Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrolysis of extracellular matrix is a necessary step for malignant cells to invade, and metastasize. Three groups of proteinases, mainly serine, thiol and metalloproteinases, have been found to be secreted by cancer cells and responsible for the proteolytic cascade triggered during invasion. Previous studies from our group and others have shown that the thiol proteinase cathepsin B1 is a constant indicator of tumor invasion in carcinoma of the cervix, although others point to plasminogen activators and collagenases. So far, there are no systematic studies to correlate cathepsin B and plasminogen activator activity with advancing malignant disease and thus estimate its capability as a marker of progression. The purpose of this study was to determine the activity of cathepsin B like proteinase and plasminogen activators in invasive carcinoma of the breast at various clinical stages and with different estrogen receptor status. One hundred patients with carcinoma of the breast at different clinical stages were studied. Cathepsin B and plasminogen activators activity was assessed in tumor cytosols using different synthetic oligopeptides as substrates following the method of Smith. Estrogen receptor concentration was determined with monoclonal antibodies. A statistical analysis and correlation with different clinical stages was performed. Cathepsin B-like activity had a consistent and progressive elevation in direct correlation with clinical stage (stage I, 1.97 SE +/- 0.46; stage II, 6.67 SE +/- 1.12; stage III, 28.19 SE +/- 3.48; nmol/mg/30 min), while plasminogen activators, although constantly elevated, had no correlation with tumor progression. No relation could be found with estrogen receptor status. It is concluded that cathepsin B, but not plasminogen activator, is a good indicator of tumor progression in invasive carcinoma of the breast.
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PMID:Proteinase activity in invasive cancer of the breast. Correlation with tumor progression. 884 43

Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which selectively inhibits endothelial cell proliferation. When given systemically, angiostatin potently inhibits tumor growth and can maintain metastatic and primary tumors in a dormant state defined by a balance of proliferation and apoptosis of the tumor cells. We identified angiostatin while studying the phenomenon of inhibition of tumor growth by tumor mass and have elucidated one mechanism for this phenomenon. In our animal model, a primary tumor almost completely suppresses the growth of its remote metastases. However, after tumor removal, the previously dormant metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kD plasminogen fragment which we have sequenced and named angiostatin. Human angiostatin, obtained from a limited proteolytic digest of human plasminogen, has similar activities. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases and primary tumors. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by the angiogenesis inhibitor angiostatin.
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PMID:Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth. 900 23

Endogenous murine angiostatin, identified as an internal fragment of plasminogen, blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. A recombinant protein comprising kringles 1-4 of human plasminogen (amino acids 93-470) expressed in Pichia pastoris had physical properties (molecular size, binding to lysine, reactivity with antibody to kringles 1-3) that mimicked native angiostatin. This recombinant Angiostatin protein inhibited the proliferation of bovine capillary endothelial cells in vitro. Systemic administration of recombinant Angiostatin protein at doses of 1.5 mg/kg suppressed the growth of Lewis lung carcinoma-low metastatic phenotype metastases in C57BL/6 mice by greater than 90%; administration of the recombinant protein at doses of 100 mg/kg also suppressed the growth of primary Lewis lung carcinoma-low metastatic phenotype tumors. These findings demonstrate unambiguously that the antiangiogenic and antitumor activity of endogenous angiostatin resides within kringles 1-4 of plasminogen.
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PMID:A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. 910 21

Increased urokinase plasminogen activator (uPA) levels are increased in a number of malignancies and have been correlated with decreased disease-free interval and decreased overall survival. We have, therefore, examined components of this plasminogen activating system in patients with Non-Small Cell Lung Cancer (NSCLC). Levels of uPA, urokinase-plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) were measured semiquantitatively in paraffin sections of tumours from 147 patients with NSCLC. Immunohistochemically stained sections of tumour were allocated a score for stain intensity and results correlated to: survival; tumour stage(T); nodal stage(N); stage grouping (I to IIIb), survival status and sex. Increased levels of PAI-1 were associated with a decreased survival in squamous cell carcinoma (SCC) X2 = 5.72, p = 0.017 (n = 74). There was a significant positive relationship between PAI-1 levels and N-stage (p = < 0.05), presence of nodal metastases (p = < 0.05), stage grouping (p = < 0.01) and extent of disease (p = < 0.05) in the total group and the SCC subgroup, but not adenocarcinoma. There was a significant positive relationship between PAI-1 levels and T-stage (p = < 0.05) in the total group, and survival status (p = < 0.05) in the SCC subgroup alone. uPA and uPAR levels were not significantly associated with tumour staging or survival. We conclude that increased PAI-1 antigen levels may be associated with a decreased survival in patients with SCC.
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PMID:Changes in plasminogen activator inhibitor-1 levels in non-small cell lung cancer. 917 85

