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

A chromogenic substrate assay for the plasminogen activator (PA) activity of Lewis lung carcinoma cells has been developed. The cells were incubated with plasminogen, the activation of which to plasmin was measured by the amidolysis of the chromogenic substrate S-2251. This was routinely performed as a 4h serum-free assay, but a variation lasting 24 h, in medium supplemented with plasminogen-free inhibitor-reduced serum, produced similar results. The assay also detected PA released into the medium. PA activity was proportional to cell density, and the assay was non-toxic to the cells. Assays were performed on cultures derived from primary and metastatic tumours. Host cells were effectively eliminated from such cultures but, because of an initial phase of tumour-cell death, PA assays were not carried out until cultures became established. No consistent difference was detected between PA levels in primary and metastatic cultures. However, these cultures were shown to be atypical of the parent tumour; they grew slowly when reinjected at the primary site, and their metastatic potential was impaired.
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PMID:Plasminogen activator in cultured Lewis lung carcinoma cells measured by chromogenic substrate assay. 719 13

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

The receptor for urokinase-type plasminogen activator (uPAR) is an integral membrane protein that specifically binds urokinase-type plasminogen activator (uPA) and plays a crucial role in cell surface plasmin generation. We have previously found that transforming growth factor-beta, type 1 (TGF-beta 1), increases uPAR gene transcription in the human lung carcinoma cell line A549 and now report that also epidermal growth factor (EGF) and the tumour promoter phorbol 12-myristate 13-acetate (PMA) cause increased uPAR transcription and that PMA and TGF-beta 1 in addition increase the stability of uPAR mRNA, while EGF has no effect on this parameter. All three compounds also increase the uPAR protein level, as measured by cell-binding experiments with radiolabelled ligand. The increase in uPAR protein level was however considerably lower with all three compounds than the increase in mRNA level, suggesting that they also exert a translational or post-translational control. Accompanying the increase in the number of uPAR molecules there was a proportional decrease in their ligand-binding affinity, the mechanism of which is unknown. Platelet-derived growth factor, basic fibroblast growth factor and cyclic AMP analogues did not induce any change in the uPAR mRNA level in A549 cells. Previous studies have shown that expression of uPA and its type-1 inhibitor is regulated by a variety of cytokines in a cell-specific manner. The present study indicates that cytokines in addition influence cell surface plasminogen activation by regulating uPAR expression.
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PMID:Transcriptional and post-transcriptional regulation of the receptor for urokinase-type plasminogen activator by cytokines and tumour promoters in the human lung carcinoma cell line A549. 764 66

Endogenous murine angiostatin, identified as an internal fragment of plasminogen, blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. A recombinant protein comprising kringles 1-4 of human plasminogen (amino acids 93-470) expressed in Pichia pastoris had physical properties (molecular size, binding to lysine, reactivity with antibody to kringles 1-3) that mimicked native angiostatin. This recombinant Angiostatin protein inhibited the proliferation of bovine capillary endothelial cells in vitro. Systemic administration of recombinant Angiostatin protein at doses of 1.5 mg/kg suppressed the growth of Lewis lung carcinoma-low metastatic phenotype metastases in C57BL/6 mice by greater than 90%; administration of the recombinant protein at doses of 100 mg/kg also suppressed the growth of primary Lewis lung carcinoma-low metastatic phenotype tumors. These findings demonstrate unambiguously that the antiangiogenic and antitumor activity of endogenous angiostatin resides within kringles 1-4 of plasminogen.
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PMID:A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. 910 21

To determine the mechanism responsible for the in vivo production of angiostatin that inhibits growth and metastasis in Lewis lung carcinoma (3LL), we implanted 3LL variant cells into the subcutis of syngeneic C57BL/6 mice. The tumors were infiltrated by macrophages and expressed high levels of steady-state mRNA for metalloelastase (MME). Successive passages (more than three) of cultures established from the tumors resulted in complete depletion of macrophages; steady-state MME mRNA, elastinolytic activity, and production of angiostatin (in the presence of plasminogen) were correspondingly reduced. Coculture of macrophages with either 3LL cells or their conditioned media containing granulocyte-macrophage colony-stimulating factor resulted in secretion of MME and production of angiostatin by the macrophages, suggesting that angiostatin is produced by tumor-infiltrating macrophages whose MME expression is stimulated by tumor cell-derived granulocyte-macrophage colony-stimulating factor.
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PMID:Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. 911 23

