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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased plasminogen activator (PA) secretion has been observed in malignant cells and tissue and PA is thought to be involved in the processes of tumorigenesis, cancer invasion and metastasis. Recently two types of plasminogen activator--tissue type PA(tPA) and urokinase type PA(uPA)--have been detected in human plasma. In this study, to investigate the relationship between circulating PA and the malignant state, we measured the plasma PA concentrations (PA activity, tPA and uPA antigen) in 69 women with gynecologic malignancies (cervical cancer 50, ovarian cancer 19). These concentrations were compared to those in control groups of 33 women with benign gynecologic tumors (uterine tumor 8, ovarian tumor 25). An enzyme-linked immunoassay for tPA and uPA antigens was performed by the modified method described by Takada et al. (1986). PA activity was measured by the sensitive spectrophotometric assay of Verheijen et al. (1982). The blood samples were taken from an arm vein with a minimum of venous occlusion before treatment. There was no correlation between PA activity or uPA antigen levels and the malignant state. However, in the case of uterine tumors, a significantly higher concentration of tPA antigen (10.5 +/- 5.1 ng/ml) was found in patients with cervical cancer, in stage IV, than in those in the benign group (5.2 +/- 2.0 ng/ml). Moreover the tPA antigen concentration in cervical cancer, stage IV, was higher than in stages 0-III.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Study on the plasma plasminogen activators in patients with malignant gynecologic tumors]. 251 Dec 60

Ascitic fluid from tumour patients (hepatoma, gastric cancer, gallbladder cancer, colorectal cancer, ovarian cancer) and from non-malignant diseases (liver cirrhosis, congestive heart failure) were compared with respect to their content of determinants of the fibrinolytic system, tissue-type plasminogen activator antigen (t-PAag) and activity (t-PAact), urokinase-type plasminogen activator antigen (u-PA) and plasminogen activator inhibitor activity (PAI). Furthermore, SDS-polyacrylamide slab-gel electrophoresis (SDS-PAGE) was performed to evaluate molecular weight distribution of the detectable fibrinolytic parameters. In malignant ascites, PAI activity was three to four times higher, and increased complex formation of PAI with t-PA could be demonstrated, compared with non-malignant ascitic fluid. Tissue-type plasminogen activator antigen and activity showed a similar concentration in ascites of both study groups. Urokinase-type plasminogen activator antigen was detectable neither in ascites of malignant nor in ascites of non-malignant origin. It is concluded that t-PA is the physiological plasminogen activator in ascites and that increased PAI levels followed by increased complex formation between t-PA and PAI might reflect a reaction of the peritoneum.
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PMID:Plasminogen activators and plasminogen activator inhibitor in malignant and non-malignant ascitic fluid. 285 12

The plasminogen activator (PA) activity and oestrogen and progestin receptor concentrations were determined in normal, benign and malignant tissues of human breast and ovary. The geometric mean of PA activity was significantly higher (p less than 0.05) in malignant than in normal breast tissue specimens. PA activity was also higher in benign breast tumours than in normal tissue, but lower than in malignant tumours. The geometric means of PA activity in normal, benign and malignant ovarian tissue specimens differed even more clearly (analysis of variance: p less than 0.001). There was no significant correlation between PA activity and cytosol oestrogen or progestin receptor concentrations in either breast or ovarian cancer tissues. Our data confirm the finding that increased tissue PA activity is associated with human malignant breast tumours, compared with normal tissue and benign mammary lesions, and show that a similar situation prevails in human ovarian tissues. In addition, they show that the possible female sex steroid dependency of PA activity in human breast and ovarian malignancies cannot be demonstrated by cytosol receptor assays alone.
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PMID:Plasminogen activators and steroid receptor concentrations in normal, benign, and malignant breast and ovarian tissues. 668 90

Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's). It has been contemplated that these inhibitors counteracted the proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications. 766 68

