Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An enzyme-linked immunosorbent assay (ELISA) using monoclonal and polyclonal antibodies against t-PA was used to measure the concentration of tissue-type plasminogen activator (t-PA) in plasma from 34 healthy donors and 92 breast cancer patients with a varying extent of disease. The mean value of t-PA in plasma for the healthy donors was 2.4 +/- 2.1 ng ml-1 (s.d.). The mean value for the breast cancer patients was 5.3 +/- 4.3 ng ml-1. This increase was statistically significant at the 1% level. There was a positive correlation between the mean t-PA plasma concentration and the extent of disease in different groups of patients. Taking 5.0 ng ml-1 as cut-off point, about 40% of the patients were positive, and 6% of the normal controls were false positive. Twenty-five per cent of the patients in complete remission, 28% of the patients with minimal tumour burden, 60% of the patients with moderate tumour burden, and 90% of the patients with massive tumour burden were positive. It is possible that the patients with an elevated plasma t-PA represent a group with a particularly bad prognosis.
Br J Cancer 1990 Mar
PMID:Tissue-type plasminogen activator in plasma from breast cancer patients determined by enzyme-linked immunosorbent assay. 210 29

Trophoblast cells of normal first trimester human placenta share with malignant tumor cells the ability for significant cellular proliferation and invasion of basement membranes. Because tumor cell metastasis in vivo and invasion of basement membranes in vitro have recently been shown to require the expression of -GlcNAc beta 1-6 Man alpha 1-6 Man beta 1-branched complex type Asn-linked oligosaccharides in tumor cell surface glycoproteins, we decided to determine if such structures were also necessary for invasion by trophoblast cells. We report here that invasive first trimester trophoblasts express leukoagglutinin-reactive beta 1-6 branched Asn-linked oligosaccharides on their surface. Moreover, basement membrane invasion by trophoblast was significantly inhibited by pretreating the cells with swainsonine, a non-toxic inhibitor of Golgi alpha-mannosidase II which blocks beta 1-6 branching of Asn-linked oligosaccharides. The first trimester trophoblast cells pretreated with swainsonine attached more avidly to the amnion basement membrane and to an extracellular matrix (ECM) preparation compared to control non-treated erophoblast cells. Swainsonine treatment did not inhibit secretion of gelatinase or plasminogen activator activities by trophoblast cells. These results suggest that expression of beta 1-6 branched oligosaccharides in trophoblast cells may be functionally important for the implantation and placentation processes by reducing cell adhesion to ECM and thereby facilitating trophoblast cell invasion.
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PMID:Basement membrane invasion by first trimester human trophoblast: requirement for branched complex-type Asn-linked oligosaccharides. 211 36

Increasing attention is being paid to alterations of the hemostatic balance in tumors, in general, and brain tumors, in particular. Apparently divergent results, showing excess fibrinolysis (i.e., increased plasminogen activator activity) or its inhibition (i.e., increased inhibitor activity), have been reported. The 9L rat brain tumor is a gliosarcoma and a model used to study treatment paradigms for human gliomas. To study the roles of fibrin and fibrinolysis in this brain tumor model, we used these features to investigate the nature of the plasminogen activator (PA) and thrombin inhibitors in normal rat brain and in the 9L rat brain tumor, growing both in vitro and in vivo in rat brain. The results indicate that cells cultured from the tumor in vitro express PA inhibitory activity which is both of the protease nexin I and PA inhibitor 1 types. However, the serpin PA inhibitory activity in extracts of both the normal brain and tumor is of the protease nexin I/PA inhibitor 3 type. This activity is higher in the tumor than in the surrounding "normal" tissue. In addition, we present evidence for a novel thrombin inhibitor which (a) is present only in the tumor growing in rat brain and undetectable either in the normal brain tissue or in vitro, (b) is in a latent, but sodium dodecyl sulfate-activatable, state, and (c) does not bind urokinase. In current studies, investigators are exploring the roles of these molecules and the target serine proteases they inhibit in the pathogenesis of gliomas.
Cancer Res 1990 Aug 15
PMID:Serpin inhibitors of urokinase and thrombin in normal rat brain and the 9L brain tumor: evidence for elevated expression of protease nexin I-like inhibitor and a novel sodium dodecyl sulfate-activated tumor antithrombin. 211 23

