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)

Tumor cells from the murine T241 fibrosarcoma, which rapidly and reproducibility produces pulmonary metastases, were tested in vitro for their ability to degrade isolated pulmonary basement membrane. Degradation of basement membrane substrate was quantified by the culture of the substrate with tumor cells and measurement of the solubilized hydroxyproline and hexose glycoprotein at neutral pH. It was found that tumor cells collected in the tumor venous drainage were associated with a significantly greater solubilization of basement membrane than were tumor cells obtained from the primary tumor mass. Tumor cells were also assayed for their ability to solubilize type I collagen purified from human dura. Venous effluent tumor cells solubilized collagen to a significantly greater level than primary tumor cells, spleen cells, or liver cells. These findings raised the possibility that metastasizing tumor cells may be a distinct tumor subpopulation with regard to invasive potential.
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PMID:Degradation of basement membrane by murine tumor cells. 19 1

Gelatinolytic and collagenolytic proteinases were separately isolated by different extraction methods from the mouse ascites hepatoma MH134, and from rat ascites hepatoma AH109A. The activities of two proteinases in each extract showed no significant differences, but after trypsin activation the activities of proteinases from the highly metastatic MH134 were significantly increased compared to the enzyme activities in AH109A, which has low metastatic potential. The total activities of collagenase and gelatinase were increased 7.2- and 5.1-fold; their specific activities were increased 5.2- and 4.8-fold, respectively. Gelatinase and collagenase from MH134 were characterized on gelatin zymography. The gelatinase had a molecular weight of 99 and activation by 4-aminophenylmercuric acetate (APMA) or trypsin resulted in its conversion to 79 or 79-95 kD, respectively. The collagenase revealed a major gelatinolytic band at 89 kD, which was converted to 85 and 70 kD by APMA-activation, and a minor gelatinolytic band at 60 kD. These proteinases could degrade native type I collagen to small fragments in a cooperative manner. Trypsin inhibitor, which affects the trypsin activation of latent gelatinase, was extracted together with gelatinase. The inhibitory activity of the enzyme from AH109A showed a 4.1-fold higher specific activity and 3.7-fold greater total activity than that from MH134. The proteinase(s) capable of activating the gelatinase was also extracted from MH134.
Clin Exp Metastasis
PMID:Sequential degradation of interstitial collagen by metalloproteinases extracted from tumors of murine ascites hepatomas. 165 24

The ability to metastasize requires that tumor cells be able to degrade matrix. Nontoxic compounds that inhibit matrix digestion might be useful as anti-metastatic agents. We have investigated whether phenytoin, a drug commonly used in clinical practice that inhibits the production of collagenase by some cells, inhibits metastases in a standard animal model of metastasis: In vitro, phenytoin inhibited the proliferative response of B16 F10 melanoma cells to serum-containing media (75% inhibition at 25 micrograms/ml) but had no effect on their ability to degrade a type I collagen gel (1-100 micrograms/ml). Treatment of these cells with phenytoin prior to inoculation in vivo did not inhibit tumor growth, implantation in a surgical wound, or incidence of spontaneous metastases from a primary tumor growing in the foot. Pretreatment of mice with phenytoin (15, 40, and 75 mg/kg/day) diminished pulmonary metastases following tail vein injection in a minimal but dose dependent fashion; mean number of pulmonary colonies 4.6 +/- 3.1 (75/mg/kg/day) vs. 10.2 +/- 9.9 (control). However, tumor growth, implantation, and spontaneous metastases were not inhibited by pretreating the mice with the same doses of phenytoin. It is concluded that phenytoin has an insignificant inhibitory effect on tumor growth and metastasis.
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PMID:Search for anti-metastatic therapy: effects of phenytoin on B16 melanoma metastasis. 173 31

