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)

Malignant cells have the ability to invade and metastasize in great part because they secrete proteolytic enzymes. In order to investigate if the abnormal proteinase/antiproteinase balance of cancer bearing patients changes when the malignant tumor is destroyed, we studied 50 patients with invasive carcinoma of the cervix and 33 healthy women as a control group. Patients with cancer were treated with radiation according to the protocols of our hospital. The following serum determinations were performed: plasminogen activators (PA), cathepsin B (CB), antiproteinase alpha-1-antitrypsin (A1AT), trypsin inhibitory capacity (TIC) and antiproteolitic activity ratio (AAR), all of them before and after treatment. Serum proteolytic activity was elevated manyfold in all patients with invasive tumor as well A1AT. The antiproteolytic activity however, was significantly reduced to about 50% of its normal value in the same group of patients. In patients with good response to radiotherapy (tumor necrosis) a great reduction of proteinase activity as well as a recovery to normal of the AAR was observed. Contrary, in those with a poor response after radiation, proteolytic activity remained elevated and AAR diminished. It is concluded that serum PA, CB, A1AT and AAR values can be precise indicators of the presence of malignancy. These tests might be also of help for improving follow-up studies and for better prognostic estimates.
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PMID:[Protease-antiprotease balance in patients with invasive carcinoma of the cervix and uterus before and after radiotherapy]. 278 98

Tumor cells from a murine fibrosarcoma (FSa) produce plasminogen activator (PA), a protease that converts the zymogen plasminogen into the trypsin-like enzyme plasmin. Several studies indicate that tumor cell invasion is accompanied by proteolysis and that PA, generated by highly malignant cells, is by far the most ubiquitous protease associated with malignant transformation. Subpopulations of FSa cells were isolated by using density gradient centrifugation and the ability of these populations to form lung colonies was compared with their associated levels of PA production. Five populations of cells from a murine fibrosarcoma were separated in continuous gradients of Renografin in the density range 1.05-1.18 g/cm2. The PA activities of an unseparated control cell lysate and cell lysates of the five separated populations were determined by using [125I]fibrin as a substrate in a reaction between cell lysate and plasminogen. The assay was based on the release of digested [125I]fibrin from the surface of Petri dishes into the supernatant solution, and the results were expressed as a percentage of the total radioactivity. The cell populations collected at densities of 1.05 and 1.09 (B1, B2) were the more clonogenic with relative clonogenic efficiencies of 2.6 and 3.3 times that of the unseparated tumor population, respectively. Analysis for PA demonstrated that enzyme formation was restricted mostly to these two populations. Cells from populations 4 and 5 did not secrete increased amounts of PA and had reduced clonogenic efficiencies compared with the unseparated FSa control population. These results are consistent with the hypothesis that PA activity is correlated with the clonogenicity of tumor subpopulations isolated from a heterogeneous and complex tumor system such as the FSa.
Clin Exp Metastasis
PMID:Plasminogen activator activity in clonogenic cell populations separated from a murine fibrosarcoma. 292 Apr 77

We have carried out enzymatic, immunofluorescence, and surface iodination studies which show that B16 melanoma cells express the single chain form of the urokinase type plasminogen activator (uPA) on their cell surface, and that these cells are capable of plasminogen-dependent fibronectin degradation. The significance of the expression of surface single-chain uPA and uPA activity to the metastatic process was examined by preincubating melanoma cells with uPA modulating agents followed by i.v. injection of the cells into mice and enumeration of pulmonary nodules 17 days later. B16 cells that had been pretreated with anti-uPA immunoglobulins that were inhibitory to uPA activity invariably showed significantly decreased numbers of metastases compared to controls. On the contrary, pretreatment with plasmin, which is not only the product of the uPA catalyzed reaction but is also able to convert single-chain uPA to uPA, significantly increased the numbers of metastases. Control treatments, which included normal rabbit and mouse immunoglobulins, monovalent noninhibitory anti-uPA Fab fragments, and various monoclonal and polyclonal antibodies directed against other B16 cell surface antigens, did not affect the metastatic potential of the cells. Divalent inhibitory anti-uPA F(ab)2 fragments, on the contrary, inhibited metastasis as efficiently as intact IgG. The results support the hypothesis that proteolysis of extracellular matrix components by cell surface-localized uPA may be a critical step during the process of tumor cell invasion and metastasis.
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PMID:Modulation of metastatic potential by cell surface urokinase of murine melanoma cells. 296 89

