Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-type 1 (PAI-1) was identified in extracts of Lewis lung carcinoma, and its immunohistochemical localization was studied together with that of urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators. All primary tumors (n = 11) contained heterogeneously distributed immunoreactivity against each of the three components. Most often, areas that contained u-PA immunoreactivity also contained PAI-1 immunoreactivity. However, several areas showed a strong u-PA immunoreactivity, but no or low PAI-1 immunoreactivity. The latter staining pattern was only found in peripheral areas, and usually in areas with histological signs of tissue destruction. Lung metastases always contained u-PA immunoreactivity, while PAI-1 immunoreactivity was found in most, but not all, metastases. t-PA immunoreactivity was found in a few scattered tumor cells, in primary carcinomas as well as metastases. Controls that included absorption with highly purified antigen preparations and immunoblotting, indicated that all the immunoreactivity represented genuine PAI-1, u-PA and t-PA, respectively. The results are consistent with an assumption that the plasminogen activation system, and particularly u-PA and PAI-1, plays a role in regulation of breakdown of extracellular matrix proteins during invasive growth in this carcinoma.
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PMID:Plasminogen activator inhibitor-type 1 in Lewis lung carcinoma. 210 45

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

Prognostic variables in breast cancer are urgently needed to individualize adjuvant cytotoxic therapy, especially in those patients where metastases in the lymph nodes have not been detected (node-negative disease). So far histomorphological criteria, the determination of receptors for steroid hormones or EGF (epidermal growth factor), the protease cathepsin D or DNA-ploidy are used to distinguish between low- and high-risk patients. High-risk patients have a higher incidence of recurrences and/or shorter overall survival after surgery of the primary tumour than low-risk patients. High-risk patients (node-positive; hormone-receptor-negative) would receive adjuvant hormone therapy or chemotherapy. In the node-negative patient, adjuvant therapy is only recommended if a high content of cathepsin D and aneuploidy of the tumour (or high S-phase in diploid tumours) has been diagnosed. Determination of cathepsin D in tumour extracts as a variable in breast cancer patients is based on the fact that invasion and metastasis is correlated with elevated levels of tumour-associated proteases such as cathepsins B and D, collagenase IV and plasminogen activators. The urokinase-type plasminogen activator (uPA) which is secreted by tumour cells as an enzymatically inactive proenzyme (pro-uPA) seems to play a key role in mediating tumour cell invasion in cancer tissues. Receptor-bound uPA converts enzymatically inactive plasminogen into the serine protease plasmin which then degrades the extracellular matrix surrounding the tumour cells (tumour stroma). We localized pro-uPA/uPA immunohistochemically in paraffin-embedded formalin-fixed breast cancer tissue sections. Pro-uPA/uPA was detected in the cytoplasm and on the plasma membrane of the tumour cells reflecting receptor-bound pro-uPA/uPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumour-associated fibrinolysis: the prognostic relevance of plasminogen activators uPA and tPA in human breast cancer. 213 50

The effects of dexamethasone on protein synthesis were studied in human fibrosarcoma (HT-1080) cells. Dexamethasone induced a new protein of 46 kD which was rapidly secreted into the medium, while neither progesterone nor estradiol would induce the synthesis of this protein and only a small increase in its amount could be seen in the presence of testosterone. The 46 kD protein was partially purified by ammonium sulfate precipitation and gel filtration and mouse monoclonal antibodies to it were produced in mouse hybrid cells. Altogether 13 positive clones were found, of which six reacted only with native and seven reacted with the unreduced 46 kD protein in Western blotting. It was possible by using polyclonal antibodies to plasminogen activator inhibitor type I (PAI-1) and purified plasminogen activator inhibitor type I to confirm that the 46 kD protein purified and characterized here was PAI-1. In addition, the 46 kD protein clearly inhibited plasminogen activation, thus further confirming that protein isolated was an inhibitor of plasminogen activator. Since the induction of PAI-1 by dexamethasone was very extensive, it is possible that glucocorticoids regulate proteolysis and fibrinolysis in vivo by increasing the amount of the inhibitor of plasminogen activator and thus preventing the activation of plasminogen to plasmin. The reduction of activation of plasminogen to plasmin by glucocorticoid-induced inhibitor could be of great importance, e.g., in various blistering diseases, in metastases from malignant cells, and in the migration of inflammatory cells.
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PMID:Dexamethasone-induced plasminogen activator inhibitor: characterization, purification, and preparation of monoclonal antibodies. 214 2

