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)

Proteolytic factors belonging t the plasminogen activator family (plasmin, u-PA, t-PA, u-PAR, PAI-1, and PAI-2), which usually are involved in blood clotting and degradation of blood clots, are also present in healthy and diseased tissue of the kidney, lung, liver, gastro-intestinal tract, breast, prostate, ovary, and brain. These factors are engaged in brain development, angiogenesis and vascular invasion, wound healing as well as in placenta development and embryogenesis. Plasminogen activators u-PA and t-PA, their inhibitors PAI-1 and PAI-2, and the u-PA-receptor (u-PAR, CD87) are often elevated in solid malignant tumour tissues compared to their normal counterparts. In breast cancer patients, an elevated tumour tissue extract antigen content of u-PA, PAI-1, and u-PAR is associated with increased tumour aggressiveness and poor prognosis; in contrary, an elevated content of t-PA and PAI-2 indicates a favourable prognosis. For clinical relevant determination of these proteolytic factors in tumour tissue extracts, only enzymo-immunometric tests (ELISA) are recommended. Enzymometric and enzymographic tests are actually conducted only in an experimental, preclinical context.
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PMID:[Tumor-associated prognostic factors of the plasminogen activator family: determination and clinical value of u-PA, t-PA, PAI-1, and PAI-2]. 1611 55

Lingual squamous cell carcinoma is common and the survival rate is relatively low. The invasion of cancer cells from the primary tumour into the surrounding tissue is an early step in the process of metastasis and urokinase-type plasminogen activator receptor (uPAR) is a vital mediator of cellular migration in some carcinomas. By binding urokinase-type plasminogen activator, uPAR localises proteolytic activity to the leading edge of the cells, thereby facilitating cellular migration and penetration through tissue boundaries. uPAR also binds directly to vitronectin and associates with integrins within the plasma membrane, which alters the strength of cellular adhesion. In this study we used reverse transcription polymerase chain reaction, immunocytochemistry, and Western-blot to examine the expression of uPAR mRNA and protein in Ts and Tca 8113 cell lines of lingual squamous cell carcinoma and in normal oral mucosal cells. uPAR mRNA and protein were expressed in Ts cells, but not in Tca 8113 cells or in normal oral epithelial cells. Ts cells have higher metastatic potential than Tca 8113 cells. The results suggest that uPAR has an important role in the aggressiveness of lingual squamous cell carcinoma.
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PMID:Expression of urokinase-type plasminogen activator receptor is correlated with metastases of lingual squamous cell carcinoma. 1635 5

The low density lipoprotein receptor-related protein (LRP), a large scavenger receptor reported to mediate the uptake and degradation of various ligands, emerges as a promising receptor for targeting the invasive behaviour of human cancer cells. However, the accurate function of LRP during tumor invasion seems to be highly dependent on cellular context and remains controversial. The expression patterns of both this receptor and the main proteolytic systems involved in cell invasion were examined in two follicular thyroid carcinoma cell lines exhibiting different invasive phenotypes. We established that a low expression of LRP at the cell surface was associated to elevated extracellular MMP2 and urokinase plasminogen activator (uPA) activities as well as to high invasiveness properties. Surprisingly, neither exogenously added receptor-associated protein, an antagonist of LRP, nor LRP blocking antibodies significantly modified the amount of extracellular MMP2. Furthermore, the invasive phenotype of thyroid carcinoma cells was not related to their matrix metalloproteinases amount since different specific inhibitors of these proteases failed to affect the invasive properties of both cell lines. Additionally, blocking LRP-mediated clearance led to a further increase of the uPA amount and activities and to increased invasiveness in both cell lines. Finally thyroid carcinoma cells aggressiveness was widely increased by exogenous uPA; and anti-uPA antibodies treatments abolished both basal and receptor-associated protein-induced thyroid cell invasion. Overall our results identified the LRP-mediated clearance of uPA as one of the mechanisms involved during the control of human thyroid carcinoma cell invasion.
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PMID:Human thyroid carcinoma cell invasion is controlled by the low density lipoprotein receptor-related protein-mediated clearance of urokinase plasminogen activator. 1680 59

The esophageal cancer-related gene 2 (ECRG2) is a novel gene that shows sequence similarity to KAZAL-type serine protease inhibitor. In this study, the migration and invasion of PG cancer cells were inhibited by ectopic expression of ECRG2 in vitro, and metastases decreased after injecting PG/pcDNA3.1-ECRG2 cells into the tail veins of nude mice. Control mice were injected with PG/pcDNA3.1 cells. To test the hypothesis that ECRG2 interacts with proteases and inactivates extracellular matrix degradation, binding affinity and co-immunoprecipitation experiments were performed using serum-free conditioned medium. The results showed that ECRG2 bound to two species of urokinase-type plasminogen activator (uPA) with molecular weights of 55 and 33 kDa. Furthermore, analysis of the uPA/plasmin activity showed that expression of ECRG2 reduced proteolysis of the plasmin substrate D-Val-Phe-Lys-p-nitroanilide, which was seen by a decrease of absorbance at 405 nm. Taken together, these results suggested that ECRG2 inhibits aggressiveness of cancer cell, possibly through the down-regulation of uPA/plasmin activity.
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PMID:ECRG2 inhibits cancer cell migration, invasion and metastasis through the down-regulation of uPA/plasmin activity. 1760 71

Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) contribute to gastric cancer aggressiveness by up-regulating the expression of proteases. We evaluated the expression and the prognostic significance of angiogenic factors and proteases in 148 patients with R0-resected gastric cancer. Expression of VEGF, Ang-2, cyclooxygenase-2 (COX-2), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1, matrix metalloproteinases (MMP)-1 and -9 were assayed by immunohistochemistry. After a mean of 63 +/- 4 months, 81 out of 148 patients had died due to disease. The probability of being free of recurrence was 62, 48, and 42% at 2, 5, and 10 years, respectively. Single bivariate analysis identified VEGF, Ang-2, COX-2, PAI-1, and MMP-9 expression, along with several clinicopathological parameters (grade of curability, lymph node ratio, pTNM, pT, pN), as variables associated with both decreased disease-specific survival and recurrence. On multivariate analysis, after adjusting for significant clinical covariables, positive VEGF immunostaining was the primary prognostic factor, and no other tumor marker variable could add any significant improvement for the prediction, for both disease-specific survival (p = 0.001; HR, 3.27; 95% CI, 1.76 to 6.10) and tumor recurrence (p = 0.002; HR, 2.81; 95% CI, 1.48 to 5.35). Our study suggests that VEGF alone may be clinically useful for establishing therapeutic decisions in gastric cancer patients.
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PMID:Positive VEGF immunostaining independently predicts poor prognosis in curatively resected gastric cancer patients: results of a study assessing a panel of angiogenic markers. 1797 43

The plasminogen activator system is a complex system with multiple interactions and members participating in fibrinolysis, cell migration, angiogenesis, wound healing, embryogenesis, tumor cell dissemination, and metastasis in a variety of solid tumors. Increased levels of uPA and/or PAI-1 in primary tumor tissues of breast cancer patients correlate with tumor aggressiveness and poor clinical outcome. Patients with high tumor tissue antigen content of uPA and/or PAI-1 have a worse probability of disease-free and overall survival than patients with low levels of both of the biomarkers, serving as prognostic markers. The clinical utility of uPA and PAI-1 has been proven on the highest level of evidence (LOE-I). Next to being clinically useful prognostic factors allowing estimates of the course of disease in early breast cancer, uPA and PAI-1 may also serve as predictive factors predicting response to systemic therapy. Node-negative primary breast cancer patients with high uPA/PAI-1 levels benefit significantly from adjuvant chemotherapy. The aim of the ongoing NNBC-3 trial is to determine the benefits of a sequential anthracycline-docetaxel regimen in high-risk node-negative breast cancer patients compared to the current standard of anthracycline-based chemotherapy. At present, uPA and PAI-1 provide the unique opportunity to allow validated and clinically relevant risk assessment of breast cancer patients, over and above that provided by established risk factors. Therefore, in the evidence-based, annually updated AGO guidelines for breast cancer management, the German Working Group for Gynecological Oncology (AGO) has recommended both biomarkers as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, next to established clinical and histomorphological factors.
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PMID:uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial. 1842 92

Myofibroblasts are frequent in the stroma of neoplasm and by the expression of proteinases they can influence tumor infiltration and progression. In the present study, presence of myofibroblasts and expression of matrix metalloproteinase-2 (MMP-2) and urokinase plasminogen activator (uPA) were examined in intra-osseous solid multicystic ameloblastomas to determine their roles in the clinicopathological features of the tumors. Fifty seven ameloblastomas were analyzed immunohistochemically with antibodies against the isoform alpha of the smooth muscle actin (alpha-SMA), a specific marker of myofibroblasts, MMP-2 and uPA. Myofibroblasts were found in the stroma, in close contact with neoplastic cell islands, of approximately 58% (n = 33) of the ameloblastomas. MMP-2 and uPA were found in the cytoplasm of both neoplastic and stromal cells. A significant correlation between presence of myofibroblasts and MMP-2 expression was observed. Abundant presence of myofibroblast in the stroma of the tumors and expression of MMP-2 in the neoplastic or stromal cells were significantly correlated with rupture of the osseous cortical, which has been considered an important prognostic marker of ameloblastoma aggressiveness. Ours results suggest that abundant presence of myofibroblasts and expression of MMP-2 in solid ameloblastomas may be associated with a more aggressive infiltrative behavior.
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PMID:Presence of myofibroblasts and expression of matrix metalloproteinase-2 (MMP-2) in ameloblastomas correlate with rupture of the osseous cortical. 1909 16