We quantitated urokinase and tissue plasminogen activator (u-PA, t-PA), plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2), and fibrinolytic activity in peripheral blood (PB), tumour blood (TB), peritoneal/ascitic fluid (PAF) and cystic fluid (CF) from 104 patients with benign and 36 patients with malignant ovarian tumours, and in peripheral blood from 62 healthy controls. PB levels of u-PA were higher in patients with benign and malignant tumours than in controls. High concentrations of u-PA were found in CF, but not in TB, suggesting that u-PA is released by the tumour tissue, but not by the tumour vasculature. PB levels of t-PA were higher in both tumour groups than in controls. Increased levels of t-PA were found in TB, but not in CF, indicating that t-PA is released by the tumour vasculature, but not by the tumour tissue. PB levels of PAI-1 were higher in patients with both benign and malignant tumours than in controls. High levels of PAI-1 were present in both TB and CF from malignant tumours, suggesting that PAI-1 is released from the tumour vasculature as well as the tumour tissue. Elevated concentrations of PAI-2 were found in CF, but not in TB, indicating release from the tumour tissue, but not from the vasculature. High levels of t-PA, PAI-1 and PAI-2 were found in PAF of malignant tumours, and resorption from this compartment may explain elevated PB levels in patients with ascites. None of the PAs/PAIs proved useful as a PB marker for detection of early stage ovarian cancer. However, an index based on PAF levels of t-PA and PAI-1 discriminated between malignant and benign ovarian cysts in the absence of ascites. In addition, our study stresses the importance of including patients with benign tumours as well as healthy controls when markers for malignant tumours are evaluated.
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PMID:Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer. 799 18

Epithelial ovarian carcinoma, the leading cause of gynecologic cancer death, is characterized by widespread intra-abdominal metastases mediated primarily by surface shedding of tumor cells and peritoneal implantation. Whereas hematogenous metastasis is known to involve cellular adhesion, extracellular matrix proteolysis and cell migration, the role of these processes in the intraperitoneal dissemination of ovarian cancer remains unclear. To analyze further the role of adhesion and proteolysis in ovarian carcinoma dissemination, we have characterized the adhesive profiles of 4 primary cultures of ovarian carcinoma cells and 5 ovarian carcinoma cell lines. Our data demonstrate preferential adhesion of ovarian carcinoma cells to interstitial type I collagen. Analysis of adhesion molecule expression demonstrated the presence of the alpha2 and beta1 integrin subunits by cell surface ELISA, immunoprecipitation and immunohistochemistry. Furthermore, antibodies directed against the alpha2 and beta1 subunits inhibited adhesion of ovarian carcinoma cells to type I collagen by 56% and 95%, respectively. Plasminogen activator and matrix metalloproteinase production by adherent cells was not altered as a consequence of adhesion to individual extracellular matrix proteins; however, adhesion to an extracellular matrix comprised primarily of interstitial collagen increased plasminogen activator activity in 5 of 5 cell lines. Since the ovarian carcinoma micro-environment is rich in type I collagen, our data suggest that preferential adhesion to type I collagen followed by secretion of serine and metalloproteinases may represent a biochemical mechanism by which the intraperitoneal dissemination of ovarian carcinoma is mediated.
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PMID:Evidence for preferential adhesion of ovarian epithelial carcinoma cells to type I collagen mediated by the alpha2beta1 integrin. 878 61

Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy among North American women. The vast majority of women are diagnosed after the cancer has metastasized into the peritoneum, resulting in a low 5-year survival. Because of difficulties associated with early detection of ovarian carcinoma and the invasive potential of these malignancies, a more detailed understanding of the mechanism(s) by which ovarian carcinomas metastasize may suggest novel therapeutic approaches which could impact favorably on long-term survival. Connective tissue degrading proteinases are necessary for tumor cell invasion and enzymes in the plasminogen activator (PA) and matrix metalloproteinase (MMP) families have been implicated in ovarian cancer metastasis. The goal of this review is to summarize current data regarding the role of these proteinases in ovarian carcinoma invasion.
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PMID:The role of proteolytic enzymes in the pathology of epithelial ovarian carcinoma. 947 94