Herpes simplex virus type 2-transformed hamster embryo fibroblasts (333-8-9 cells) produce increased plasminogen activator (PA) compared with normal hamster cells. These cells produce undifferentiated fibrosarcomas at the inoculation site in newborn hamsters, and metastasize to the lungs. Using a direct PA assay, in which 125I-labeled plasminogen is cleaved, the optimum pH and osmolarity for detection of the 333-8-9 extracellular PA were pH 8.9 and approximately 150 mOsmol. Secretion of enzyme did not vary significantly on a per cell basis over cell densities from 0.1 to 8.0 X 10(7) cells/T-75 cm2 flask. This assay demonstrates that the 333-8-9 cells produce at least 20-fold greater levels of PA than normal cell counterparts. Based on the molecular weight (50-58 kDa) of secreted 333-8-9 cells PA and lack of fibrin stimulation, we conclude that it is a urokinase type PA. Subclonal lines of the 333-8-9 cells, selected for an increased PA phenotype were stable in culture, more tumorigenic and probably more metastatic. Correlation of these two events was examined by passaging 333-8-9 cells in vivo to select for greater tumorigenic potential and then determining the production of PA by the in vivo-derived sublines. The metastatic potential of the resulting cells was heterogeneous. Increased PA production upon increased passage in vivo did not always occur, whether the cells were passaged as subcutaneous tumors or as ascites tumors. Thus, while enzyme production correlated with tumorigenicity when selecting cells for an increased protease phenotype, this correlation was not observed when selecting for in vivo tumorigenicity. The results suggest that increased ability to make PA represents only one of multiple selective advantages for tumor growth.
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PMID:Phenotypic properties of herpesvirus-transformed cells with high tumorigenic and metastatic ability. 215 88

Using B16 F10 murine melanoma cells and sublines generated from the JB/MS melanoma which exhibit various degrees of melanogenesis, the relationships among differentiation, tumorigenicity, and metastatic potential were examined. The effect of melanocyte-stimulating hormone (MSH), which specifically stimulates differentiation of melanocytes, was also studied. All melanoma lines tested were capable of growing as experimental pulmonary metastases but, surprisingly, the undifferentiated and amelanotic JB/MS-w cells failed to grow as primary subcutaneous tumors. JB/MS-w cells, which had few surface MSH receptors, did not respond to MSH with an increase in melanin production, unlike the other cell lines. Although in vitro treatment with MSH did not change the rates of growth of primary tumors by these cell lines, such treatment decreased the number of pulmonary metastases from B16 F10, JB/MS cells, JB/MS-b1 cells and JB/MS-w cells. Conversely, MSH treatment significantly increased the rates of pulmonary metastases from JB/MS-p cells. The expression of surface melanoma antigens, urokinase-type plasminogen activity and susceptibility to natural killer cells were examined. MSH did not significantly alter surface melanoma antigen expression, but increased the natural killer cell susceptibility of B16 F10, JB/MS and JB/MS-b1 cells, cells which possess abundant surface MSH receptors. There was an inverse correlation between differentiation (pigmentation) and proliferation in vitro, and the more pigmented melanoma cells (B16 F10, JB/MS and JB/MS-b1) expressed relatively lower levels of class-I MHC, relatively higher levels of class-II MHC and the highest metastatic capacity. These results demonstrate that MSH possesses the capacity to regulate not only melanogenesis, but also other factors critical to the metastatic growth of the cells.
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PMID:Differentiation and the tumorigenic and metastatic phenotype of murine melanoma cells. 216 2