Activation of protein kinase C- (PKC) and Fos/Jun-dependent signal transduction pathways are thought to be major effects of oncogene action in different tumor systems including human non-small-cell lung carcinoma (NSCLC). We have previously shown that the phorbol ester analogue phorbol-myristate-acetate (PMA), which is a potent activator of PKC, can induce squamous-type cellular differentiation and the expression of proteinases, such as plasminogen activators and pro-cathepsin L, in several NSCLC cell lines. To investigate the PMA-dependent effect on proteinase secretion in more detail, we have now analysed the role of a downstream transmitter of PKC activity in this process, namely Fos, which is part of the AP-1 transcription factor in the nucleus. We transfected a cell line derived from an undifferentiated squamous-cell lung carcinoma with different chimeric fos-estrogen receptor constructs (fos-ER) which makes selective activation of this transcription factor possible. The resulting clones were treated either with PMA as activator of PKC, or with diethylstilbestrol (DES), an estrogen analogue binding to and thereby activating preformed Fos-ER molecules. We show that cells treated with either substance undergo similar phenotypic changes (change from cuboidal to spindle-cell type) and decrease their doubling rates and cloning efficiencies. This is paralleled by the induction of several proteinase genes such as t-PA, urokinase, and pro-cathepsins B and L. Contrary to activated PKC, Fos in this system seems to be unable to initiate terminal squamous-cell differentiation, as assessed by the production of cornified envelopes. It is, however, efficient in the stimulation of neutral or lysosomal proteinase secretion as determined by Western-blot analysis and zymography. This Fos-ER expressing system thus seems to be a valuable tool in the molecular dissection of pathways that lead to the activation and secretion of proteinases in NSCLC cells.
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PMID:Control of proteinase expression by phorbol-ester- and Fos-dependent pathways in human non-small-cell lung-cancer cells. 913 54

The components of the plasminogen activation system have been reported to have prognostic impact in several cancer types, e.g. breast-, colon-, gastric- and lung cancer. Most of these studies have used quantification by enzyme-linked immunosorbent assay (ELISA) on tumour tissue extracts. However, results in non-small cell lung cancer (NSCLC) studies obtained by quantitative ELISA and semiquantitative immunohistochemistry differ. If the prognostic value of the components of the plasminogen activation system is to be exploited clinically in the future, it is important to choose an easy and valid methodology. In the present study we investigated levels of plasminogen activator inhibitor type 1 (PAI-1) and urokinase plasminogen activator receptor (uPAR), as quantitated by ELISA in tumour extracts from 64 NSCLC patients (38 squamous cell carcinomas, 26 adenocarcinomas), and compared them to staining intensity as semiquantitated by immunohistochemistry for PAI-1 and uPAR on corresponding cryostat sections. A significant association (r = 0.49, P < 0.0001) was found between the PAI-1 levels measured by ELISA and semiquantitated by immunohistochemistry. No association was found for uPAR. When correlating levels of PAI-1 and uPAR determined by ELISA and immunohistochemistry, respectively, to survival status, no significant correlation was found for any of the subgroups. At present neither of the methods examined in the present study can be recommended as superior for quantitating PAI-1 and uPAR with the aim of predicting prognosis. In conclusion, a larger comparative study is needed to clarify the relationship between ELISA and immunohistochemical results, before a methodology for clinical use can be chosen in non-small cell lung cancer.
Lung Cancer 1997 Jul
PMID:Levels of plasminogen activator inhibitor type 1 and urokinase plasminogen activator receptor in non-small cell lung cancer as measured by quantitative ELISA and semiquantitative immunohistochemistry. 923 55

Angiostatin, a 38 kDa internal fragment of plasminogen, is an antiangiogenic endothelial cell inhibitor. It regresses several primary and metastatic tumors in mice. To produce recombinant angiostatin for further structural and functional studies, the mouse angiostatin gene preceded by a sequence including a signal peptide of plasminogen was introduced into baculovirus. Recombinant murine angiostatin was purified from the culture medium of angiostatin baculovirus-infected insect cells (yield = 1 mg/liter) with a single-step of lysine-Sepharose chromatography. The angiostatin baculovirus-infected insect cells expressed and secreted a 52 kDa polypeptide that demonstrated all of the biological activities of angiostatin. A partial amino acid sequence of the NH2-terminus of the secreted protein revealed that the signal peptide was recognized and properly cleaved in insect cells. The recombinant murine angiostatin potently inhibited the proliferation of bovine capillary endothelial cells in vitro (half maximal inhibition = 50 ng/ml) and suppressed the growth of primary Lewis lung carcinoma in vivo (6 mg/kg/day, T/C = 0.08).
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PMID:Suppression of tumor growth with recombinant murine angiostatin. 924 7

Plasminogen activation has been proposed to play a critical role in cancer invasion and metastasis. The effects of complete ablation of plasminogen activation in cancer was studied by inoculation of a metastatic Lewis lung carcinoma expressing high levels of plasminogen activator into plasminogen-deficient (Plg-/-) mice and matched control mice. Primary tumors developed in all mice with no difference in the rate of appearance between Plg-/- and control mice. However, the primary tumors in Plg-/- mice were smaller and less hemorrhagic and displayed reduced skin ulceration. In addition, dissemination of the tumor to regional lymph nodes was delayed in Plg-/- mice. Surprisingly, no quantitative differences were observed in lung metastasis between Plg-/- and control mice. In addition, Plg deficiency was compatible with metastasis of the primary tumor to a variety of other organs. Nevertheless, Plg-/- mice displayed a moderately increased survival after primary tumor resection. These findings suggest that plasmin-mediated proteolysis contributes to the morbidity and mortality of Lewis lung carcinoma in mice, but sufficient proteolytic activity is generated in Plg-/- mice for efficient tumor development and metastasis.
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PMID:Growth and dissemination of Lewis lung carcinoma in plasminogen-deficient mice. 937 63

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-L-cysteine, D-penicillamine, captopril, L-cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.
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PMID:The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. 938 Jul 26


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