UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Two human breast epithelial cell lines (HBL-100, HMT-3522) of non-malignant origin and six (MCF-7, T47-D, ZR-75-1, CAMA-1, BT-20, HMT-3909) of malignant origin have been studied to evaluate whether in vitro invasion and/or secretion of urokinase-type plasminogen activator are related to tumorigenicity in athymic nude mice. Only the six cell lines of malignant origin were tumorigenic. Two of these were invasive in the in vitro assay. These two cell lines were oestrogen receptor negative. Three of the other four cell lines of malignant origin contained oestrogen receptors. The two cell lines of non-malignant origin were neither tumorigenic nor invasive. Thus tumorigenicity was correlated to malignant origin of the cell line whereas invasiveness in vitro was a property of the most undifferentiated cell lines of tumor origin. Secretion of urokinase-type plasminogen activator was neither correlated to tumorigenicity nor to invasion in vitro nor to malignancy of tissue origin.
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PMID:Relationship between tumorigenicity, in vitro invasiveness, and plasminogen activator production of human breast cell lines. 214 97

Components of coagulation and fibrinolysis reactions were identified in situ by immunohistochemical staining in fresh frozen sections of small cell carcinoma of the lung tissue. Tumor cells stained positively for tissue factor, a protein that is capable of activating the extrinsic pathway of coagulation (the components of which have been seen within small cell carcinoma of the lung [SCCL] tissue), and for proteins C and S antigens. Fibrin was seen in a focal distribution at the host-tumor interface, indicating that thrombin had acted upon the fibrinogen found throughout the tumor stroma. Staining with a neoepitope-specific antibody, which does not discriminate between fibrinogen fragment D and fibrin fragment D-dimer, was similar to that of the fibrin antibody. High molecular weight urokinase-type and tissue-type plasminogen activators were seen in vascular endothelium, but neither existed within the tumor. Low molecular weight urokinase was found in rare isolated foci of tumor cells primarily adjacent to areas of necrosis. Plasminogen activator inhibitor-3 occurred in tumor cell cytoplasmic blebs and in necrotic tumor cells, but plasminogen activator inhibitors 1 and 2 were not seen. Our data suggest a mechanism for thrombin generation and fibrin formation within SCCL tissues that could support cell proliferation, stroma formation, and preservation. These features could be conductive to perpetuation of this tumor and conceivably could form the basis of the beneficial effects of antithrombotic therapy seen in SCCL.
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PMID:Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. 215 29

Stable transfection of human tumor cell lines with the adenovirus-5 E1A gene repressed the expression of the secreted proteases, type IV collagenase, interstitial collagenase and urokinase. In addition, E1A blocked the 12-O-tetradecanoyl phorbol acetate (TPA) induction of interstitial collagenase transcription in HT1080 fibrosarcoma cells. Plasmids bearing the interstitial collagenase or type IV collagenase 5' flanking regions linked to a chloramphenicol acetyl transferase coding sequence were constructed and analysed for expression by transient cotransfections into HT1080 cells. Cotransfection with a plasmid bearing a functional E1A gene repressed transcription of the type IV collagenase promoter and blocked the TPA induction of the interstitial collagenase promoter. Furthermore, E1A repressed transcription from a TK promoter driven by AP-1 complex binding sites (TRE), suggesting that E1A interferes with the AP-1 trans-activation pathway. This effect was not, however, due to the repression of c-jun gene transcription by E1A. In fact, the expression of E1A rendered the c-jun gene hypersensitive to TPA induction. Concomitant with reduction in expression levels of secreted proteases, stable E1A transfectants showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibodies inhibited invasive activity of parental tumor cell lines in the in vitro assay, suggesting a possible causal relationship between the repression of secreted proteases and loss of metastatic properties of the transformants.
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PMID:Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. 215 83

