Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence and localization of the plasmin system components urokinase (UPA), tissue type plasminogen activator (TPA), plasminogen (PG), a neoantigen expressed by the plasmin-alpha 2-antiplasmin complex, and plasmin inhibitors alpha 2-antiplasmin (AP) and alpha 2-macroglobulin (MG) have been tested by immunofluorescence on sections of 11 benign and 40 malignant lesions of the breast in an attempt to apply a morphological approach to the problem of tumor invasion in vivo. In benign lesions, TPA was seen in secretions of mammary glands and MG was seen in edematous zones. In one involuting lactating adenoma, UPA, TPA, PG, PAP, and AP were associated with glandular cells. UPA was detected in 11 carcinomas, TPA in 22, PG in 31, PAP in 12, AP in 23, and MG in all 40. All these components were essentially present in invasive territories, with a cellular labeling for UPA and TPA and a fluorescent staining frequently at the periphery of tumoral foci for PG and PAP. AP was more closely associated with cancer cells than MG, which was present in the stroma. Intraductal proliferations were rarely positive and there was no correlation between the localization of PG and the distribution of a basement membrane glycoprotein laminin. These data argue strongly for the involvement of the plasmin system in the infiltrating process of the stroma. This system seems to play a limited role in the breakdown of basement membrane in breast carcinomas in vivo.
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PMID:Detection of the plasmin system in human mammary pathology using immunofluorescence. 242 83

A new cell sorter technique was employed to study the role of interferon gamma (INF gamma) in fibrinolysis induced by U937 monocytic cells. INF-gamma induced the differentiation of U937 cells as evidenced by the appearance of CD 14 antigen on the cell surface. Scatchard analysis and dose response curves showed a parallel increase in the number of receptors on U937 cells capable of accepting exogenous plasminogen and urokinase (UPA) synthetized by differentiating U937 monocytic cells. This would favour an activation of plasminogen by UPA. This adds a new parameter in the regulation of cell-mediated fibrinolysis and may be important in a number of biological processes.
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PMID:Parallel induction of fibrinolysis and receptors for plasminogen and urokinase by interferon gamma on U937 cells. 284 85

Increased expression of plasminogen activator inhibitor-1 (PAI-1) has been demonstrated in the human atherosclerotic vessel wall and may contribute to the impaired plasma fibrinolytic capacity in patients at high risk of atherothrombotic events. In addition, the mural PA/plasmin system may have important pathobiologic functions during atherogenesis. We quantitatively analyzed PAs of the tissue type (TPA) and urokinase type (UPA), PAIs, and plasminogen in protein extracts from different layers of human aorta in relation to the presence and severity of atherosclerotic lesions. In comparison with normal control vessels, intimal and neointimal TPA concentrations were reduced in atherosclerotic aortas except in the necrotic core areas of advanced plaques, where TPA was mainly complexed to PAI-1 in extracellular matrix deposits. In the media, TPA antigen was higher in lesional segments and closely associated with smooth muscle cells. UPA antigen was increased in the intima of atherosclerotic lesions and colocalized with tissue-infiltrating macrophages and neointimal smooth muscle cells. By spectrophotometric assay, neither TPA nor UPA activity could be detected in intimal or medial extracts. PAI-1 concentrations increased significantly in the intima of atherosclerotic segments compared with adjacent uninvolved areas or control aortas. The immunohistochemical distribution of PAI-1 was similar to that observed for TPA. A large excess of PAI-1 over PA concentrations, particularly in the intimal layer, characterizes atherosclerotic lesions of the human aorta and suggests that PA action is locally confined and counterbalanced by enhanced PAI expression and accumulation.
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PMID:Quantification of plasminogen activators and their inhibitors in the aortic vessel wall in relation to the presence and severity of atherosclerotic disease. 760 Jan 21

It was recently found that urokinase-type plasminogen activator (uPA) is involved in the cleavage of its receptor (uPAR) on cultured cells, thereby releasing one of the receptor's 3 domains (the ligand binding domain I) and leaving the 2 others [uPAR(2 + 3)] anchored to the cell surface. With monoclonal antibodies (MAbs) we have now identified human uPAR(2 + 3) in lysates of invasive human MDA-MB-231 mammary carcinomas xenografted into nude mice. The production of peptide antibodies recognizing different domains of murine uPAR made it possible to identify a similar cleaved form of uPAR, murine uPAR(2 + 3), in extracts of primary Lewis lung carcinomas. Cleavage of uPAR also occurs in cultured MDA-MB-231 cells and Lewis lung carcinoma cells. This cleavage is inhibited by anticatalytic antibodies to either human or murine uPA, respectively, indicating that it is catalyzed by either uPA or plasmin generated by uPA. The amount of uPAR(2 + 3) may therefore be directly related to the activity of the uPA system and it is possible that the level of uPAR(2 + 3) in cancer tissue may prove to be a stronger prognostic parameter than the levels of either full-length uPAR or UPA.
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PMID:A cleaved form of the receptor for urokinase-type plasminogen activator in invasive transplanted human and murine tumors. 792 82