Aberrant expression or activity of the epidermal growth factor (EGF) receptor family of tyrosine kinases has been associated with tumor progression and an invasive phenotype. In this study, we utilized 4 ovarian cancer cell lines, OVCA 432, DOV 13, OVEA6 and OVCA 429, to determine the effects of EGF on the regulation of proteolytic enzymes and their inhibitors, cellular migration and in vitro invasion. Induction of urinary-type plasminogen activator (u-PA) activity and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was observed in all 4 cell lines. OVCA 432 cells showed strong PAI-1 induction; however, the other 3 lines displayed substantial baseline PAI-1 expression that was not induced by EGF. EGF-dependent stimulation of migration and induction of matrix metalloproteinase (MMP)-9 (gelatinase B) was observed in OVEA6 and OVCA 429 cells only. Upon EGF receptor activation, DOV 13, OVEA6 and OVCA 429 cells were induced to invade through an artificial basement membrane (Matrigel); however, no invasion was detected in OVCA 432 cells. Cell lines displaying induction of migration and MMP-9 (OVEA6 and OVCA 429) demonstrated robust EGF-induced invasion (5- to 20-fold), and cell invasion was substantially reduced in the presence of anti-catalytic MMP-9 antibody. Addition of anti-catalytic u-PA antibody inhibited the modest (<2-fold) EGF-induced invasion in a cell line that did not express MMP-9 (DOV 13) and in OVEA6 cells that displayed the highest baseline u-PA activity. Together, our findings indicate that multiple proteinases are important in ovarian cell invasion and implicate EGF induction of MMP-9 and migration as key components of more aggressive ligand-induced invasion.
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PMID:Proteinase requirements of epidermal growth factor-induced ovarian cancer cell invasion. 976 68

Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and inhibitor, plasminogen activator-type 1 (PAI-1) are proposed to be of prognostic significance in some cancers. To determine the prognostic value of the urokinase plasminogen activation system in ovarian cancer, levels of uPA, uPAR, and PAI-1 were measured in extracts of ovarian cancer tissue using ELISA tests. uPA and PAI-1 were determined in 70 tumor extracts and uPAR in 43 extracts. Levels were correlated with age, tumor histology, stage, grade, lymph node and metastatic status, residual disease, risk of recurrence, epidermal growth factor receptor (EGFR) expression, cathepsin D (Cath-D), and c-erbB-2 levels. uPA and uPAR did not exhibit correlation with any of these parameters. However, patients with high grade tumor, recurrence, and lower EGFR and Cath-D had significantly higher PAI-1 levels compared to those of others (P < 0.05). Kaplan-Meier plots of survival were compared. uPA and uPAR were not related to disease-free or overall survival. Although low PAI-1 appeared to predict a longer overall survival, the difference was not statistically significant. Multivariate analysis revealed that PAI-1 was a predictor for overall survival although it was not as strong as stage. These results suggest that elevated PAI-1 seems to be correlated with an unfavorable prognosis in ovarian cancer.
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PMID:Clinical relevance of urokinase-type plasminogen activator, its receptor and inhibitor type 1 in ovarian cancer. 1124 Jul 1

The urokinase type plasminogen activator (uPA), together with its receptor uPAR and the plasminogen activator inhibitor type-1 (PAI-1) plays a pivotal role during tumor invasion and metastasis. Integrins, via interaction with the extracellular matrix (ECM), control cell adhesion and motility. The two systems are functionally linked because uPAR and PAI-1 bind to the ECM component vitronectin (VN). Because integrin signaling alters gene expression patterns, we investigated whether the expression levels of uPA, uPAR, and PAI-1 are affected by ECM/integrin interactions. Expression of uPA, uPAR, and PAI-1 was significantly enhanced when human ovarian cancer cells (OV-MZ-6) were cultivated on fibronectin or collagen type IV. In contrast, VN induced down-regulation of uPA and uPAR while increasing PAI-1 by up to 4-fold. VN-dependent decrease of uPA protein was paralleled by a significant reduction of uPA promoter activity that was even more pronounced upon alpha(v)beta(3) overexpression and depended on the presence of intact Rel protein-binding sites. The activity of Rel transcription factors was also significantly reduced upon alpha(v)beta(3)-mediated cell adhesion to VN. The activity of the Rel-unresponsive PAI-1 promoter was up to 5-fold induced as a function of alpha(v)beta(3)/VN interaction. Thus, the balance between available concentrations of uPA, uPAR, PAI-1, and integrins in human ovarian cancer cells might provide a switch within the regulation of their invasive phenotype.
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PMID:Integrin alpha(v)beta(3)/vitronectin interaction affects expression of the urokinase system in human ovarian cancer cells. 1133 Dec 80


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