Binding of the serine protease urokinase (u-PA) to its receptor on tumor cell surfaces facilitates proteolysis and tumor invasion. We undertook this study to determine whether the role of u-PA in prostate cancer induced angiogenesis and secondary tumor growth by developing a homologous, immunocompetent in vivo model in which the tumors cells secrete an inhibitor of the murine u-PA receptor. A mutant recombinant murine u-PA that retains receptor binding but not proteolytic activity was made by PCR mutagenesis. Mutant u-PA and a reporter gene pRK luciferase were transfected and stably expressed in the highly metastatic rat Dunning MAT-LyLu prostate cancer cell line. Several clones expressing mutant u-PA and luciferase were identified by Western blotting, plasminogen zymography, and reverse transcription-PCR. One of these clones, 5C4, was injected s.c. into Copenhagen rats. Compared to animals injected with clones expressing pRK luciferase alone, tumors in animals injected with 5C4 cells were significantly smaller. Moreover, there were fewer lung micrometastases in the 5C4 animals. Primary tumor angiogenesis was measured by microvessel quantification of tissue stained with antibodies against von Willebrand factor. Mean microvessel density in 5C4 tumors was 4.3-fold lower than that in animals with tumors derived from the control tumor cell line (P < 0.0001). Significant inhibition of tumor growth was also observed for two additional MAT-LyLu cell lines expressing mutant u-PA. These findings suggest that cell surface u-PA contributes to prostate cancer growth by enhancing angiogenesis.
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PMID:Inhibition of prostate cancer neovascularization and growth by urokinase-plasminogen activator receptor blockade. 927 33

Metalloproteases, plasminogen urokinase activator, plasmin and cathepsins enable the expansion of neoplastic tumors, leading to metastases formation. They cause neoplastic cells to detach from tumor, facilitate cell movement, implantation and participate in tumor vascularization. The regulation of these processes is accomplished during the synthesis and activation of proenzymes. Enzyme activity control is realized by their bonds with cellular membranes, and inhibitor action.
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PMID:Proteolytic enzymes in proliferation and neoplastic metastases formation. 933 23

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-L-cysteine, D-penicillamine, captopril, L-cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.
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PMID:The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. 938 Jul 26

In ovarian cancer cells, the macrophage colony-stimulating factor-1 (CSF-1) induces the release of plasminogen activator inhibitor-2 (PAI-2), and high levels of PAI-2 as well as of CSF-1 in ovarian cancer ascites are independently correlated with poor outcome. We now study the effect of CSF-1 on PAI-2 expression in vitro and the significance of cellular PAI-2 expression in vivo. Immunohistochemical detection of PAI-2 was studied in primary and metastatic tissues from 130 epithelial ovarian cancer cases. Kaplan-Meier curves of survival were compared with the results of log-rank test. The Cox regression model was used for multivariate analysis. The effect of CSF-1 on PAI-2 expression in ovarian cancer cells was also examined in vitro. Fifty-eight percent of the primary tumors and 68% of the metastases expressed PAI-2. PAI-2 expression in the metastases of invasive stages III and IV cases was strongly predictive of a prolonged disease-free and overall survival. This finding was associated with low residual disease and was also an independent factor for disease-free survival. In vitro, CSF-1 treatment of ovarian cancer cells resulted in a decrease in cellular staining for PAI-2 while increasing the release of PAI-2 into the conditioned medium. In vivo, we also found an inverse correlation between expression of CSF-1 and that of PAI-2 in the primary tumors. We thus describe the favorable independent prognosis of cellular PAI-2 expression in the metastases of ovarian cancer. Moreover, an inverse correlation was observed between CSF-1 and PAI-2 expression in vivo. This lends support for a primary role of cell-surface (vs. secreted)-mediated events of plasminogen activation in the development of invasive, poor prognostic phenotypes.
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PMID:Expression of plasminogen activator inhibitor-2 in epithelial ovarian cancer: a favorable prognostic factor related to the actions of CSF-1. 942 50