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

Plasminogen activator (PA) activities were measured in extracts of ventral and dorsolateral prostate lobes in Fischer 344 (F344) rats of different ages. Ventral prostates of 30-month-old animals demonstrated widespread epithelial atrophy, some foci of inflammation, intraglandular atypical hyperplasia and/or adenocarcinoma, and a marked increase in PA activities compared with younger animals. Both low- and high-molecular-weight forms of activator were found in zymograms and both forms of activator showed an increase at 30 months. However, the PA activity of the aged rats showed a greater resistance to amiloride inhibition, suggesting a greater relative increase in the tissue-type activator activity than that of urokinase. These changes were not observed in the dorsolateral prostate. The lobe-specific changes in activator activity appear related to dysplasia/neoplasia and not aging.
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PMID:Plasminogen activator activities in the ventral and dorsolateral prostatic lobes of aging Fischer 344 rats. 218 19

Plasminogen activators (PAs) are specific proteolytic enzymes which convert the inactive proenzyme plasminogen to plasmin. The plasmin formed is a potent and nonspecific protease which cleaves blood fibrin clots and several other extracellular proteins. In addition to their primary role in the initiation of fibrinolysis, PAs are implicated in a variety of basic biological processes, such as, degradation of the extracellular matrix, tumor invasiveness, tissue remodelling, and cellular differentiation. This review describes recent observations on the biochemical and biophysical characteristics of the different components of the plasminogen activation system. This complex system includes: the proenzymes of tissue type PA (tPA) and urokinase type PA (uPA); the active enzymes tPA, uPA and plasmin; the substrate plasminogen; several natural inhibitors of PA and plasmin activity; and the cellular receptors that bind the proenzymes, enzymes, and inhibitor-enzyme complexes. Through the coordinated interactions of these components, the location, timing, and extent of potent proteolytic activity is controlled. Recent findings on the structure, properties, biological functions, and regulation of the different components of the plasminogen activation cascade are reviewed. Current methods for assay of the amount and activity of the enzymes, inhibitors, and receptors are described. Observations implying specific functions of the system in health and disease, and its potential utilization for diagnosis are examined. Specifically, the potential application of PAs as laboratory markers of neoplasia, as diagnostic tools in diseases of the blood clotting system, their use for monitoring of thrombolytic therapy, and their possible relevance in certain disease states are described.
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PMID:Biochemical and biological aspects of the plasminogen activation system. 219 30

A case of pulmonary embolism associated with diabetes insipidus is reported in an 18-year-old male. The patient, who had been treated with DDAVP for diabetes insipidus and hydrocortisone for hypocorticism for two years after first operation for the removal of craniopharyngioma, was admitted with recurrence of that tumor. Diabetes insipidus immediately after second operation was controlled with intermittent drip infusion of a small amount of aqueous pitressin under monitorings of body weight hourly using a patient weighing system to keep the weight changes within +/- one kilogram. Serum and urine electrolytes levels, osmolarity, and free water clearance were also monitored every three hours to maintain water-electrolytes balances appropriately. Postoperative course had been uneventful except that CSF rhinorrhea occurred 7 days after operation. The patient was, then, kept in bed with horizontal plane to avoid further leakage of CSF. Two days later, he developed chest pain suddenly with tachypnea, tachycardia, and general cyanosis. The arterial-BGA showed PaO2 of 53.5mmHg and PaCO2 of 35.3mmHg in room air. The definite diagnosis of pulmonary embolism was made by technetium microaggregate lung perfusion scans and by pulmonary angiograms. The patient was treated with heparin, 15000IU/day, and urokinase, 720000IU/day. The symptoms due to pulmonary embolism had improved gradually within a couple of weeks. Recent articles have shown an unexpected high incidence of deep vein thrombosis and pulmonary embolism in neurosurgical patients associated with the elevation of blood coagulability. Brain tumors, especially suprasellar mass with hypothalamic dysfunction have been suggested to cause thromboembolic disorders frequently. The clinical course was described and factors causing pulmonary embolism on this patient was discussed.
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PMID:[A case of pulmonary embolism with diabetes insipidus developed after removal of craniopharyngioma]. 233 47

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