Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to evaluate the type of enzymes involved in tumor-associated fibrinolysis of the stroma component fibrin in ovarian cancer patients. For this purpose, the high-molecular-mass fibrin degradation products (HMM-XDP) were isolated from malignant ascitic fluid by protamine sulfate precipitation and further purified by gel filtration and acid precipitation. After reduction with 2-mercaptoethanol, the peptide chain components were separated by reverse-phase high-performance liquid chromatography (RP-HPLC). The nature of these components was elucidated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and N-terminal amino acid sequence analysis and compared with fibrin-derived fragments formed in vitro. The results indicate that plasmin is the essential protease involved in the degradation of the stroma-derived fibrin portion found in ovarian cancer ascites.
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PMID:Role of plasmin in the degradation of the stroma-derived fibrin in human ovarian carcinoma. 213 49

Recently, it was reported that there is a significant elevation of total plasma apolipoprotein(a) level in cancer patients. Because of their structural homology and immunological cross-reactivity, localization of the plasminogen and the apolipoprotein(a) was comparatively studied in cancerous tissues of breast (N = 4) and colon (N = 3) by immunofluorescence. The following results were obtained: 1) Tumor cells isolated or in nodules were strongly stained in all cancerous samples using antiserum against Pg, absorbed or not with Lp(a). 2) Tumor cells were lightly stained in two breast carcinomas, using anti-Lp(a) serum. All other carcinomas were negative. The staining was abolished when anti-Lp(a) serum was absorbed with Pg. 3) Blood vessels were strongly stained using antiserum against Lp(a) even when it was absorbed with Pg. Anti-Pg serum decorated only a few capillaries. These results show that the two proteins have different localizations: Lp(a) is seen exclusively in the vascular system. The component present at the surface of tumor cells is plasminogen (or plasmin) but not Lp(a).
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PMID:A comparative study of the localization of plasminogen and apolipoprotein(a) in human carcinomas. 214 Nov 96

Three human tumor cell lines, Bowes' melanoma, HT1080 and Osmond cells, were characterized for their ability to invade the amniotic membrane and their production of plasminogen activator. Bowes' melanoma cells, which release large amounts of tissue plasminogen activator (tPA), were poorly invasive on the amniotic membrane. The addition of plasmin inhibitors, anti-tPA antibody or tissue inhibitor of metalloproteinase (TIMP) to the amnion assay enhanced invasiveness. The depletion of plasminogen from the growth medium also enhanced the degree of invasiveness. Similarly, HT1080 cells, which produce high levels of urokinase-type plasminogen activator (uPA), were poorly invasive under standard conditions but invasion was enhanced by plasmin inhibitors or anti-uPA antibodies. Conversely, Osmond cells, which produce low levels of uPA, were very invasive on the amniotic membrane. Invasion by these cells was blocked by the addition of plasmin inhibitors or anti-uPA antibodies to the amnion assay. These results suggest that invasion requires only a minimum level of PA activity and that, as PA production exceeds this optimal level, the degree of invasion decreases. We propose that high levels of plasmin, generated by the tPA or uPA secreted by the cells, may cause uncontrolled matrix degradation and interrupt the interaction of cells and matrix in the early stages of invasion. The inhibition of excessive plasmin activity may stabilize and increase cell matrix contacts and result in an enhancement of invasion.
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PMID:Bimodal relationship between invasion of the amniotic membrane and plasminogen activator activity. 214 42

Extracellular matrix (ECM) produced by bovine corneal endothelial cells was used to investigate the role of the plasminogen activator/plasmin system in the degradation of ECM by human squamous cell carcinoma (SqCCs) and human foreskin epidermal cells (HFEC). SqCCs caused an 8- to 34-fold greater solubilization of 3H-glucosamine-labeled ECM than HFEC. This action in SqCCs was dependent upon the presence of acid-treated serum, indicating that tumor-associated proteinases were sensitive to the inhibitory action of acid-labile proteinase inhibitors present in the serum. SqCC mediated digestion of radiolabeled ECM was decreased by 14- to 55-fold in plasminogen depleted serum, and the addition of 100 micrograms/mL of purified human plasminogen resulted in up to a 30-fold increase in the degradation of the ECM. Inhibitors of this proteinase system and murine monoclonal antibodies (MAb) specific for human urokinase plasminogen activator (uPA) decreased the SqCC mediated digestion of radiolabeled ECM in a concentration dependent manner. SqCCs exhibited 10- to 30-fold higher extracellular uPA levels than HFEC, as assayed by substrate hydrolysis, zymography, micro-ELISA, western analysis, and northern analysis. These findings reflect the differential ability of these cell types to degrade the ECM. In addition, immuno-cross-reactive plasminogen activator inhibitor type I (PAI type 1) and type II (PAI type 2) were identified in cell-free conditioned medium produced by both tumor cells and normal epidermal cells, using a micro-ELISA assay. Indirect immunofluorescence flow cytometry, employing MAbs directed against uPA, detected the presence and localization of uPA on the SqCC cell surface. These findings were specific for uPA, since cell surface associated tissue plasminogen activator was not detected in these cell types under analogous conditions. In addition, partially purified SqCC plasma membrane preparations exhibited 2- to 10-fold higher uPA-like activity than HFEC, as determined by zymography. The findings support the concept that the plasminogen activator system is important in the breakdown of ECM by SqCCs and suggest that regulatory mechanisms involved in this proteolytic system may be important targets for chemotherapeutic intervention to limit tumor cell invasion and metastasis.
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PMID:Plasminogen activator mediated degradation of subendothelial extracellular matrix by human squamous carcinoma cell lines. 214 33

