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)

A large body of evidence has been assembled to indicate the substantial importance of proteolytic processes in various physiological functions. It has recently become clear too that endo-acting peptide bond hydrolases provisionally characterized and classified at present as serine, cysteine, aspartic and metallo together with unknown catalytic mechanism proteinases sometimes act in cascades. They are controlled by natural proteinase inhibitors present in cells and body fluids. In the first part of the present monograph the author was concerned to present an overview on the morphological and physiological approach to localization, surveying reaction principles and methods suitable for visualization of proteolytic enzymes and their natural and synthetic inhibitors. In the second part the roles played by proteinases have been summarized from the point of view of cell biology. The selection of earlier and recent data reviewed on the involvement of proteolysis in the behavior of individual cells reveals that enzymes, whether they be exogeneous or intrinsic, can be effective and sensitive modulators of cellular growth and morphology. There exists a close correlation between malignant growth and degradation of cells. It appears likely that as yet unknown or at least so far inadequately characterized factors that influence the survival or the death of cells may turn out to be proteinases. The causal role of extracellular proteolysis in cancer cell metastases, in stopping cancer cell growth and in cytolysis remains for further investigated. Ovulation, fertilization and implantation are basic biological functions in which proteolytic enzymes play a key role. The emergence of new approaches in reproductive biology and a growing factual basis will inevitably necessitate a reevaluation of present knowledge of proteolytic processes involved. The molecular aspects of intracellular protein catabolism have been discussed in terms of the inhibition of lysosomal and/or non-lysosomal protein breakdown. Peptide and protein hormone biosynthesis and inactivation are still at the centre of interest in cell biology, and a number of proteinases have been implicated in both processes. A number of conjectures partly based on the author's own work have been discussed which suggest the possibility of the involvement of proteolysis in exocytosis and endocytosis. The author's optimistic conclusion is that through the common action of biochemists, cell biologists, cytochemists, and pharmacologists the mystery of cellular proteolysis is beginning to be solved.
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PMID:Proteinases and their inhibitors in cells and tissues. 265 64

Treatment of the metastatic melanoma cell lines B16-F1 and B16-F10 with 1.5-2 per cent butanol elevates their experimental metastatic potential, whereas reconstitution of butanol-extracted B16 cells with crude butanol extracts decreases the number of experimentally induced lung foci. We partially purified the biologically active components from crude butanol extracts of B16-F1 by high-performance liquid chromatography and isoelectric focusing, and found the inhibitory activity (i) was in the low-molecular-weight (5-10 kDa) fraction of the chromatogram, (ii) had an isoelectric pH between 5.6 and 5.8, (iii) was distinct from a thiol-protease activity eluted from the isoelectric focusing bed at pH 4.9-5.3 and (iv) was not itself an inhibitor of serine or thiol proteases. Incubation of butanol-extracted B16-F10 cells with known inhibitors of serine, acid and thiol protease inhibitors had no effect on the experimental metastatic phenotype. Although the apparent molecular weight was low, the inhibitor(s) tended to aggregate after focusing, probably owing to the presence of carrier ampholines. Using two-dimensional gel electrophoresis, we observed slight differences between intact and butanol-extracted cells, most of them in the low-molecular-weight region. These results suggest that butanol treatment may reversibly release certain inhibitors of cell surface enzymes other than proteases, which might be involved in invasion and metastasis.
Clin Exp Metastasis
PMID:Low-molecular-weight membrane component inhibits the metastatic phenotype of B16-F10 melanoma. 292 48

A high-molecular-weight proteinase in rat ascites hepatoma AH109A cells was purified to apparent homogeneity by conventional chromatographic techniques. The purified proteinase degraded over the broad pH range, 7.0-9.0, not only denatured hemoglobin but also type I and IV collagen in the absence of calcium. Its activity was maximum at pH 8.0, heat-labile and affected by thiol reagents. Serine proteinase inhibitors such as diisopropyl fluorophosphate, soybean trypsin inhibitor, leupeptin, and antipain also partially inhibited its activity. The enzyme was found mainly in the cytosol fraction, and had a molecular weight of 450 kilodaltons (Kd) as determined by gel filtration chromatography and showed a single band on polyacrylamide gel electrophoresis under nondenaturing condition, although it was dissociated into lower-molecular-weight subunits, 25.5-32 Kd in the presence of sodium dodecyl sulfate and 2-mercaptoethanol. These properties suggested that it was a kind of a cytosolic high-molecular-weight proteinase. The collagenolytic activity of this proteinase may play an important role in cancer cell invasion and metastasis.
Invasion Metastasis 1988
PMID:High-molecular-weight neutral proteinase of rat ascites hepatoma cells and their collagenolytic activity. 305 24

