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)

To assess the postulated role of plasminogen activation in tumor invasion, we have investigated the cellular sites of synthesis for urokinase-type (uPA) and tissue-type (tPA) plasminogen activators and their inhibitors (PAI-1 and PAI-2) in two human cutaneous neoplasia that differ in their metastatic potential. The combined use of zymography on tissue sections and in situ hybridization demonstrates that uPA is produced by malignant cells of squamous cell carcinomas (SCC) but not by basal cell carcinomas (BCC), whereas tPA is detected exclusively in nonmalignant dermal tissue. In addition, we show that SCC neoplastic cells simultaneously produce variable amounts of PAI-1, and that PAI-1 production correlates inversely with uPA enzymatic activity. These observations establish that invasive human malignant cells in vivo can activate plasminogen through uPA production during the early phases of tumor growth; they also demonstrate that the proteolytic activity of tumor cells can be modulated by the concomitant production of PAI-1. Because SCC have a higher invasive and metastatic potential than BCC, our findings lend further support to the involvement of plasminogen activation in malignant behavior.
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PMID:Differential protease expression by cutaneous squamous and basal cell carcinomas. 191 64

Urokinase type plasminogen activator (u-PA) was purified from three different chest fluids obtained from patients with liver cirrhosis and pleuritis, aplastic anemia and pneumonia, and lung tumor, and the relationship between molecular weight and plasminogen activator (PA) activity was examined by zymography. The molecular weights of u-PAs from the chest fluids were 200 Kd, 150-180 Kd, 95 Kd, 55 Kd, 44 Kd, 33 Kd and 14 Kd, and PA activity was observed at molecular weights of 95 Kd, 55 Kd and 33 Kd. Fibrin binding of u-PA was observed at molecular weights of 55 Kd and 33 Kd.
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PMID:Properties of urokinase type-plasminogen activator found in chest fluid. 210 19

Keratinocytes in culture represent cells which exhibit continued and controlled growth in the organism. We have investigated the synthesis of urokinase plasminogen activator mRNA in exponentially growing cultures of primary murine keratinocytes and the keratinocyte cell line BALB/MK. The tumor promotor 12-O-tetradecanoyl phorbol-13-acetate (TPA) and epidermal growth factor (EGF) induced urokinase mRNA synthesis. We made a series of progressive 5' deletions as well as internal deletions in the region upstream of the murine uPA gene. These were joined to the cat reporter gene, and used to map the TPA and EGF responsive regions of the promoter. We found both responsive sequences within a 90 base pair Hae III fragment, located 2.4 kb. upstream of the mRNA cap site. This DNA fragment conferred TPA inducibility on reporter gene expression independent of its distance and orientation to the transcription initiation site. Footprinting and gel retardation studies identified the responsible sequence to be a binding site for PEA3 juxtaposed to an octameric TRE-element. Transfections with point mutants showed that these target sequences were necessary for TPA and EGF induction of transcription.
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PMID:Transcription factor PEA3 participates in the induction of urokinase plasminogen activator transcription in murine keratinocytes stimulated with epidermal growth factor or phorbol-ester. 211 94

Supernatant obtained from granulocytes stimulated in the presence of cytochalasin B by the chemotactic peptide N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl- lysine displayed an inhibitory effect on the plasmin-dependent conversion of tumor urokinase-type plasminogen activator proenzyme (pro-uPA) to the active form of uPA. Moreover, the supernatant was also found to inhibit the fibrinolytic activity of human vulva (A431) and breast (MCF7) carcinoma cell lines, which contain large amounts of pro-uPA, by 87% and 96%, respectively. By using eglin C (elastase inhibitor) and a monoclonal antibody to elastase (proteolytic activity blocker of the enzyme), elastase was identified as the key enzyme of the supernatant in these phenomena. Purified elastase converted pro-uPA to an enzymatically inactive molecule composed of two polypeptide chains of Mr = 33,000 and 22,000 linked to each other by a disulfide bond. Elastase-containing granulocytes were identified by immunohistochemistry techniques in the tissues of squamous cell carcinoma and adenocarcinoma of uterus. The cells were found close to the tumor cells and in the stroma surrounding the tumor nests. By immunohistochemical staining, uPA was also found in the tumor cells. Evidently, elastase released by chemotactically activated granulocytes, which are attracted into tumor tissues, may inhibit the conversion of pro-uPA to enzymatically active uPA in the tumor cells.
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PMID:Inactivation of human tumor cell pro-urokinase by granulocyte elastase. 212 85

The correlation between urokinase-type plasminogen activator (uPA) expression and tumor cell invasion and metastasis has been well documented. Urokinase converts the zymogen plasminogen to plasmin, a trypsin-like enzyme with broad substrate specificities. Net uPA activity is determined not only by the amount of the enzyme itself, but also by its state of activation and the amount of specific plasminogen activator inhibitors (PAIs) present. Both uPA and its substrate, plasminogen, can bind to cells via specific membrane-associated receptors. Expression of uPA, uPA receptor (uPAR), and PAIs is regulated by growth factors, oncogenes, and other effector molecules. In the present review we discuss the interactions of uPA with its receptor, inhibitors, and substrate and how these interactions influence malignant behavior. We also review recent reports in which investigators have used anti-catalytic antibodies and/or gene transfection to demonstrate that uPA is directly involved in tumor cell invasion and metastasis.
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PMID:The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. 212 23