The diuretic drug amiloride (AMLD), which competitively inhibits the catalytic activity of urokinase plasminogen activators (UPA), was used to study its effects on the proteolytic enzymes implicated in the invasiveness and metastases in a prostatic tumor model carrying two different sublines of adenocarcinoma of the prostate. Our data showed that UPA activity was significantly higher, both in the cytosol and pellet of R3327-AT3, a fast-growing highly metastatic and androgen-insensitive tumor, as compared to the G3327-G subline, a slow-growing nonmetastatic tumor of the prostate. The UPA activity in AT3 tumor dropped when the rats were treated with AMLD for 3 weeks. The UPA activity in the sera and tumor effusions from rats with AT3 tumor was significantly higher as compared to those with G subline tumor. The number of pulmonary metastatic foci was the same in untreated rats as compared to those treated with AMLD. The lymph node inspection after 3 weeks revealed no secondary tumor in the AMLD-treated group. The role of UPA in the metastases of prostate cancer is discussed.
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PMID:Inhibitory effect of amiloride on the urokinase plasminogen activators in prostatic cancer. 942 83

Expression of proteolytic parameters of the urokinase-type plasminogen activator (uPA) system [uPA receptor (uPA-R), plasminogen activator inhibitor (PAI)-1] has been proven to be an independent prognostic parameter in cancer. However, it has not been considered that the uPA system is interacting with several other protease/inhibitor systems, neither has a comparable prognostic role of these factors been investigated. Moreover, studies evaluating specific protease patterns indicating high individual risk are missing completely. Therefore, in a consecutive prospective series of 203 gastric cancer patients, the expression of activators (plasminogen, tPA, MMP-2, cathepsin D, antithrombin 3) and inhibitors (alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, alpha-1-antichymotrypsin) of proteolysis was studied immunohistochemically in the tumor epithelium semiquantitatively (score 0-3) in addition to the uPA system. Kaplan-Meier analysis (median time of follow-up 31 months) revealed a significant association of cathepsin D (P=0.0042), alpha-2-macroglobulin (P=0.0281) and antitrypsin (P=0.0372) with disease-free survival and of cathepsin D (P=0.0018), antitrypsin (P=0.0112) and antichymotrypsin (P=0.0002) with overall survival. Multivariate Cox analysis performed to correct these results for relative impact of the uPA system and established prognostic factors showed PAI-1 (disease-free survival: P=0.002, relative risk 1.86; overall survival: P=0.005, relative risk 1.39), pT and pN as independent parameters. Cathepsin D was shown to have an independent impact on disease-free survival (P=0.020, relative risk 2.98). Comparative chi-square analysis of cases with poor and good prognoses revealed that in patients with good clinical outcome, inhibitors of proteolysis are correlated significantly, whereas in patients with poor prognosis activators of proteolysis are significantly associated preferentially and significant correlations with the uPA-R are dominant. For detailed pattern analysis, stepwise overall Kaplan-Meier analyses were performed in subgroups of high uPA-R-, uPA-, PAI1- and cathepsin D expression for two additional proteases each. From these analyses, the combination of high (score 2/3) expression of uPA-R, PAI-1, antichymotrypsin and alpha-2-macroglobulin was identified as a high-risk pattern, representing parameters known to be essential for uPA-R internalization and recycling. This suggests some of the uPA-associated proteases and inhibitors investigated as univariate prognostic parameters in gastric cancer. Cathepsin D is a new independent parameter for disease-free survival. The study further demonstrates that a protease pattern promoting uPA-R recycling in tumor cells especially indicates high individual risk tumors in gastric cancer.
Clin Exp Metastasis 1998 Jan
PMID:Tumor-associated proteases and inhibitors in gastric cancer: analysis of prognostic impact and individual risk protease patterns. 950 78


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