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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastatic spread of malignant tumor appears to correlate with activation of the fibrolytic system. The role of fibrinolysis in growth and metastasis was examined in Lewis lung carcinoma of mice. The inhibition of fibrinolysis or proteases decreased the primary tumor growth and pulmonary metastasis, whereas the activation of fibrinolysis or proteases increased the number of metastatic foci in the lung. Electronmicroscopically, thrombus formation in the primary site prevented tumor invasion and metastasis formation. Plasminogen activator (PA) content of excised tumors was determined by SDS-PAGE, and major PA was found to be urokinase (UK) type. Immunohistochemical study with specific antisera was done. When tumor cells possessed a high level of UK, laminin and type IV collagen, components of the basement membrane, disappeared from tumor tissues. These findings suggest that PA through protease cascade plays a role in tumor invasion and metastasis. Clinically, patients with advanced cancer are usually in a hypercoagulable state with elevated fibrinogen, and fibrin deposition around tumor mass is a serious problem in cancer chemotherapy. UK infusion prior to 5-fluorouracil increased tissue concentration of antitumor agent. However, development of consumption coagulopathy characterized by progression from hypercoagulable state to disseminated intravascular coagulation has also been found in several cases.
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PMID:[Tumor metastasis and the fibrinolytic system]. 273 23

Transforming growth factor-beta (TGF beta) is a regulator of cellular proliferation which can alter the proteolytic activity of cultured cells by enhancing the secretion of endothelial type plasminogen activator inhibitor and affecting the secretion of plasminogen activators (PAs) in cultured fibroblastic cells. We used the TGF beta-responsive malignant human lung adenocarcinoma cell line A549 to study the relationships between the known TGF beta-induced growth inhibition and the effects of TGF beta on the secretion of PA activity by A549 cells. PA activity was quantitated by caseinolysis assays, and characterized by urokinase mRNA analysis, immunoprecipitation, and zymography assays. PA-inhibitor production was observed in autoradiograms of SDS-polyacrylamide gels and reverse zymography assays. It was found that TGF beta enhanced the production of PA activity by these cells, in accordance with an enhancement of urokinase mRNA levels. A concomitant stimulation of type 1 PA-inhibitor production was also observed in A549 cells in response to TGF beta. In contrast to the observations of A549 cells, TGF beta caused a decrease in the expression of both urokinase and the tissue-type PA mRNA in human embryonic WI-38 lung fibroblasts indicating opposite regulation of the expression of PAs in these cells. The results suggest that TGF beta may play a role in the regulation of the invasive, proteolytically active phenotype of certain lung carcinoma cells.
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PMID:Regulation of the synthesis and activity of urokinase plasminogen activator in A549 human lung carcinoma cells by transforming growth factor-beta. 327 18

Plasminogen activator (PA; urokinase) levels were studied in metastatic and nonmetastatic clones of the Lewis lung carcinoma (3LL) and of the T10 sarcoma. Tests of clones grown in vitro revealed that the cell content and secretion of PA correlated positively with the metastatic capacity of the clones of both tumors. When cell-associated activities were examined in cloned cell populations grown subcutaneously in vivo, the apparent activities in the solid tumors produced by low-metastatic clones were equal to or even higher than those in solid tumors produced by high-metastatic clones. This finding was attributed to the observation that solid tumors produced by low-metastatic clones, but not those produced by high-metastatic clones, were highly infiltrated with macrophages. Subsequent tests indicated that the ip inoculation of X-irradiated or mitomycin-treated tumor cells of low-metastatic clones elicited a significantly greater peritoneal infiltration of macrophages than did tumor cells of high-metastatic clones. Such "tumor-associated" macrophages manifested high levels of PA, whereas resident (nonactivated) peritoneal macrophages did not. These findings suggest that although PA may cause the initial detachment from the local tumor of both nonmetastatic (via the macrophage PA) and metastatic cells (via their own PA), the PA secreted by the metastatic cells may enable them to complete subsequent stages of the metastatic process that may be PA-dependent.
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PMID:Proteolytic enzymes in tumor metastasis. I. Plasminogen activator in clones of Lewis lung carcinoma and T10 sarcoma. 385 89