The ability of cultured human fibroblasts to reorganize and contract three dimensional collagen I gels is regarded as an in vitro model for the reorganization of connective tissue during wound healing. We investigated whether adhesion receptors of the integrin family are involved. It was found that synthesis and transcription of the alpha 2 beta 1 integrin (but not of alpha 1 beta 1 or alpha 3 beta 1) is selectively upregulated when fibroblasts are seeded into type I collagen gels. Time course experiments revealed that high synthetic levels of alpha 2 beta 1 parallel the gel contraction process and return to "baseline" levels after the contraction has subsided. Furthermore, function-blocking mAbs directed to the alpha 2 and beta 1 chain of integrins inhibited gel contraction. Remodelling of connective tissue can be important for tumor cells during invasion and formation of metastases. Therefore, we tested human melanoma cell lines for this function. Five out of nine melanoma lines contracted collagen gels in vitro. Among these, two highly aggressive melanoma cell lines (MV3 and BLM) most efficiently contracted gels almost reaching the rate of normal adult fibroblasts. In these cells, synthesis of alpha 2 beta 1 was also significantly upregulated when seeded into collagen I gels. Moreover, function blocking anti-alpha 2 in conjunction with anti-beta 1 chain mAbs completely inhibited gel contraction for several days. Other melanoma cells (530) with lower metastatic potential which were not able to contract gels, showed no induction of alpha 2 beta 1 synthesis in gel culture. Our results suggest an important role of integrin alpha 2 beta 1 in the contraction of collagen I by normal diploid fibroblasts during wound healing and in the reorganization of collagen matrices by highly aggressive human melanoma cells.
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PMID:Integrin alpha 2 beta 1 is upregulated in fibroblasts and highly aggressive melanoma cells in three-dimensional collagen lattices and mediates the reorganization of collagen I fibrils. 195 83

Metalloproteinases secreted by tumor cells play an important role in metastasis. In the present study, we determined whether an inhibitor of these proteinases could inhibit the ability of tumor cells to degrade collagen and to metastasize. Metalloproteinases with degradative activities for type I collagen, type IV collagen, gelatin, and casein were secreted by a highly metastatic rat embryo cell line (4R) transfected by c-Ha-ras1 (also known as HRAS1). These metalloproteinases were identified by sodium dodecyl sulfate substrate-polyacrylamide gel electrophoresis as 92-kilodalton and 68-kilodalton gelatinolytic enzymes and 48-kilodalton and 45-kilodalton caseinolytic proteinases. A recombinant human tissue inhibitor of metalloproteinases (rTIMP) completely inhibited the proteolytic activities of these enzymes and was also a potent inhibitor of the proteolytic degradation of collagen by intact c-Ha-ras1-transfected cells. The ability of these cells to colonize the lungs after intravenous injection into nude mice was inhibited by 83% when rTIMP was repeatedly injected intraperitoneally into the animals. These data demonstrate that rTIMP is a potent inhibitor of the metalloproteinase activities of these cells and can also inhibit their metastatic potential.
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PMID:Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. 215 82

Type IV and interstitial collagenolytic activities were compared in human malignant and normal trophoblast cells cultured on plastic, in presence or absence of laminin in solution, on matrigel (a gel of basement membrane components) and on type I collagen gel. Laminin highly stimulated the type IV collagenolytic activity but not the interstitial collagenolytic activity, in malignant trophoblast cells. This glycoprotein had no effect on the interstitial collagenolytic activity and doubled the type IV collagenolytic activity in normal trophoblast cells. Thus malignant trophoblast cells produce preferentially the enzyme able to degrade basement membrane when in contact with laminin, and the enzyme able to degrade interstitial collagen fibers when cultured on type I collagen. On the contrary, type I collagen gel and matrigel equally increased both type IV and interstitial collagenolytic activities by normal trophoblast cells. Interactions of tumor trophoblast or normal trophoblast cells with the extracellular matrix result thus in distinct stimulations of collagenolytic activities. Increased production of type IV collagenolytic activity upon exposure to laminin appears to be specific of the metastatic phenotype.
Invasion Metastasis 1990
PMID:Type IV and interstitial collagenolytic activities in normal and malignant trophoblast cells are specifically regulated by the extracellular matrix. 215 47

Human fibrosarcoma cells derived from a patient with multiple metastases extensively degrade artificial basement membranes (BM) and secrete interstitial type of collagenase, a proteolytic enzyme responsible for degradation of type I collagen. Exposure of invasive cell line to TGF beta abrogates destruction of BM.TGF beta reduces collagenase activity and stimulates specific metalloproteinase inhibitor (TIMP) in invasive tumor cells. We preassume that TGF beta could play a protective role in tumor invasion.
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PMID:Protective role of transforming growth factor beta (TGF beta) in tumor-induced degradation of basement membranes. 216 65