Some malignant tumors of soft tissues that metastasize to bones are characterized by an insignificant increase in the levels of certain amino acids in the serum of the host. Primary malignant bone tumors, on the other hand, tend to increase significantly the concentration of amino acids in the host serum. We found that malignant transformation of bones, cartilage, and connective tissue induced changes in the metabolism of the patients which led to a significant elevation of several amino acids in their serum. Only alanine and cysteine showed a decreased level in the sera of patients with bone tumors. A significant increase in the concentration of amino acids in the sera of patients with bone tumors, as compared to control subjects, was found in serine, glutamine, leucine, isoleucine, lysine, arginine, and histidine (p less than 0.001). The elevated levels of serine and glutamine suggest their possible use in diagnostics, differential diagnostics, and in the study of therapeutic effects in these malignancies.
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PMID:The role of serine and glutamine in the metabolism of malignant bone tumors and their significance in the diagnosis and prognosis of bone tumors. 313 89

Tumor cell metastasis is a complex process that depends in part on tumor cell adhesion to components of basement membranes and the extracellular matrix. Previous studies have indicated that the experimental metastasis of murine melanoma cells can be inhibited by ex vivo pretreatment of cells with purified adhesion-promoting fragments of laminin or the synthetic peptide arginyl-glycyl-aspartyl-serine (RGDS) prior to tail vein injection. This study extended the earlier reports to demonstrate that adhesion-promoting fragments of laminin and fibronectin can inhibit the metastasis of a tumor of different histologic origin, such as murine fibrosarcoma cells. Furthermore, ex vivo pretreatment of cells with a purified 33-kDa heparin-binding fragment of fibronectin, which promotes tumor cell adhesion by an RGDS-independent mechanism, was effective at inhibiting experimental melanoma and fibrosarcoma pulmonary metastases. The survival rate of animals receiving tumor cells pretreated with this fragment was significantly enhanced relative to control groups. As with previous studies, the mechanism of inhibition appeared to involve an increased clearance rate of tumor cells from the pulmonary microcirculation. These results suggest a role for cell surface proteoglycans in the adhesion and metastasis of certain malignant neoplasms. Furthermore, this study emphasizes the complexity of tumor metastasis and suggests that multiple strategies may be developed to inhibit hematogenous metastasis formation.
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PMID:Metastasis inhibition of different tumor types by purified laminin fragments and a heparin-binding fragment of fibronectin. 334 86

Activity of neutral protease was increased in sera of rats bearing ascites hepatoma AH109A compared to those of normal rats. The protease was isolated from serum protein and partially purified approximately 1,150 times in specific activity after sequential column chromatography of hemoglobin affinity, lysine-Sepharose, Ultrogel AcA34 and TSK-gel G2000SW in that order. The protease fraction still seemed to contain at least two kinds of proteases, serine and cysteine protease. It had a molecular weight of 18-21 kilodaltons with broad optimal pH range of 7.0-9.0, maximum at 8.0. Intradermal injection of the crude preparation of the neutral protease fraction induced extravascular emigration of circulating tumor cells in vivo. Moreover, partially purified protease degraded pepsin-treated chains of bovine glomerular type IV collagen in vitro, but such an in vitro action of the protease was inhibited by an addition of soybean trypsin inhibitor or mercuric chloride. It failed to cleave salt-extracted rat skin type I collagen under the same digestive conditions for bovine type IV collagen. The serum neutral proteases of tumor-bearing host may play some cooperative roles during extravascular emigration of tumor cells by destruction of vascular basement membrane.
Invasion Metastasis 1986
PMID:Partial purification and characterization of serum protease from tumor-bearing rats which cleaves type IV collagen. 353 Oct 79

Oncogenes encoding serine/threonine or tyrosine kinases were introduced into the established rodent fibroblast cell line NIH 3T3 and tested for tumorigenic and metastatic behavior in T cell-deficient nude mice. Transforming oncogenes of the ras family were capable of converting fibroblast cell lines to fully metastatic tumors. Cell lines transformed by the kinase oncogenes mos, raf, src, fes, and fms formed experimental metastases and (in some cases) these genes were more efficient at metastatic conversion than a mutant ras gene. In contrast, cells transformed by either of two nuclear oncogenes, myc or p53, were tumorigenic when injected subcutaneously but were virtually nonmetastatic after intravenous injection. These data demonstrate that, in addition to ras, a structurally divergent group of kinase oncogenes can induce the metastatic phenotype.
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PMID:Transformation by oncogenes encoding protein kinases induces the metastatic phenotype. 365 11