We have investigated whether urokinase-type plasminogen activator (u-PA) is present in the mouse in vivo as the proenzyme or as the active enzyme. u-PA in extracts of various murine tissues was of a one-polypeptide chain form with an electrophoretic mobility indistinguishable from purified proenzyme (pro-u-PA), as demonstrated by SDS-polyacrylamide gel electrophoresis under reducing conditions followed by immunoblotting. No 2-chain u-PA was detected in any of the extracts (detection limit 10% of that of one-chain u-PA). In bladder urine more than half of the u-PA was of the one-chain form. Together with previous immunocytochemical studies of the normal murine tissues and studies of the Lewis lung carcinoma, the present results indicate that in these tissues the one-chain proenzyme is the predominant form of u-PA in intracellular stores and for the first time demonstrates that at least in some cases the one-chain form constitutes a sizeable fraction of the u-AP in extracellular fluids in the intact organism.
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PMID:Proenzyme to urokinase-type plasminogen activator in the mouse in vivo. 388 75

The invasively growing and metastasizing Lewis lung carcinoma consistently contained urokinase-type plasminogen activator (u-PA) enzyme activity. When investigated immunocytochemically with antibodies against u-PA, different parts of individual tumors showed a pronounced heterogeneity in staining intensity. Strong staining was found in areas with invasive growth and degradation of surrounding normal tissue, while other areas were completely devoid of staining. Immunoreactivity occurred both with a perinuclear cytoplasmic localization in tumor cells and associated with apparently extracellular material. SDS PAGE of tumor extracts, under both reducing and nonreducing conditions, followed by immunoblotting, showed only one immunocytochemically stainable band with an electrophoretic mobility corresponding to that of purified proenzyme to u-PA, while no two-chain u-PA was detected. This indicates that the major part of the activator in Lewis lung carcinoma is present as one-chain pro-u-PA.
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PMID:Immunocytochemical localization of urokinase-type plasminogen activator in Lewis lung carcinoma. 637 27

Lewis lung carcinoma cells were implanted in the foot-pads of mice and the effects of the plasminogen-plasmin inhibitor tranexamic acid (t-AMCHA) and of the plasminogen activator urokinase on metastasis were examined by electron microscopy. The intravascular tumour cells were not associated with thrombus formation in either control or urokinase-treated mice. Polymerized fibrin deposition around tumour cells and thrombi composed of fibrin and platelets was observed only in the mice given t-AMCHA. This suggests that the inhibition of fibrinolysis by tACC caused fibrin deposition and thrombus formation around intravascular tumour cells, which prevented release of the cells from primary foci to form secondary tumours. On the other hand, fibrinolysis induced by urokinase prevented thrombus formation, and accelerated cell release from primary foci.
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PMID:Ultrastructural study of the effects of tranexamic acid and urokinase on metastasis of Lewis lung carcinoma. 675 64

When Lewis lung carcinoma with low thromboplastic and low fibrinolytic activities was implanted subcutaneously to mice, administration of tranexamic acid inhibited metastasis formation in the lungs. This effect was considered to be mediated by prevention of cell release from the implanted sites. Fibrin formation around tumor cells in the vessels of primary foci was observed in the mice given tranexamic acid. On the other hand, urokinase significantly enhanced pulmonary metastases and many free tumor cells were observed intravascularly in primary foci of the mice given urokinase.
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PMID:Effects of tranexamic acid and urokinase on hematogenous metastases of Lewis lung carcinoma in mice. 718 85

