellular matrix.
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PMID:Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. 1140 46

TGF-beta strongly promotes local tumor progression in advanced epithelial tumors, though the underlying mechanisms are poorly understood. In the present study, we demonstrate the potential of TGF-beta to increase the invasiveness of the pancreatic cancer cell lines PANC-1 and IMIM-PC1. TGF-beta-induced tumor cell invasion occurred in a time-dependent manner, started after 12 hr and continued to increase even 48 hr after a single application of the growth factor. Blocking of secreted TGF-beta1 by application of neutralizing antibodies 24 hr after TGF-beta treatment completely prevented the sustained effects of TGF-beta on tumor cell invasion. Together with our previous observation that TGF-beta1 up-regulates its own expression in both cell lines, our data suggest that TGF-beta1 acts in an autocrine manner to maintain tumor cell invasion. As measured by Northern blot hybridization and zymography, TGF-beta treatment of PANC-1 and IMIM-PC1 cells resulted in strong up-regulation of expression and activity of both matrix metalloproteinase-2 (MMP-2) and the urokinase plasminogen activator (uPA) system. Treatment with MMP inhibitors or inhibitors of the uPA system caused significant reduction of TGF-beta-induced invasiveness in both cell lines. In contrast, expression and activity of MMP-2 and uPA as well as tumor cell invasiveness remained unaffected in cell lines with defects of the TGF-beta type II receptor (MiaPaca2) or the Smad4 gene (IMIM-PC2 and CAPAN-1). In these cell lines, TGF-beta also failed to auto-induce its own expression. In conclusion, our results suggest that TGF-beta1 is a strong promotor of pancreatic cancer progression. TGF-beta thereby acts in an autocrine manner to induce tumor cell invasion, which is mediated by MMP-2 and the uPA system.
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PMID:TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. 1141 Aug 67

Altered expression of alphav integrins plays a critical role in tumor growth, invasion, and metastasis. In this study, we show that normal human epithelial ovarian cell line, HOSE, and ovarian cancer cell lines, OVCA 429, OVCA 433, and OVHS-1, expressed alphav integrin and associated beta1, beta3, and beta5 subunits, but only ovarian cancer cell lines OVCA 429 and OVCA 433 expressed alphavbeta6 integrin. The expression of alphavbeta6 in OVCA 429 and OVCA 433 was far higher than alphavbeta3 and alphavbeta5 integrin and correlated with high p42/p44 mitogen activated protein kinase (MAPK) activity and high secretion of high molecular weight urokinase plasminogen activator (HMW-uPA), pro-metalloproteinase 2 and 9 (pro-MMP-9 and pro-MMP-2). In contrast to HOSE and OVHS 1, OVCA 433 and OVCA 429 exhibited approximately 2-fold more plasminogen-dependent [3H]-collagen type IV degradation. Plasminogen-dependent [3H]-collagen IV degradation was inhibited by inhibitor of uPA (amiloride) and MMP (phenanthroline) and by antibodies against uPA or MMP-9 or alphavbeta6 integrin, indicating the involvement of alphavbeta6 integrin, uPA and MMP-9 in the process. The alphavbeta6 correlated increase in HMW-uPA and pro-MMP secretion could be inhibited by tyrosine kinase inhibitor genistein or the MEK 1 inhibitor U0126, consistent with a role of active p42/44 MAPK in the elevation of uPA, MMP-9, and MMP-2 secretion. Under similar conditions, genistein and U0126 inhibited plasminogen-dependent [3H]-collagen type IV degradation. These data suggest that sustained elevation of p42/44 MAPK activity may be required for the co-expression of alphavbeta6 integrin, which in turn may regulate the malignant potential of ovarian cancer cells via proteolytic mechanisms.
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PMID:Association between alphavbeta6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen-dependent matrix degradation in ovarian cancer. 1183 93

Prostate cancers ability to invade and grow in bone marrow stroma is thought to be due in part to degradative enzymes. The formation of prostate skeletal metastases have been reproduced in vitro by growing co-cultures of prostatic epithelial cells in bone marrow stroma. Expression of urokinase plasminogen activator, matrix metalloproteinase 1 and 7 by prostatic epithelial cells were identified using immunocytochemistry. Also, in vivo tissue sections from human prostatic bone marrow metastases were stained. To establish the role of these enzymes on colony formation, inhibitory antibodies directed against urokinase plasminogen activator, matrix metalloproteinase 1 and matrix metalloproteinase 7 were added into primary prostatic epithelial cells and bone marrow stroma co-cultures. All prostatic epithelial cell cultures stained positively for matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator. Generally prostatic epithelial cells derived from malignant tissues showed increased staining in comparison to epithelia derived from non-malignant tissue. In agreement with in vitro co-cultures, the in vivo tissue sections of prostate bone marrow metastases showed positive staining for all three enzymes. Inhibition studies demonstrated that blocking matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator function reduced the median epithelial colony area significantly in bone marrow stroma co-cultures in vitro. Using a human ex-vivo model we have shown that matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator play an important role in the establishment of prostatic epithelial cells within bone marrow.
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PMID:Role of proteolytic enzymes in human prostate bone metastasis formation: in vivo and in vitro studies. 1195 62

Chronic myeloproliferative disorders (MPD) are characterized by progressive remodelling of bone marrow stroma as evidenced by increased deposition of extracellular matrix proteins, neoangiogenesis and displacement of normal haematopoietic cells by fibrotic tissue. The family of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) serve to facilitate and inhibit matrix degradation processes, respectively. In an attempt to investigate potential markers for bone marrow remodelling processes, we investigated plasma levels of total-, free- and complexed TIMP-1, TIMP-2, MMP-2 and MMP-9 in a patient cohort comprising 17 with myelofibrosis (MF), 17 with polycythaemia vera (PV), 15 with essential thrombocythaemia (ET), 1 with a transitional MPD and 30 controls. Compared with controls, total- (P < 0.0001) (median: 132.6 microg/L vs. 80.8 microg/L), free- (P < 0.0001) (median: 126.4 microg/L vs. 65.8 microg/L) and complexed TIMP-1 (P = 0.0009) (median: 17.7 microg/L vs. 10.7 microg/L) concentration was significantly higher in the patients. TIMP-1 was significantly correlated with plasma soluble urokinase plasminogen activator receptor (P = 0.003) and urokinase plasminogen activator (P < 0.0001), respectively, suggesting a common cellular origin. No statistical significant difference between TIMP-2 and MMP-2 levels was observed between patients and controls. Furthermore, a significant correlation between free TIMP-1 and TIMP-2 levels was detected (r = 0.56; P < 0.0001). Median MMP-9 concentration was significantly higher among PV patients compared with controls (P = 0.0015), and 41% of patients with PV (7/17) had MMP-9 values that were above the mean + 2SD of plasma MMP-9 levels found in controls. The ratio of total TIMP-1/MMP-9 was significantly higher in patients with MF compared with controls (P = 0.0004). These findings suggest that a disturbed TIMP-1/MMP ratio may reflect an imbalance of the extracellular homeostasis towards an increased matrix deposition promoting fibrosis.
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PMID:Elevated plasma levels of TIMP-1 correlate with plasma suPAR/uPA in patients with chronic myeloproliferative disorders. 1466 1


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