Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transplantable pregnancy-dependent mouse mammary tumor line TPDMT-4 behaves like a preneoplastic lesion in virgin mice when implanted with tissue pieces. This study was conducted to elucidate whether enzymatic cell dissociation enhances the tumorigenic potential as in hyperplastic mammary nodules. When tissue pieces were implanted in virgin mice, there was an increase in tumor incidence from 0% at generation 14 (F14) to 40% at 38 (F38) during the 6-month observation; early (F8), middle (F16-18) and late (F39-40) transplant generation (ETG, MTG and LTG respectively) tumors were dissociated with collagenase and hyaluronidase. DDD strain females receiving an injection of 10(5) dissociated cells into the fat pad were observed as virgin or ovariectomized. ETG cells formed palpable tumors in 18 (43%) and 21 (50%) of 28 virgins at latent periods of 133 +/- 11 (mean +/- SE) and 142 +/- 10 days for 6 and 8 months respectively. MTG and LTG cells did so in 24 (60%) of 40 and 25 (89%) of 28 virgins at 77 +/- 5 and 68 +/- 5 days respectively for 6 months. In ovariectomized mice, however, no palpable tumors developed from any of these cells. Most ETG and MTG cell-derived tumors repeated palpable growth and total regression one or more times, and subsequently disappeared or grew slowly, whereas almost all LTG tumors grew progressively from the onset. MTG cells infiltrated into the fat pad more extensively than ETG and LTG cells: MTG cells occupied almost the whole fat pad at 6 weeks, whereas the outgrowths of the other cells were confined to one-eight of the fat pad. Southern blot analyses demonstrated the absence of certain extra MMTV DNA fragments in MTG tumors, although the distinct behaviors of MTG cells could not be ascribed to it alone. The results suggest that enzymatic cell dissociation may enhance tumorigenesis by hormone-dependent mammary tumor cells at lower hormone levels.
Carcinogenesis 1988 Jun
PMID:Enhancement of tumorigenic potential in virgin mice of a pregnancy-dependent mouse mammary tumor (TPDMT-4) by enzymatic cell dissociation. 283 7

Cells of clone JTC-12 derived from monkey kidney epithelial cells were found to produce latent collagenase in serum-containing cultures. Collagenase production by JTC-12 cells was stimulated more than ten-fold with the addition of 12-0-tetradecanoyl-phorbol-13-acetate. The JTC-12 cell collagenase was purified 2,370-fold over the conditioned medium to a specific activity of 5,940 units/mg with a yield of 79% by heparin-Sepharose, ion-exchange and immunoadsorption chromatography. Thus the JTC-12 cell culture appears to be a useful model for studying the initial degradation of surrounding connective tissues by epithelial tissue in carcinogenesis.
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PMID:Collagenase synthesis in clonal monkey kidney epithelial cells (JTC-12 cells). 284 85

Sequential carcinogen treatment (diethylnitrosamine/partial hepatectomy followed by 2-acetylaminofluorene (2-AAF] induced multiple hepatocarcinomas in rats with 100% certainty within a year. Enzyme-altered lesions, i.e. gamma-glutamyltranspeptidase (GGT)-positive and/or ATPase-negative cell foci, were numerous already at 8 weeks, and suspensions of purified hepatocytes isolated (by collagenase perfusion) at this time contained 30-40% GGT-positive cells. These hepatocyte suspensions were markedly deficient with respect to autophagic protein degradation (in comparison with cell suspensions from normal rats), and the cells lost less protein and survived much better than normal hepatocytes in culture under conditions of amino acid deprivation (which activates the autophagic mechanism). The anabolic advantage of reduced autophagy may possibly contribute to the selective outgrowth of preneoplastic cells during the earliest stage of liver carcinogenesis. Inclusion of the autophagy inhibitor 3-methyladenine in the culture medium elevated the survival of normal hepatocytes up to the level seen with hepatocytes from carcinogen-treated animals, suggesting that protection of normal cells by autophagy suppression may be a potentially interesting therapeutic principle.
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PMID:Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. 285 48