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.
Cancer Metastasis Rev 1990 Dec
PMID:The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. 212 23

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.
Int J Cancer 1990 Jul 15
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.
Cancer Commun 1990
PMID:Plasminogen activator mediated degradation of subendothelial extracellular matrix by human squamous carcinoma cell lines. 214 33

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.
Cancer 1990 Feb 01
PMID:Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. 215 29

We have developed a human melanoma metastasis model in nude mice. In this model, a human variant cell line (451-LU) was obtained that spontaneously metastasized in nude mice. This variant cell line was selected from the lung of a nude mouse after several in vivo passages of human melanoma WM164 cells previously isolated from a melanoma metastasis of a patient. The WM164 cells were not competent for metastasis in nude mice prior to this selection. We compared the phenotypes of the parental nonmetastatic cell line and the metastatic variant with respect to growth at clonal seeding densities in protein-free medium (growth factor independence), in vitro invasion through reconstructed basement membranes, secretion of proteolytic enzymes, expression of tumor-associated antigens, and chromosomal abnormalities. Metastatic 451-LU cells showed significantly increased growth factor independence when grown at clonal seeding densities as compared to the parental cells. In in vitro chemoinvasion assays, metastatic 451-LU cells were significantly more invasive than the parental cells. The metastatic variant secreted collagenase and tissue type plasminogen activator at levels 10- and 3-fold higher than the parental WM164 cells, respectively. Polyclonal antibodies to tissue type plasminogen activator significantly inhibited invasion through reconstructed basement membranes. In metastatic 451-LU cells, expression of nerve growth factor receptor was elevated, both at the protein and transcriptional level. Metastatic cells were aneuploid with a mode of 97 chromosomes, whereas the parental nonmetastatic cells had a mode of 52 chromosomes. Our studies suggest that metastatic melanoma cell variants selected in vivo show increased independence of exogenous growth factors when grown at clonal cell densities, enhanced invasiveness in vitro, greater secretion of proteolytic enzymes, and increased chromosome mode as compared to the nonmetastatic parental cells. The data further suggest that melanoma cells isolated from metastatic lesions and maintained in vitro have an unstable invasive phenotype but that metastatic variant cells can readily be selected.
Cancer Res 1990 Apr 15
PMID:In vitro properties of human melanoma cells metastatic in nude mice. 215 14

Understanding of the leukemic evolution of human non-Hodgkin's lymphomas is hindered by the lack of appropriate animal models. For this purpose, a highly leukemic cell line NQ22, derived from a MCF 247 murine leukemia virus (MuLV)-induced murine T-cell lymphoma, was established, and its preliminary characterization is described. The NQ22 cell line is easily transplantable subcutaneously (s.c.) into syngeneic AKR mice exhibiting early peripheral blood invasion and widespread dissemination with a leukemic pattern of infiltration. Such peculiar in vivo behavior is a stable phenotypic feature, probably determined genetically. Biological and differentiation characteristics of the NQ22 cell line were analyzed and compared to those of other non-leukemic T-lymphoma lines. In addition, no evidence of possible involvement of plasminogen activator (PA) enzymes and of their inhibitors (PAI) in the spreading ability of NQ22 cells was observed.
Int J Cancer 1990 May 15
PMID:Establishment and characterization of a leukemic murine cell line derived from MCF 247 MuLV-induced T-cell lymphoma. 215 41

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.
Cancer Commun 1990
PMID:Invasion of extracellular matrix by cultured colon cancer cells: dependence on urokinase receptor display. 216 13


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