Phenotyping of cytokeratin (CK)18-positive cells in bone marrow is gaining increasing importance for future prognostic screening of carcinoma patients. Urokinase-type plasminogen activator receptor (uPA-R) is one example of a potential aggressive marker for those cells. However, a valid and reliable double staining method is needed. Using monoclonal antibodies against uPA-R and CK18, we modified an immunogold/alkaline phosphatase double staining protocol. UPA-R/CK18-positive tumor cell controls exhibited black uPA-R staining in 15-80% of cases and red CK18 staining in almost 100% of tumor cells. Isotype- and cross-matched controls were completely negative. Bone marrow from healthy donors was always CK18-negative. Reproducibility of CK18-positive cell detection was estimated in a series of specimens from 61 gastric cancer patients comparatively stained with the single alkaline phosphatase-anti-alkaline phosphatase (APAAP) and our double staining method (10(6) bone marrow cells/patient). In four cases, double staining could not reproduce CK18-positive cells. In 34 cases it revealed fewer or equal numbers, and in 23 cases more CK18-positive cells than the APAAP method. Overall quantitative analysis of detected cell numbers (838 in APAAP, range 1-280 in 10(6); double staining 808, range 0-253) demonstrated relative reproducibility of APAAP results by double staining of 97%. Correlation of results between both methods was significant (p < 0.001, linear regression). Sensitivity of double staining tested in logarithmic tumor cell dilutions was one CK18-positive cell in 300,000. Specific uPA-R staining was seen on CK18-positive cells in bone marrow from 29 of 61 patients, and also on single surrounding bone marrow cells. To test the specificity of this staining, bone marrow cytospins from 10 patients without tumor disease were stained for uPA-R with the APAAP method. uPA-R expression was confirmed in all 10 cases, with a mean of 6.5% uPA-R-positive cells in 1000 bone marrow cells (SEM 1.2%). These results suggest that our double staining protocol is a sensitive, reproducible, and specific method for routine uPA-R phenotyping of disseminated CK18-positive cells in bone marrow of carcinoma patients.
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PMID:Immunocytochemical phenotyping of disseminated tumor cells in bone marrow by uPA receptor and CK18: investigation of sensitivity and specificity of an immunogold/alkaline phosphatase double staining protocol. 901 10

We have previously observed in vitro that some stromal proteinases (MMP-2, MT1-MMP) were expressed or activated by invasive carcinoma cell lines exhibiting mesenchymal features, presumably acquired through an epithelial to mesenchymal transition (EMT). To examine the potential contribution of c-ets-1 to this phenotype, we have compared here the expression of c-ets-1 with invasiveness in vitro and expression of vimentin, E-cadherin, uPA, MMP-1 and MMP-3 in a panel of human breast cancer cell lines. Our results clearly demonstrate an association between c-ets-1 expression and the invasive, EMT-derived phenotype, which is typified by the expression of vimentin and the lack of E-cadherin. While absent from the two non-invasive, vimentin-negative cell lines, c-ets-1 was abundantly expressed in all the four vimentin-positive lines. However, we could not find a clear quantitative or qualitative relationship between the expression of c-ets-1 and the three proteinases known to be regulated by c-ets-1, except that when they were expressed, it was only in the invasive c-ets-1-positive lines. UPA mRNAs were found in three of the four vimentin-positive lines, MMP-1 in two of the four, and MMP-3 could not be detected in any of the cell lines. Intriguingly, MDA-MB-435 cells, which exhibit the highest metastatic potential of these cell lines in nude mice, expressed vimentin and c-ets-1, but lacked expression of these three proteinases, at least under the culture conditions employed. Taken together, our results show that c-ets-1 expression is associated with an invasive, EMT-derived phenotype in breast cancer cells, although it is apparently not sufficient to ensure the expression of uPA, MMP-1 or MMP-3, in the vimentin-positive cells. Such proteases regulation is undoubtedly qualified by the cellular context. This study therefore advances our understanding of the molecular regulation of invasiveness in EMT-associated carcinoma progression, and suggests that c-ets-1 may contribute to the invasive phenotype in carcinoma cells.
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PMID:Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines. 924 54