Conditioned media from explants of human colorectal and gastric tumors in short-term organ culture were analysed for plasminogen activator activity, activity toward the synthetic urokinase substrate, Spectrozyme-UK, and for the presence of urokinase antigen using monospecific goat antibody, by enzyme-linked immunosorbent assay. Comparisons were made between primary tumors, adjacent normal mucosa and metastatic lesions. These analyses were carried out on unfractionated culture fluids and on fractions obtained by fast protein liquid chromatography separation using Superose 6 gels. Plasminogen activator activity, tested by azocaseinolysis in the presence of added plasminogen, was restricted to peaks of 55 kD and 155 kD. These were of the urokinase type as shown by specific immunoinhibition and by absorption by an antiurokinase antibody-Affigel 10 column. Spectrozyme-UK, in addition to these peaks, detected a series of higher molecular weight activities, the largest of which appeared in the void volume, and were therefore of greater than 10(6) molecular weight. These activities were greatly increased by inclusion of trace plasmin indicating that these components were mostly in their proenzyme forms. The characteristics of these very large enzymes were similar to those isolated earlier from a human lung cancer cell line. Comparison of the primary and metastatic tumors confirmed earlier observations showing that urokinase secretion by the metastatic tumors was greatly reduced in comparison with the primary tumors: in the colon carcinomas it was 10 per cent of the value for the primary, in the gastric tumors 3 per cent, whether means or medians were compared (P less than 0.0001). This large difference was characteristic only of plasminogen activator secretion assayable by azocaseinolysis; activities toward Spectrozyme-UK, and antigen reacting with anti-urokinase antibody, were considerably less different in the two groups. In individual tissues, no correlation was found between the amount of extractable plasminogen activator and amounts secreted, or between the latter and the amount of lactic acid released. It is postulated that the greatly reduced plasminogen activator secretion by explants of metastatic tumors may be a phenotypic characteristic of distinct advantage for cancer cells destined to initiate metastatic foci, and may contribute to the ability of circulating cancer cells to lodge in the blood vessels of the target organ.
Clin Exp Metastasis
PMID:Secretion of plasminogen activators by human colorectal and gastric tumor explants. 340 59

The parent R3230 AC rat mammary carcinoma cell line and the two variant cell lines, R3230 AC MET and R3230 AC LR, differ with respect to their abilities to invade bony matrices and to form lung colonies (experimental metastases). Both the R3230 AC and the R3230 AC MET, a cell line selected in vivo for enhanced metastatic capability, express high potentials for invasiveness and lung colony formation, while the Con A- and WGA-resistant R3230 AC LR cell line grows expansively at the periosseus implantation site and is unable to form lung colonies after intravenous inoculation. The abilities to invade bone and to metastasize to the lung are well correlated with the fibrinolytic activity and the production of urokinase-type plasminogen activators. The contribution of plasminogen activators to invasiveness and metastasis has been ascribed to its role in the fibrinolytic and collagenolytic (i.e., activation of latent collagenase) cascades.
Invasion Metastasis 1987
PMID:Correlation of fibrinolytic activity with invasion and metastasis of R3230 AC rat mammary carcinoma cell lines. 359 83

The immunoperoxidase technique, using antibodies against human urinary urokinase (Mr 55,000), was used for the localization of this enzyme in histological preparations of human colon tumors and normal colon tissue. The localization of tissue (vascular) activator was also investigated using antibodies against enzyme purified from human malignant melanoma. Both the "indirect method" and the peroxidase-antiperoxidase technique were found to be useful. Urokinase-reactive material was found in all tissues examined (33 primary cancers, 11 metastases, and 8 adenomas). In the normal colon, urokinase was found only in some of the goblet cells of the mucosal epithelium. In colon cancer, diffuse specific staining was observed in the cytoplasm, but the most intense staining was localized at the edge of the cancer cells bordering the lumen of the glands. In some cases, intense supranuclear staining could be observed in a location corresponding to the Golgi apparatus. In a few instances, urokinase could be seen associated with fibroblasts near the advancing front of an invading tumor. Adenoma, a benign tumor but often a precursor of cancer, also showed the presence of urokinase. Most significant were the observations showing that, in regions of the mucosal glands where normal epithelial cells were abruptly replaced by cancer cells, the appearance of cytoplasmic urokinase showed strict and exclusive association with the malignant cells, and the same was the case in transitions from normal epithelium to adenoma. In contrast to urokinase, tissue plasminogen activator was not associated with cancer cells, but was consistently present in the stroma which separates the cancer glands and was localized in the endothelium of the blood vessels. This visual evidence was supported by results of extraction of plasminogen activators from tumors, and from the separated mucosal and submucosal layers of the normal colon of the same patients, which showed that urokinase is most abundant in the tumor tissue and least abundant in the submucosa, while tissue activator is most prevalent in the well-vascularized mucosa and submucosa and scarce in the usually poorly vascularized adenocarcinomas.
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PMID:Localization of plasminogen activators in human colon cancer by immunoperoxidase staining. 388 45