Hepatocyte growth factor receptor/c-Met is associated with malignant aggressiveness and survival in various cancers including bladder cancer. Although phosphorylation of hepatocyte growth factor receptor/c-Met is essential for its function, the pathologic significance of phosphorylated hepatocyte growth factor receptor/c-Met in bladder cancer remains elusive. We investigated the clinical significance of its expression, and its correlation with cancer cell progression-related molecules. The expression levels of 2 tyrosine residues of hepatocyte growth factor receptor/c-Met (pY1234/1235 and pY1349) were examined immunohistochemically in 133 specimens with nonmetastatic bladder cancer. We also investigated their correlation with matrix metalloproteinase-1, -2, -7, and -14; urokinase-type plasminogen activator; E-cadherin; CD44 standard, variant 3, and variant 6; and vascular endothelial growth factor. Expression of phosphorylated hepatocyte growth factor receptor/c-Met was detected in cancer cells, but was rare in normal urothelial cells. Although hepatocyte growth factor receptor/c-Met, pY1234/1235 hepatocyte growth factor receptor/c-Met, and pY1349 hepatocyte growth factor receptor/c-Met were associated with pT stage, multivariate analysis identified pY1349 hepatocyte growth factor receptor/c-met expression only as a significant factor for high pT stage. Expression of pY1349 hepatocyte growth factor receptor/c-Met was a marker of metastasis and (P = .001) and cause-specific survival (P = .003). Expressions of matrix metalloproteinase-2, matrix metalloproteinase-7, and E-cadherin correlated with pY1349 hepatocyte growth factor receptor/c-Met expression. Our results demonstrated that pY1349 hepatocyte growth factor receptor/c-Met plays an important role in tumor development, and its expression is a significant predictor of metastasis and survival of patients with bladder cancer. The results suggest that these activities are mediated, at least in part, by matrix metalloproteinase-2, matrix metalloproteinase-7, and E-cadherin.
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PMID:Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin. 1912 49

The transmembrane isoform of mucin 1 (MUC1/TM) is a well-recognized tumor antigen, contributing to tumorigenesis and immune evasion. Although MUC1/TM has been correlated with malignancy, we have previously reported on antitumor properties and prevention of tumor development by a secreted splice variant of MUC1 (MUC1/sec). Because myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-induced immunosuppression, we investigated their recruitment by tumor cells expressing either MUC1/TM or MUC1/sec. DA-3 tumor cells expressing MUC1/sec recruit dramatically lower levels of MDSCs, relative to MUC1/TM-expressing DA-3 cells. Because MUC1/sec was previously shown to down-regulate tumor expression of urokinase plasminogen activator (uPA), a protease linked to tumor aggressiveness and metastasis, the potential role of uPA in MDSC recruitment was investigated. Tumor-derived uPA is capable of recruiting MDSCs, and correlates with tumor development. In addition to diminishing recruitment of MDSCs, the effect of MUC1/sec on MDSC-suppressive mechanisms was investigated. MUC1/sec, or its unique immunoenhancing peptide, is capable of blocking expression of arginase 1 and production of reactive oxygen species in MDSCs, implicated in the suppression of T cells. These findings demonstrate a new mechanism of MDSC recruitment, and provide evidence that MUC1/sec has antitumor properties affecting MDSCs.
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PMID:Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec. 1919 63

The extent of resection and the intrinsic biological aggressiveness of the tumor have been repeatedly identified as the primary determinants of meningioma recurrence. Invasive growth limits the resectability of meningiomas. Tumor invasion is mediated by matrix metalloproteases and their inhibitors such as uPA and PAI-1. In some cancers uPA expression is controlled in part by promoter methylation. In the work reported in this paper we investigated the role of uPA/PAI-1 expression and methylation of the uPA promoter in meningiomas. Sixty-five tumor tissue samples (WHO grade I: 26, grade II: 27, grade III: 12) from 58 patients were analyzed for uPA and PAI-1 protein content using a commercially available ELISA kit. For uPA promoter methylation analysis, a 365-bp promoter fragment was amplified by PCR after bisulfite treatment and subjected to a methylation-sensitive restriction digest with AciI. Pertinent clinical data were retrieved from the patients' charts. uPA and PAI-1 protein expression correlated significantly with WHO grade (uPA: P < 0.033, PAI-1: P < 0.001). High (>6 ng/ml = median) PAI-1 levels were seen more frequently in tumors with brain invasion (P = 0.006) and proved a significant predictor of the patients' prognosis (Kaplan-Meier estimates of progression-free survival: P = 0.004). Increased methylation of the uPA promoter was found to correlate significantly with lower levels of uPA expression. Our data suggest PAI-1 (and possibly to a lesser degree uPA) as potential prognostic markers in meningiomas. uPA expression in meningiomas might, in part, be controlled by promoter methylation.
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PMID:uPA/PAI-1 expression and uPA promoter methylation in meningiomas. 2086 17


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