Current hypotheses suggest that both the plasmin system and metalloproteinases are involved in tumor invasion of basement membrane. In this study, we demonstrate that plasmin can directly degrade native and denatured type IV collagen in solution as well as in tissue sections. Tumor cell lines secreted plasminogen activators into culture supernatants that activated exogenous plasminogen to degrade type IV collagen in zymograms and to remove collagen IV immunoreactivity from tissue sections. Inhibition of metalloproteinase activity in culture supernatants by EDTA did not interfere with plasminogen-mediated type IV collagen degradation. We propose that tumor cells possess a mechanism for the degradation of basement membrane type IV collagen, independent of metalloproteinases but dependent on plasminogen conversion to plasmin.
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PMID:Basement membrane type IV collagen degradation: evidence for the involvement of a proteolytic cascade independent of metalloproteinases. 214 9

Thrombin-antithrombin III complex (TAT) and Plasmin-alpha 2 plasmin inhibitor complex (PIC) were examined in fifty two cases of various chronic liver diseases. TAT was significantly elevated in cases of hepatocellular carcinoma (HCC), but PIC did not show significant changes in any chronic liver diseases. Elevations of TAT and PIC were seen in cases of HCC accompanied by tumor enlargement and extensive tumor thrombosis. In cases of HCC undergoing transcatheter arterial embolization (TAE), TAT and PIC increased on the next day after TAE, and tended to recover with time, returning to almost normal at fourth week. Prolongation of prothrombin time, elevation of FDP and positive FM test were noted more often in liver cirrhosis with disseminated intravascular coagulation (DIC) than in severe liver dysfunction without DIC. Of five cases confirmed as DIC, only three cases were diagnosed as DIC by DIC score. On the other hand, TAT and PIC were significantly elevated in DIC cases. Especially, TAT exceeded 30 ng/ml in all DIC cases. TAT was regarded to be useful for the diagnosis of DIC in severe liver dysfunction.
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PMID:[Clinical significance of thrombin-antithrombin III complex and plasmin-alpha 2 plasmin inhibitor complex in chronic liver diseases]. 214 51

The pre-incubation of human colorectal carcinoma cells SW 1116 with 25 to 100 uM purified gangliosides resulted in 35-60% inhibition of specific (125I)-plasmin binding to the cell surface. After 5 to 6 days in culture, tumor cells were pre-incubated at 4 degrees for 1 to 4 h followed by post-incubation with (125I)-plasmin by techniques previously described. At 25 uM the capacity for inhibition of plasmin binding was GT1b greater than GQ1b greater than or equal to GD1a greater than GM1 less than or equal to GgOse 4Cer. Thus a terminal sialyl moiety appears to be necessary (p less than 0.05) although exogenous N-acetyl neuraminic acid was ineffective (p greater than 0.05), indicating a role for the lipid portion of the ganglioside. Other (glyco)lipids such as sphingosine, fucolipid H-1 and sulfatide were without significant effect. The inhibition could not be reversed by the presence of 10 mM Ca+2, EDTA, pre-treatment of the cell with carboxypeptidase or pretreatment of plasmin with neuraminidases. The inhibition was however reversed by post-incubation in control medium without exogenous ganglioside. Cell counts determined prior to, and after ganglioside incubation showed that the effect was not due to cell death or detachment from the culture surface. The dissociation constant for (125I)-plasmin binding was 5.6 x 10(-8) M (700,000 sites/cell), but in the presence of trisialoganglioside (GT1b), Scatchard plots suggested diversification of binding sites with 280,000 sites/cell at Kd 2.6 x 10(-8) M and 820,000 sites/cell at Kd 2.1 x 10(-7) M. Another interpretation of the Scatchard plot in the presence of ganglioside was that the glycolipid imposed negative cooperativity on plasmin binding to the cell surface. These results suggest that certain gangliosides can affect tumor cell invasiveness by altering protease binding to the cell surface.
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PMID:Ganglioside inhibition of (125I)-plasmin binding to colorectal carcinoma cells. 215 Apr 16