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

The interaction of epidermal growth factor (EGF) with specific cell surface receptors initiates biochemical events in target cells which result in cellular proliferation and differentiation. In this report the regulation of extracellular-associated plasminogen activator (PA) production by EGF in human squamous cell carcinomas and its influence on tumor cell-mediated degradation of extracellular matrix (ECM) is described. The studies utilized the vulvar carcinoma cell line A431, which possesses an unusually large number of EGF receptors (EGF-Rs), and two A431 EGF-R expression variants (A5 and A7), which contain up to 20-fold fewer cell surface EGF-Rs. EGF enhanced the production of urokinase (u) PA activity by two- to threefold in A431 tumor cells, in a concentration-dependent manner, following a 24-h treatment, as determined by substrate hydrolysis assays, while no changes in tissue-type PA occurred. In contrast, A5 and A7 tumor cells failed to demonstrate such a response. Time course studies of the EGF-mediated induction of uPA activity in A431 tumor cells indicated that within 8 h after exposure to EGF, a twofold increase above basal untreated control levels was observed using the substrate hydrolysis assay. EGF increased the steady state levels of uPA mRNA threefold in A431 tumor cells following a 24-h treatment, while in contrast, no such response was observed in EGF-R variant tumor cells. In accord with an EGF enhancement of uPA mRNA levels in A431 tumor cells, a similar increase of two- to threefold in the de novo synthesis of [35S]methionine-radiolabeled uPA was observed by immunoprecipitation following EGF treatment, while no measurable increase was observed in the EGF-R tumor variants. A431 tumor cells progressively degraded [3H]glucosamine-radiolabeled bovine corneal subendothelial ECM in the presence of EGF, resulting in 8.7-, 4.3-, and 1.7-fold increases above untreated control values, after a 48-h exposure to 100, 10, and 1 ng/ml of EGF, respectively. In contrast, A5 and A7 tumor cells did not demonstrate an increase in ECM degradation in the presence of EGF, even though these tumor cells possessed the ability to degrade ECM in the absence of the growth factor. The observed increase in ECM degradation mediated by EGF in A431 tumor cells was dependent upon the presence of plasminogen and could be inhibited by an anticatalytic uPA monoclonal antibody.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation by epidermal growth factor of human squamous cell carcinoma plasminogen activator-mediated proteolysis of extracellular matrix. 249 75

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

Proteolytic enzymes released from granulocytes upon stimulation with the chemotactic N-formyl peptide FNLPNTL (in the presence of cytochalasin B) prevented activation of tumor cell single-chain urokinase-type plasminogen activator (pro-uPA) by plasmin. Elastase was identified by the use of eglin C (elastase inhibitor) and a monoclonal antibody to elastase as the functional proteolytic enzyme in granulocyte supernatants. Action of purified granulocyte elastase on pro-uPA generated enzymatically inactive two-chain uPA linked by disulfide bridges which was indistinguishable by SDS-PAGE from plasmin-generated HMW-uPA. The major elastase cleavage site in pro-uPA was located between Ile159 and Ile160. a minor one between Thr165 and Thr166. Elastase cannot substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. However, when pro-uPA was first activated by plasmin to form enzymatically active HMW-uPA, this enzymatic activity was not impaired by subsequent elastase treatment.
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PMID:Elastase released from human granulocytes stimulated with N-formyl-chemotactic peptide prevents activation of tumor cell prourokinase (pro-uPA). 252 37

The ability of the chick embryo chorioallantoic membrane (CAM) to withstand invasion by tumor cells can be intentionally compromised by altering its morphological integrity. Using a newly developed quantitative assay of invasion we showed that intact CAMs were completely resistant to invasion by tumor cells, wounded CAMs did not pose a barrier to penetration, and CAMs that were wounded and then allowed to reseal displayed partial susceptibility to invasion. The invasion of resealed CAMs required catalytically active plasminogen activator (PA) of the urokinase type (uPA); the invasive efficiency of tumor cells was reduced by 75% when tumor uPA activity or tumor uPA production was inhibited. The invasive ability of human tumor cells, which have surface uPA receptors but which do not produce the enzyme, could be augmented by saturating their receptors with exogenous uPA. The mere stimulation of either uPA or tissue plasminogen activator production, in absence of binding to cell receptors, did not result in an enhancement of invasiveness. These findings suggest that the increased invasive potential of tumor cells is correlated with cell surface-associated proteolytic activity stemming from the interaction between uPA and its surface receptor.
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PMID:In vivo invasion of modified chorioallantoic membrane by tumor cells: the role of cell surface-bound urokinase. 284 51


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