In this report we describe the isolation and characterization of a neutral metalloproteinase, from human small cell lung cancer cells, which degrades a wide range of connective tissue proteins. Treatment of tumor cytosol by ammonium sulphate precipitation followed by zinc chelated column chromatography, anion exchange chromatography, and gel filtration chromatography yielded a single enzymatically active protein, which on SDS-PAGE appeared as a diffuse band of 65,000-70,000 daltons. The tumor metalloproteinase, which was inhibited by metal chelators and serum, was able to digest gelatin, type I collagen, type IV collagen, laminin, and fibronectin. We propose that the capacity of this proteinase to degrade both components of blood vessel basement membranes and other connective tissue matrices facilitates the dissemination of human lung cancer cells during the multistep process of metastasis.
Clin Exp Metastasis
PMID:Characterization of a connective tissue degrading metalloproteinase from human small cell lung cancer cells. 283 54

We have shown previously that an increase in tumor invasion and metastases occurred concurrently with a decrease in collagen content of the extracellular matrix surrounding the C3H mouse mammary adenocarcinoma borne by C3H/HeJ mice. In this paper we report the production of collagenase and elastase activities by the primary tumor cultures and three types of cloned C3H mouse mammary adenocarcinoma cell cultures. The primary tumor cell cultures and tumor-associated stromal cultures produced large amounts of collagenase and elastase activities. On the other hand, the primary tumor capsule cultures produced little or no collagenase and elastase activities even though they produced type I collagen. The production of proteases by the primary tumor cultures decreased along with time and with an alteration in the morphology of cell populations and/or passage of the cultures. The three clones of tumor cell cultures produced variable amounts of collagenase in response to induction by phorbol myristate acetate, an agent that stimulates maximal collagenase production. In contrast, all three cloned cultures elaborated significant amounts of elastase that degraded insoluble ligamental elastin, and most of the elastase production was increased further in response to induction by phorbol myristate acetate. Each cloned cell population exhibited differences in their production of collagenase and elastase in parallel with their difference in growth kinetics, yet these cells still possess the distinctive properties of the tumor. However, a unit amount of collagenase produced by each of the cloned cultures, with or without induction by phorbol myristate acetate, was less than that of the primary tumor cultures. Results suggest that some cell types or combination of cell types in the heterogeneous cell population of the tumor and/or their products appear to be responsible for the increased production of collagenase and elastase activities and for the invasiveness of a malignant tumor.
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PMID:Collagenase and elastase production by mouse mammary adenocarcinoma primary cultures and cloned cells. 302 19

In an experimental model of lung metastasis we have observed that more metastatic tumors are located on the pleura of the lung than in the parenchyma. To study possible reasons for this differential pattern we have now related the initial distribution of injected tumor cells to the later location and growth rate of metastases in different regions of the lung in C57bl/6 mice. It was found that labeled murine fibrosarcoma cells were evenly distributed throughout the lungs 24 h after intravenous injection into controls and animals previously treated with bleomycin or by exposure to hyperoxia. These treatments, known to induce pulmonary endothelial injury, were associated with increased tumor cell localization in the lung. In all cases, using morphometric methods, we found that after 2 weeks, approximately 75 per cent of metastatic tumors were located at the pleura. By [3H]thymidine labeling in autoradiographs, pleural tumors in all experimental groups had a growth rate 14 times the growth rate of tumors located in the internal regions of the lung. In vitro, the fibrosarcoma cells proliferated more rapidly on connective tissue matrices prepared from normal pleuras than they did on matrices from the remainder of the lung. Protease digestion of these matrices indicated differences in composition with more insoluble collagen, probably type I collagen, present at the pleura. These data suggest that, in spite of the initial random distribution and localization of tumor cells in the lung, there is preferential growth of metastatic tumors at the pleura which may be related to regional differences in the composition of the extracellular matrix.
Clin Exp Metastasis
PMID:Preferential growth of metastatic tumors at the pleural surface of mouse lung. 334 65


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