Proteolytic destruction of basement membrane and tumor surrounding is a prerequisite of invasion and metastasis. In 587 frozen samples of malignant and nonmalignant tissue of breast, uterus, vulva, and ovary, levels of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were examined with enzyme-linked immunosorbent assay (ELISA) and cathepsin D (cath D) with radioimmunoassay. UPA, PAI-1 and cath D were raised in malignant tissue with significantly higher levels in breast cancer (uPA, PAI-1) and ovarian cancer (cath D). TPA levels were lower in malignant tissue. In 393 primary breast cancer samples, uPA, PAI-1, and cath D were not related to other prognostic factors, whereas tPA levels were significantly raised in prognostic more favorable carcinomas. Over a follow-up period up to 46 months (median 30 months) the log-rank test showed in the whole group of breast cancer patients a significantly higher rate of relapse (p < 0.05) and death (p < 0.001) with tPA levels < 2.5 ng/mg. PAI-1 levels > 3 ng/mg were associated with shorter overall (p < 0.02; p = 0.01), disease-free (p < 0.008; p < 0.01), and metastasis-free (p < 0.04; p = 0.005) survival in all patients and in the node-negative subgroup, respectively. Higher uPA and cath D levels were not associated with rate of relapse or death over this follow-up period. The prognostic value of tumor-associated proteases could be of interest also in ovarian and cervical cancer.
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PMID:Protease levels in breast, ovary, and other gynecological tumor tissues: prognostic importance in breast cancer. 930 48

The aim of this study was to determine whether enhanced expression of N-myc in a neuroblastoma cell line affects the balance of plasminogen activator/plasminogen activator inhibitor (PA/PAI), a shift towards proteolysis having been observed in other malignant tissues. Two transfected neuroblastoma cell lines with (WAC2 cells) or without (SH-EP007 cells) enhanced expression of the N-myc oncogene were examined by zymography and RNA extraction to determine UPA and PAI enzyme activity and uPA RNA and PAI RNA expression, respectively. The effect of genistein, an inhibitor of tyrosine protein kinase, on uPA/PAI was also investigated. Both the uPA/PAI-1 ratio at mRNA level and the PA/PAI ratio at protein activity level were higher in the more malignant, WAC2 cell line. Genistein attenuated uPA activity and stimulated PAI activity in both cell lines, leading to a decrease in the PA/PAI ratio. This effect was more pronounced in the more malignant, WAC2 cell line.
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PMID:Modulation of the proteolytic balance plasminogen activator/plasminogen activator inhibitor by enhanced N-myc oncogene expression or application of genistein. 989 62

In vivo tumor progression in mice with targeted deficiencies in urokinase-type plasminogen activator (UPA-/-) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1-/-), was studied using a fibrosarcoma tumor model. Murine T241 fibrosarcoma cells were s.c. implanted into three groups of mice with the following genotypes, wild-type (WT), UPA-/-, and PAI-1-/-. A significantly diminished primary tumor growth in UPA-/- and PAI-1-/- mice occurred, relative to WT mice. Tumors in UPA-/- and PAI-1-/- mice displayed lower proliferative and higher apoptotic indices and displayed a different neovascular morphology, as compared with WT mice. These results are consistent with the decreased growth rates of this tumor in these gene-deleted mice. Immunohistochemical analyses of the tumors revealed a decrease in vascularity and vascular endothelial growth factor expression only in tumors in PAI-1-/- mice. Analyses of the relative extents of corneal angiogenesis in these same animals, induced by basic fibroblast growth factor, corroborated the resistance of PAI-1-/- mice to neovascularization. The results obtained suggest that the host fibrinolytic system plays an important role in tumor growth in this model. Alterations in host expression of components of this system may alter tumor growth and dissemination by affecting the balance between tumor cell death and proliferation, as well as extracellular matrix changes needed for invasiveness and angiogenesis.
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PMID:Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. 1105 81

Arteriosclerosis and the development of restenosis still remain a significant clinical problem. Migration of vascular smooth muscle cells from the media to the intima and cell proliferation are the hallmarks of the underlying pathomechanisms. Cell migration requires chemotaxis, phenotypic changes of cells, cell adhesive and de-adhesive events and the coordinated remodeling of the extracellular matrix. One of the phenotypic changes induced in migrating cells is the increased expression of urokinase plasminogen activator (uPA) and of its specific receptor uPAR. They are polarized to the leading edge of migrating cells. Both uPA and uPAR are key mediators of extracellular proteolysis. They participate in extracellular matrix remodeling, activate cells and enable them to migrate and invade into different tissue layers. UPA/uPAR are multifunctional proteins influencing a great variety of signal transduction pathways ultimately culminating in the regulation of cell migration and proliferation. In addition to time- and space-confined proteolysis this powerful system can mediate chemotaxis, cell adhesion and gene expression, partly by interacting in concert with integrins, G proteins, or with yet unidentified coreceptors or adapter molecules. Interaction with the uPA/uPAR system or components of its specific signal transduction pathways may serve as a guide for the development of effective therapeutic strategies to prevent arteriosclerosis and restenosis after percutaneous arterial angioplastic interventions.
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PMID:[Significance of the uPA/uPAR system for development of arteriosclerosis and restenosis]. 1145 92


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