A human epithelial cell line, WISH, and a mouse cell line, LB6-uPAR, transfected with the human urokinase receptor (uPAR), both expressed high affinity uPAR but undetectable levels of urokinase (uPA). In two independent assays, binding of exogenous pro-uPA produced an up to threefold enhancement of migration. The migration was time and concentration dependent and did not involve extracellular proteolysis. This biologic response suggested that uPAR can trigger an intracellular signal. Since this receptor is a glycosyl-phosphatidylinositol-linked protein, we postulated that it must do so by interacting with other proteins, among which, by analogy to other systems, would be a kinase. To test this hypothesis, we carried out a solid phase capture of uPAR from WISH cell lysates using either antibodies against uPAR or pro-uPA adsorbed to plastic wells, followed by in vitro phosphorylation of the immobilized proteins. SDS-PAGE and autoradiography revealed two phosphorylated protein bands of 47 and 55 kD. Both proteins were phosphorylated on serine residues. Partial sequence of the two proteins showed a 100% homology to cytokeratin 18 (CK18) and 8 (CK8), respectively. A similar pattern of phosphorylation was obtained with lysates from A459 cells, a lung carcinoma, but not HL60, LB6-uPAR or HEp3 cell lysates, suggesting that the identified multiprotein uPAR-complex may be specific for simple epithelia. Moreover, immunocapture with antibody to another glycosyl-phosphatidylinositol-linked protein, CD55, which is highly expressed in WISH cells, was ineffective. The kinase was tentatively identified as protein kinase C, because it was inhibited by an analogue of staurosporine more specific for PKC and not by a PKA or tyrosine kinase inhibitors. The kinase was tentatively identified as PKC epsilon because of its resistance to PMA down-modulation, independence of Ca2+ for activity, and reaction with a specific anti-PKC epsilon antibody in Western blots. Cell fractionation into cytosolic and particulate fractions revealed that all four proteins, the kinase, uPAR, CK18, and CK8, were present in the particulate fraction. In vivo, CK8, and to a lesser degree CK18, were found to be phosphorylated on serine residues. Occupation of uPAR elicited a time-dependent increase in the phosphorylation intensity of CK8, a cell shape change and a redistribution of the cytokeratin filaments. These results strongly suggest that uPAR serves not only as an anchor for uPA but participates in a signal transduction pathway resulting in a pronounced biological response.
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PMID:Induction of cell migration by pro-urokinase binding to its receptor: possible mechanism for signal transduction in human epithelial cells. 751 43

The urokinase pathway of the plasminogen activation is involved in proteolytic degradation of various tissues, including dissolution of the extracellular matrix and basement membranes during the process of cancer cell invasion. Recent studies have demonstrated that components of the plasminogen activation system have a prognostic impact in breast-, lung-, colorectal, bladder and gastric cancer. A number of studies, reviewed here, have focused on the role of the plasminogen activation system in different lung cancer types. There seems to be an obvious difference between the expression, localization and prognostic impact of the components of the plasminogen activation system in different lung cancer types. The differences seen could be helpful in understanding the biology of different lung cancer types, and components of the plasminogen activation system may have prognostic relevance and clinical implications in some lung cancer types, even though confirmatory studies are needed.
Lung Cancer 1995 Mar
PMID:The plasminogen activation system and its role in lung cancer. A review. 760 25

Urokinase-type plasminogen activator has been administered by other investigators to patients with small cell carcinoma of the lung (SCCL) in an attempt to induce lysis of fibrin that is known to exist in the connective tissue stroma of this tumour type and that may support tumour growth. To study the fate of infused urokinase in this disease, a biopsy of a scalp metastasis was obtained from a patient with SCCL (entered on a phase I clinical trial of urokinase plus combination chemotherapy) immediately following urokinase infusion during the fourth course of therapy a time when this tumour mass had decreased to approximately 25% of its original size. Immunohistochemical procedures revealed abundant stromal fibrin in accord with previous observations from this laboratory. By contrast, urokinase, that is not a feature of small cell tumour cells, was present on the tumour cells in this specimen. Urokinase infusion was associated with a rapid increase in the amount of this enzyme associated with isolated peripheral blood monocytes. These results are consistent with uptake of infused urokinase onto monocytes and possibly tumour cells. It is postulated that substantial tumour fibrinolysis may not accompany such therapy and that urokinase, or its amino terminal fragment that bears the growth factor domain of this molecule, may bind to and alter the growth of the tumour cells.
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PMID:Studies of possible mechanisms for the effect of urokinase therapy in small cell carcinoma of the lung. 760 74


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