The plasminogen activator content of extracts of 14 prostatic carcinomas and the respective bone metastases was determined and found to be at an average 1.5 times higher in the extracts from bone metastases than in the primary tumors. Furthermore, the relative contribution of the two known types of plasminogen activators, urokinase-type (u-PA) and tissue-type (t-PA), was evaluated using specific antibodies. About 70% of the plasminogen activator activity in the primary tumors was inhibited by anti-urokinase IgG, whereas the same antibody nearly completely inhibited the plasminogen activator activity in extracts from bone metastases. Using antibodies against t-PA about 30% of the plasminogen activator activity could be quenched in extracts of primary tumors but less than 10% in extracts of bone metastases. Further studies revealed that the increased amount of u-PA in extracts of bone metastases is not caused by different extractability but is also reflected by a relative increase in the amount of u-PA demonstrable by immune histochemical techniques using anti-urokinase IgG. Upon purification, the predominant plasminogen activator from extracts of bone metastases could also be identified physicochemically as urokinase.
Invasion Metastasis 1985
PMID:Plasminogen activator activity in bone metastases of prostatic carcinomas as compared to primary tumors. 406 6

Components of the blood fibrinolytic system were measured in 18 patients with hepatic cirrhosis, in two patients with acute hepatic necrosis, and in 10 patients with hepatic metastases. The frequency of an elevation of plasminogen activator and a reduction in plasminogen in hepatic cirrhosis has been confirmed. Patients with compensated cirrhosis had low levels of the serum inhibitor of plasminogen activation while those with severe hepatic insufficiency or coma due to cirrhosis or hepatic necrosis had elevated levels. The presence of hepatic metastases was associated with reduced plasminogen activator levels and an increase in the fibrinogen concentration.
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PMID:The fibrinolytic enzyme system in hepatic cirrhosis and malignant metastases. 513 89

The effect of the presence of one cell type on the plasminogen activator activity of another cell type was studied. The cell types, AC and D, were isolated from a rat neuroblastoma (I. Imada and N. Sueoka, Dev. Biol. 66:97-108, 1978). AC cells are stem cells capable of multipotential differentiation in vitro and have little or no cell-associated plasminogen activator activity. D cells are tumorigenic and have high levels of cell-associated plasminogen activator activity. When AC cells were cocultivated with D cells, the plasminogen activator activity of the D cells was dramatically inhibited. The presence of as few as 1,250 AC cells inhibited 70% of the plasminogen activator activity of 20,000 D cells, as determined by a highly quantitative assay. The amount of inhibition by AC cells was proportional to the number of AC cells present. At increasing numbers of AC cells and a constant number of D cells, the Vmax for the activation of plasminogen proportionately decreased and the Km remained constant, implying that AC cells did not alter the structure or concentration of plasminogen. Inhibition was not mediated by a soluble inhibitor secreted by AC cells. Rather, attachment of AC cells adjacent to D cells, i.e., cell-to-cell contact, seemed to be required for inhibition. The substratum-attached material of AC cells, that which remained on the microwell surface after removal of AC cells with EDTA, inhibited D cell plasminogen activator activity. If plasminogen activator activity is involved in metastasis, then regulation of the plasminogen activator activity of one cell type by another cell type may be involved in determining which cells in a tumor can metastasize and where secondary tumors can arise.
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PMID:Modulation of cell-associated plasminogen activator activity by cocultivation of a stem cell and its tumorigenic descendant. 653 59

Plasminogen activators (PAs), a family of proteases active in blood coagulation, may play an important role in cancer. Indeed, blood coagulation disorders, such as altered fibrinogen and fibrin metabolism and increased incidence of vascular thrombosis, are common in patients with advanced malignant disease. Different types of human tumors are known to contain high levels of PA. The isoelectric focusing patterns of the PAs present in tumors and plasma from patients with breast cancer were compared with those of purified human urokinase and melanoma tissue PA. The pattern of isoelectric molecular forms of PA active at pH 8 showed two groups of several bands: in plasma from tumor-bearing patients and controls, these groups were in the pl ranges of 6.6 to 6.8 and 8.0 to 8.5; in mammary adenocarcinoma tissue, the ranges were 6.8 to 7.9 and 9.0 to 9.4. These patterns were different from those obtained with purified markers; the latter were 5.8 to 9.4 and 5.9 to 7.6 for purified human urokinase and melanoma plasminogen tissue activator, respectively. PA activity in tumor-bearing patients was very high in malignant tissue and, on the contrary, very decreased in plasma; this latter decrease was correlated with the presence of metastases in the axillary lymph nodes. These results suggest that the high PA activity in the tumor tissue might participate in the destruction of the peritumoral tissue, thus allowing its invasion by tumor cells, whereas the low activity of PA in the plasma might increase plasma fibrin, reflecting thus an early disorder in blood coagulation which would enhance the formation of metastases.
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PMID:Relationship between multiple forms of plasminogen activator in human breast tumors and plasma and the presence of metastases in lymph nodes. 653 66


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