Hepatocytes were isolated by a collagenase perfusion method from male F-344 rats fed a diet containing 0.05% phenobarbital (PB), 0.05% dichlorophenyltrichloroethane (DDT), 0.25% ethyl-alpha-p-chlorophenoxyisobutyrate (CPIB), 0.02% methapyrilene hydrochloride (MP), 0.05% amobarbital (AB) or 0.05% diphenylhydantoin (DPH) for 8 weeks. An increase in the incidence of gamma-glutamyltransferase (GGT)-positive hepatocytes was found in rats fed PB or DDT, while CPIB strikingly decreased the incidence. There was no change in the incidence in rats fed MP, AB or DPH. Sensitivity to phalloidin, in terms of formation of multiple cytoplasmic blebs, of the 1-h cultured hepatocytes of rats fed PB, DDT or MP was decreased in both GGT-negative and GGT-positive hepatocytes. The sensitivity of GGT-negative hepatocytes of rats fed CPIB was also decreased. Experiments on phalloidin consumption showed decreases in the hepatocyte toxin uptake of rats fed PB, DDT, CPIB or MP. AB and DPH had no effects on the sensitivity of both GGT-negative and GGT-positive hepatocytes.
Carcinogenesis 1986 Feb
PMID:Effects of liver-tumor promoters on phalloidin sensitivity of rat hepatocytes. 286 8

An assay for the degradation of type IV (basement membrane) collagen was developed as a biochemical marker for neoplastic cells from chemically transformed human skin fibroblasts. Type IV collagen was isolated from basement membrane of Syrian hamster lung and type I collagen was isolated from rat tails; the collagens were radioactively labelled by reductive alkylation. Both collagens were in the native form as shown by their low sensitivity to degradation by trypsin. The abilities of normal (KD) and chemically transformed (Hut-11A) human skin fibroblasts to degrade the collagens were studied. The normal cells released a collagenase into the medium which after activation by trypsin or oxidized glutathione degraded type I collagen. Hut-11A cells also produced a collagenolytic activity that degraded type I collagen; however, no activation of the medium was required for this activity. Type IV collagen was not degraded by medium conditioned with the normal (KD) cells with or without activation. In contrast, Hut-11A cells secreted an active collagenase into the medium that degraded type IV collagen extensively. Treatment of the medium from Hut-11A cells with trypsin resulted in only a loss of activity while treatment with oxidized glutathione was without effect. The degradation of type IV collagen by Hut-11A conditioned medium was linear for up to 1 h and the extent of degradation increased linearly with increasing amounts of conditioned medium. A cell-associated assay was performed by growing either normal or transformed cells in the presence of radioactively labelled type IV collagen and measuring the released soluble peptides in the medium. This assay also demonstrated that KD cells failed to synthesize an activity capable of degrading type IV collagen whereas Hut-11A cells degraded type IV collagen in a linear manner for up to 4 h. Human serum at very low concentrations, EDTA and L-cysteine inhibited the enzyme activity, whereas protease inhibitors like phenylmethyl sulfonyl fluoride, N-ethyl maleimide or soybean trypsin inhibitor did not inhibit the enzyme from Hut-11A cells. These results suggest that the ability to degrade specifically type IV collagen may be an important marker for neoplastic human fibroblasts and supports a role for this collagenase in tumor cell invasion.
Carcinogenesis 1985 Feb
PMID:Degradation of type IV collagen by neoplastic human skin fibroblasts. 298 12

Early-passage human foreskin fibroblasts were exposed to X-ray doses ranging from 100 to 600 rad. The X-ray treatments resulted in cell killing in a dose-dependent manner as judged by the colony-forming efficiency of the cells. When cultures exposed to radiation were serially passaged and checked at various times for growth in semi-solid medium they showed the presence of cells with the ability to grow under anchorage-independent conditions (in agarose) at 24 population doublings. The frequencies of colonies with the ability to grow in agarose increased with increasing doses of X-rays above the levels observed for control cultures under similar conditions. When assayed for plasminogen activator levels, the X-ray-treated cultures at various passages showed insignificant differences from levels observed in control cultures. However, the amounts of collagenase (type IV collagen-specific) increased significantly by 32 population doublings in the X-ray-treated cultures compared with control cultures. Our results suggest that the production of type IV collagen-specific collagenase could be useful as an in vitro marker for the transformation of human diploid fibroblasts by X-irradiation.
Carcinogenesis 1986 Feb
PMID:Radiation-induced anchorage-independent growth and collagenase production in diploid human fibroblasts. 300 74

