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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This manuscript reviews the molecular aspects of tumor cell invasion of extracellular matrix. The changes in cell:substrate and cell:cell receptors that characterize motile cells are discussed for their importance not only in mediating invasive cell behavior, but also as diagnostic markers for invasive potential. Autocrine motility and scatter factors probably have key roles in initiating migratory behavior, while specific and non-specific extracellular matrix alterations can facilitate cell locomotion. The manuscript reviews reported changes, such as induction of cell motility, matrix degrading enzymes, and invasive/metastatic potential, which can follow transfection with ras oncogenes, and details the key roles of metalloproteinases, heparanase, and plasminogen activator in matrix degradation. Enzymatic inhibitors of initial steps in extracellular matrix degradation, such as rTIMP, and synthetic blockers of adhesive steps in tumor cell invasion represent types of reagent with potential as anti-metastatic agents. Their potential usefulness may be increased if they can be incorporated into a novel, long-term, non-traditional delivery system.
Cancer Metastasis Rev 1990 Sep
PMID:Cell-matrix interactions during tumor invasion. 225 11

Treatment of tumor cells that have little if any metastatic potential with certain drugs that have little or no mutagenic activity has been found to result in marked phenotypic alterations of the cells, including development of a metastatic potential. We found that polar compounds and butyric acid, which are known to alter the expressions of normally silent genes, enhanced the lung-colonizing ability of cloned low-metastatic Lewis lung carcinoma cells. This change was accompanied by increases in the activities of degradative enzymes such as glycosidases, cathepsin B, and plasminogen activator; adhesion of the cells to culture dishes, monolayers of endothelial cells, and a subendothelial matrix; and homotypic aggregation. The effects of these drugs in enhancing the lung-colonizing ability of the cells was found to be reversible, suggesting that it was due to epigenetic alterations. Other investigators have shown that treatment of nonmetastatic tumor cells with 5-azacytidine, which causes hypomethylation of DNA and activates normally silent genes, results in the emergence of a small number of clones with a heritable but unstable metastatic phenotype. These findings suggest that epigenetic mechanisms are involved in rapid cellular phenotypic diversification and tumor progression.
Cancer Metastasis Rev 1986
PMID:Modification of the metastatic potential of tumor cells by drugs. 243 28

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

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

Expression of plasminogen activator (PA) activity may be an important factor in the ability of tumour cells to metastasize; however, not all metastatic cells produce detectable PA activity. Conditioned culture media from revertant metastatic clones of cells derived by fusion of metastatic and non-metastatic rat mammary adenocarcinoma cells were found to contain a potent inhibitor of PA. This inhibited thrombin, human urokinase (UK) and tumour-derived PA, but not plasmin or trypsin. Inhibition was still obtained after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate (SDS-PAGE) of mixtures of PA and inhibitor, followed by development of PA activity on fibrin overlays. The PA inhibitor eluted from Sephadex G-200 over a broad M.wt. range (35,000-80,000) and was inactivated by heating to 70 degrees for 30 min. The appearance of inhibitory activity in the culture media was time-dependent and could be reduced by incubation of cells with cycloheximide. Because of these findings, the possible presence of inhibitors should be considered in investigations into the role of PA in the metastatic process.
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PMID:An inhibitor of plasminogen activator produced by tumour cell fusion hybrids. 293 23

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

Prediction of early metastases in individual patients has been attempted by combined evaluation of a battery of recognised parameters such as blood vessel invasion (BVI) of tumor cells, Barr body frequency (BBF), plasminogen activator (PA), collagenase, estradiol receptors (ER), progesterone receptors (PgR), and peroxidase activity (PRA) in 18 malignant and 3 benign (control) breast tumors. Since breast tumor cells spread through the blood vessels, the cases were divided into BVI (+) and BVI (-) groups. Results show that in the former group, all the cases had poor prognosis and two even had distant metastases within one year. In BVI (-) group, 9 out of 12 appeared to have good prognosis.
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PMID:Prediction of biological behaviour of human breast cancer using multiple parameters. A preliminary study. 299 51

Activated ras oncogene transfection into suitable recipient cells has been shown to induce the metastatic phenotype (Thorgeirsson, et al., Mol. Cell. Biol., 5: 259-262, 1985). We have used this model system to study the correlation of basement membrane collagenolysis with metastatic propensity. The c-Ha-ras oncogene alone, or combined with v-myc, transfected into early passage rat embryo fibroblasts, induce these cells to secrete high levels of type IV collagenolytic metalloproteinase and to concomitantly exhibit a high incidence of spontaneous metastases in nude mice. Cotransfection of c-Ha-ras plus the adenovirus type 2 E1a gene yields cells which are highly tumorigenic but nonmetastatic and fail to produce type IV collagenase. This effect is due to a suppression of collagenase elaboration, not increased production of a collagenase inhibitor, and not decreased production of a collagenase activator. The characteristics of the collagenase are identical to tumor type IV collagenase described previously. The nonmetastatic cells which failed to produce type IV collagenase retain the ability to secrete high levels of plasminogen activator. Transfection with the protooncogenic forms of Ha-ras or mos, or spontaneous transformation of NIH 3T3 cells or chemical transformation of BALB 3T3 cells yields cells which fail to produce collagenase, are tumorigenic, but totally nonmetastatic. These data support a biochemical linkage of type IV collagenase expression with the metastatic phenotype in this rodent system.
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PMID:Secretion of type IV collagenolytic protease and metastatic phenotype: induction by transfection with c-Ha-ras but not c-Ha-ras plus Ad2-E1a. 302 10

The plasminogen activator content of surgically excised gynecological tumors was measured with an azocaseinolytic assay. Ovarian (10 primary, 18 metastases) and uterine (5 primary and 6 metastases) tumors showed similar mean activator activities (21 CTA units/g tissue) mainly of the urokinase type with similar wide variations in each group. About 44% (14 of 32) of the tissues placed in short term organ culture were shown to produce and secrete urokinase activity. Results of the plasminogen activator activity found in the patient tumors or produced by the tumors during culture in the absence or presence of some drugs indicate a wide range of individual variations in sensitivity to these agents.
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PMID:Plasminogen activator content of gynecological tumors and their metastases. 310 49

Changes in the plasma levels of components of the fibrinolytic system have been investigated in 80 patients suffering from gastrointestinal carcinomas. Urokinase antigen (RIA), tissue-type plasminogen activator antigen (ELISA) and plasminogen activator inhibitor (functional assay) were determined. Patients with pancreatic and colorectal carcinoma and metastases as well as those without metastases revealed significantly increased plasma urokinase levels. Those with gall bladder or gastric carcinoma did not show significantly elevated urokinase antigen levels compared to age-matched controls. Determination of tissue-type plasminogen activator antigen in all four carcinoma groups did not reveal significant differences when compared to an age-matched healthy control group. The concentrations of plasminogen activator inhibitor were significantly increased in all carcinoma groups; there being no differences between the patient groups with or without metastases. No correlations between the different parameters of the fibrinolytic system could be obtained.
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PMID:Pattern of fibrinolytic parameters in patients with gastrointestinal carcinomas. 310 63


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