By means of a radioimmunoassay, which utilized [125I]-epiglycanin and anti-epiglycanin antiserum induced in rabbits by injections of viable TA3-Ha ascites cells with Freund's complete adjuvant, picogram quantities of epiglycanin could be detected. Anti-epiglycanin antiserum was similarly produced in allogeneic mice. Unlabeled epiglycanin lost the capacity to compete with [125I]epiglycanin in the radioimmunoassay as a result of periodate oxidation or incubation with endo-alpha-N-acetyl-D-galactosaminidase (Diplococcus pneumoniae), an enzyme found to cleave only the disaccharide beta-D-galactopyranosyl-(1----3)-2-acetamido-2-deoxy-D-galactose chain from serine or threonine residues in epiglycanin. Glycosylhydrolases known to cleave alpha-D-mannose, beta-D-galactose (1,4-linked), beta-N-acetyl-D-glucosamine, and alpha-N-acetyl-D-galactosamine did not reduce the activity of epiglycanin. Neuraminidase enhanced the activity twofold to fivefold. The finding that little or no activity was demonstrated by the disaccharide, the reduced disaccharide, or other glycoproteins containing the same disaccharide chain suggested that the antigenic determinant probably involved the disaccharide and a unique amino acid sequence at the site of its attachment. By means of the radioimmunoassay epiglycanin cross-reactive antigens were detected in the peritoneal or pleural fluid and in the sera of patients with metastatic cancer. Lower concentrations of epiglycanin-like antigen(s) were found in the peritoneal fluid of patients with hepatitis or liver cirrhosis but not in normal serum.
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PMID:Antibody to epiglycanin and radioimmunoassay to detect epiglycanin-related glycoproteins in body fluids of cancer patients. 620 3

The deficits in plasma amino acids and serum unesterified fatty acids of cancer patients undergoing chemotherapy and/or radiation therapy were studied to delineate the special requirements of the patients and efficacy of our nutritional therapy. Seven general surgery patients and 13 patients treated by the Head-Neck Service had baseline levels measured as part of their nutritional evaluation prior to surgical treatment of their cancers. Fifteen chemotherapy outpatients maintained on their regular diets had fasting levels analyzed. Twenty-six patients who were admitted for their therapy had their intake of the regular hospital diet supplemented with a low-residue enteral diet formula (Vivonex High Nitrogen Diet); parenteral nutrition was used only if their oral intake was totally inadequate. Baseline and sequential measurements were made of plasma amino acid and serum unesterified fatty acid levels by gas liquid chromatographic techniques. Before operation the patients had normal levels of amino acids except for a significant deficiency of threonine and glycine observed in patients with head-neck tumors. Outpatients with and without hepatic metastases had significantly depressed levels of the essential amino acids valine, leucine, threonine, and methionine and the nonessential amino acids serine, glycine, and proline. The baseline levels of the patients admitted for treatment had similar deficiencies except for more evidence of lysine deficiency. Patients supported with total parenteral nutrition had rapid elevation of the amino acid levels. The patients whose intake was supplemented with the oral diets had improvement in their amino acid levels, but the deficiency in the leucine and threonine fractions persisted up to 4 weeks of therapy. Although the lysine levels were normal when first analyzed, significant differences developed in the patients without hepatic metastases after the start of chemotherapy with return to normal only after chemotherapy was discontinued. Fatty acid levels were not significantly different between the cancer groups except for preoperative elevated oleic acid levels noted in the general surgery tumor group; there were no deficiencies in the essential fatty acids. These studies indicate a need for enteral formulas with adequate branched-chain amino acids and enrichment with threonine and lysine for supplementing the nutrition of the cancer patient who is undergoing chemotherapy.
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PMID:Plasma amino acid and serum unesterified fatty acid deficits and the effect of nutritional support in chemotherapy treatment. 642 62

Cell fusion has been used to study some of the factors involved in the process of metastasis. Highly metastatic rat mammary adenocarcinoma cells were fused with various non-metastatic cells and the hybrid clones isolated. These were then tested for their metastatic potential either by injecting the cells intravenously and measuring lung colony formation or by injecting the cells subcutaneously and measuring their ability to form lymphatic metastases. With most hybrid clones tested, the metastatic potential was either inhibited or greatly suppressed; thus this phenotype is a recessive characteristic. We also monitored the hybrid cells' ability to produce plasminogen activator (PA) a serine proteinase thought to be involved in the formation of metastatic lung foci. Whilst the highly metastatic parent cells produced large quantities of PA, none could be detected in the non-metastatic lines. Although the hybrid clones produced little PA activity this could not be correlated with their decreased metastatic potential in that one clone, after extensive in vitro culture, reverted to a more metastatic line without a concomitant increase in PA activity. The suppressed PA activity may be due to the presence of an inhibitor that is spontaneously produced by the hybrid cells.
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PMID:The use of cell fusion to analyse factors involved in tumour cell metastasis. 668 41


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