Components of the plasmin system were comparatively studied in lymph node metastases and corresponding primary tumors by immunofluorescence. Primary tumors, all adenocarcinomas, originated from large bowel (N = 12) or breast (N = 10). We used antisera against plasminogen (Pg), plasminogen activators (PA) such as urokinase (UK) and tissue type PA (t-PA), plasmin inhibitors such as alpha 2 anti-plasmin (alpha 2AP) and alpha 2 macroglobulin (alpha 2M), plasmin-alpha 2 anti-plasmin complex (PAPC). Positivity with anti-PAPC serum was considered as proving that plasmin was formed by Pg activation. The following results were obtained. Breast adenocarcinomas were more strongly stained than colorectal adenocarcinomas using antisera against Pg, PAPC and PA, while their reactivity was much weaker with antisera against both plasmin inhibitors. Lymph node metastases from colorectal adenocarcinomas were more strongly stained than primary tumors using antisera against PAPC and PA. Reactivity with anti-Pg was similar, while that with antisera against plasmin inhibitors was much weaker. Metastasis from breast adenocarcinomas, on the average, showed the same type of staining as primary tumors. However, there was a slight decrease in reactivity with anti-Pg and PAPC in metastases. Tumor cells invading lymphoid areas in metastatic lymph nodes were often strongly labeled using antisera against Pg and UK. Staining was less strong or less frequent using antisera against PAPC and t-PA. These results favor the role of plasmin in the degradation of basement membrane and connective tissue components, thus implicating it in the invasiveness of tumor cells, at least in most primary tumors and metastases.
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PMID:The plasmin system in human adenocarcinomas and their metastases. A comparative immunofluorescence study. 243 33

To assess the postulated correlation between plasminogen activators (PAs) and malignancy, we determined the mRNA content for urokinase-type (u-PA) and tissue-type (t-PA) enzymes in a prospective series of 29 primary lung and 27 primary breast carcinomas. Dot blots of total RNAs were hybridized with appropriate cRNA probes under conditions that allow quantitative measurement of the mRNA level for each PA. Most tumors (43 of 56) had a u-PA mRNA content higher than the mean + 1 SD of nonmalignant tissue counterparts. A large, 4- to 20-fold, increase in u-PA mRNA content was demonstrated in 14 of 29 lung carcinomas and in 10 of 27 breast carcinomas. A statistically significant correlation (Fisher's test, P = 0.007) was found between elevated u-PA mRNA content in lung carcinomas and the presence of regional lymph node metastases. These results are consistent with a role for u-PA in tumor invasiveness and metastatic propensity and may have important prognostic and therapeutic implications.
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PMID:Increase of urokinase-type plasminogen activator gene expression in human lung and breast carcinomas. 244 May 56

We employed a sensitive in vitro amnion invasion assay to examine the relationship of the invasive ability of numerous mouse and human tumor cell lines and their variants to their ability to spontaneously or artificially metastasize; we also studied possible enzymatic activities involved in the in vitro invasion process. In vitro invasive ability of tumor cells was strongly correlated with spontaneous metastatic ability from the subcutaneous site, regardless of the ability of tumor cells to form artificial metastases when introduced intravenously. However, normal nontumorigenic human trophoblast cells were also highly invasive. Various collagenase inhibitors totally abrogated amnion penetration by all invasive cells; various inhibitors of plasmin, plasminogen, and plasminogen activators prevented invasion in most, but not all, cases. Thus, amnion penetration provides a rigorous test for tumor cell invasiveness required for spontaneous metastasis in vivo, and invasiveness is strongly dependent on metalloproteinase activity, which usually follows plasmin activation.
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PMID:Mechanisms of cellular invasiveness: a comparison of amnion invasion in vitro and metastatic behavior in vivo. 254 Dec 59

The levels of several tumor associated proteases, including plasminogen activators (PA), are elevated in many malignant tumors compared to their benign tumor counterparts. Extracellular matrix degradation mediated by PA may facilitate tumor cell invasion and metastasis. To assess whether PA content correlates with the aggressive phenotype in prostate cancer, we studied these activators in the PC-3 human prostate cell line and PC-3CALN, an aggressive in vivo derived variant cell line. Enzymatic assays using H-D-val-leu-lys-pNA (S-2251) as substrate and peroxidase-anti-peroxidase immunohistochemical techniques were used. In an in vitro chemoinvasion assay, the PC-3CALN variant cell line demonstrated significantly greater invasive behavior than the unselected, parental PC-3 line. The activity of PA secreted by PC-3CALN cells was 3.5 times greater than that of PC-3 cells (p less than 0.01). PC-3 metastases obtained following intrasplenic injection of PC-3 cells had greater PA activities than the corresponding primary tumors. Immunohistochemical studies of PC-3 tumors demonstrated preferential localization of urokinase-type PA to areas of apparent tumor cell invasion. These data suggest a correlation between PA and the aggressive phenotype in this model of human prostate cancer. PA, in particular u-PA, may play a role in the migration and invasion of prostate cancer cells and provide a marker of the aggressive phenotype.
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PMID:Plasminogen activators in human prostate cancer cell lines and tumors: correlation with the aggressive phenotype. 265 23


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