Extracellular matrix metalloproteases are secreted by the resident cells of the tissue in a proenzyme form, and their extracellular activity is regulated at the level of gene expression, proenzyme activation, and interaction with inhibitors. To understand the molecular mechanisms that control the activity of ECM metalloproteases and their effect on the cellular phenotype, we have established cell lines in which the transcription of the protease genes is repressed. We also have undertaken a detailed study of the pathway of extracellular activation of interstitial procollagenase. Stable transfection of three human tumor cell lines--H-ras-transformed bronchial epithelial cells TBE-1, fibrosarcoma cells HT1080, and melanoma cells A2058--with the adenovirus E1A gene dramatically repressed the expression of the secreted proteases, type IV and interstitial collagenases, and urokinase-type plasminogen activator. Concomitantly, E1A-expressing cells showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibody inhibited the invasive activity of parental tumor cell lines in the in vitro system, suggesting a possible causal relationship between the effect of E1A on the expression of secreted proteases and the reduced metastatic potential of the E1A-expressing transformants. We have also studied the mechanism of regulation of metalloprotease activity at the level of extracellular activation by investigating the cascade of proteolytic events that results in the activation of interstitial procollagenase. Cocultivation of the major cellular components of skin, dermal fibroblasts, and epidermal keratinocytes induces activation of interstitial procollagenase and prostromelysin in the presence of plasminogen. This activation occurs through a uPA-plasmin-dependent pathway in which plasmin catalyzes the first step in activation of both collagenase and stromelysin by amino-terminal processing. Activated stromelysin can in turn convert plasmin-activated collagenase into a fully active enzyme by removal of approximately 15 amino acid residues from the carboxyl end of the enzyme. This second step of activation results in a 5-8-fold further increase in specific activity of collagenase. This cascade of proteolytic events may constitute a major physiologic pathway of collagenase activation.
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PMID:Secreted proteases. Regulation of their activity and their possible role in metastasis. 215 52

Several urokinase-expressing tumor cells display surface receptors that avidly bind the plasminogen activator. The present study was undertaken to determine the importance of receptor bound urokinase in promoting the invasive phenotype by cultured colon cancer cells. An HCT 116 cell line that elaborates urokinase and displays 11 x 10(4) receptors per cell, 57% of which are tagged with endogenous plasminogen activator, invaded extracellular matrix (Matrigel) in a plasminogen dependent manner. Matrigel invasion was contingent on plasmin production mediated by urokinase, since epsilon-aminocaproic acid diminished the invasive capacity of the HCT 116 cells by 75%. A specific urokinase receptor peptide-antagonist reduced cell invasion in a dose dependent manner with a maximum effect (78% reduction in tumor cell infiltration) being achieved with a 10(-4) M concentration. These results did not reflect a non-specific "shut down" of urokinase expression by the receptor antagonist insofar as steady state urokinase transcript levels were unchanged compared with untreated controls. In addition, LH-RH, a control peptide, failed to suppress Matrigel invasion by HCT 116 cells. The CBS and FET colon cancer cell lines, which secrete amounts of urokinase similar to HCT 116 cells and display one tenth of the receptor number were found to be poorly invasive. Over a three day period, less than 0.8% of these cells invaded the Matrigel in contrast to the 6.9% seen for HCT 116 cells. These data suggest that for cultured colon cancer cells, at least, the display of receptor bound urokinase was a prerequisite for plasminogen dependent invasion.
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PMID:Invasion of extracellular matrix by cultured colon cancer cells: dependence on urokinase receptor display. 216 13

We could solubilize the plasmin receptor from the human colonic tumor cell line SW1116, using various detergents. Among these, Triton X100 and Sodium dodecyl sulfate were the most efficient. The solubilized receptor retained its plasmin binding activity, as judged by dot blot tests. After electrophoresis of the solubilisate in SDS polyacrylamide gels and transfer to nitrocellulose, specific plasmin fixation was still observed on autoradiograms as a sharp band in the 50K area. This band was not altered by treatment of the solubilisate with beta-mercaptoethanol.
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PMID:Solubilization of the plasmin receptor from human carcinoma cells. 216 6


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