In an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis, metastatic human breast cancer cell lines (MCF7, ZR75-1) were found to secrete a 52,000 dalton (52K) protein under estrogen stimulation. Following its purification to homogeneity, the 52K protein was identified as a secreted procathepsin-D-like aspartyl protease bearing mannose-6-phosphate signals. This precursor displays an in vitro autocrine mitogenic activity on estrogen-deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its autoactivation. The total protease (52K + 48K and 34K) was detected and assayed by monoclonal antibodies and was found to be highly concentrated in proliferative and cystic mastopathies. In breast cancer, its cytosolic concentration appears to be correlated more to tumor invasiveness than to hormone responsiveness. The mRNA of the 52K protease accumulates rapidly following estradiol treatment, as was shown by Northern blot analysis with cloned cDNA. The 52K cathepsin-D-like protease is the first example of a lysosomal protease induced by estrogens in cancer cells. Results obtained using different approaches suggest that two cysteinyl cathepsins are also related to cell transformation and invasiveness. It has been proposed that cathepsin-B is involved in breast cancer and metastatic melanoma, and its regulation by estrogen has been shown in the rat uterus. Cathepsin-L corresponds to the major excreted protein (MEP) whose synthesis and secretion are markedly increased by transformation of NIH 3T3 cells with Ki ras and are regulated by several growth factors. In addition to secreted autocrine growth factors and to other proteases (plasminogen activator, collagenase), lysosomal cathepsins may therefore play an important role in the process of tumor growth and invasion as long as their precursor is secreted abundantly.
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PMID:Estrogen-induced lysosomal proteases secreted by breast cancer cells: a role in carcinogenesis? 331 45

Cadmium (Cd) induces testicular tumors of interstitial cell (IC) origin in rats which can be prevented by zinc (Zn). Zn-induced synthesis of metallothionein (MT), a metal-binding protein with a high affinity for Cd, is thought to account for tolerance to Cd in most tissues by sequestration of Cd. However, the mechanism of Zn inhibition of Cd-induced carcinogenesis in the testes is unknown. Our studies with ICs obtained by collagenase dispersion of rat testes, indicate the levels of the Cd-binding protein in ICs are unaltered by Zn. This testicular protein also was found to differ from MT in amino acid content and to have a lower affinity for Cd. Thus, MT does not seem to be involved in protection of ICs against Cd carcinogenesis. Altered Cd toxicokinetics as a possible explanation for Zn-induced tolerance was therefore explored. Cd uptake into isolated ICs had passive diffusion and nonpassive (carrier mediated or active transport or both) components. The nonpassive component of Cd accumulation was markedly reduced by addition of Zn in vitro, indicative of competition for uptake at the cellular level. These results indicate that toxicokinetic alterations leading to reduced Cd accumulation may play an important role in Zn induction of tolerance to Cd carcinogenesis in the testes.
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PMID:In vitro assessment of target cell specificity in cadmium carcinogenesis: interactions of cadmium and zinc with isolated interstitial cells of the rat testes. 339 32

Liver carcinogenesis was initiated in young rats by diethylnitrosamine/partial hepatectomy and promoted by dietary 2-acetylaminofluorene (for 4 weeks). Eight weeks after initiation, hepatocytes were isolated by means of collagenase perfusion and analyzed by means of flow cytometry. Whereas cells and cell nuclei from normal or hepatectomized livers were predominantly tetraploid, most of the hepatocytes/nuclei from carcinogen-treated rats were diploid. Neoplastic liver nodules and hepatocellular carcinomas also contained almost exclusively diploid nuclei, suggesting that diploidization may be an essential feature of liver carcinogenesis. Two-parametric analysis (simultaneous flow cytometric determination of DNA and protein content within the same cell) revealed that the diploid cells were only half as big as the tetraploid cells. They could therefore be separated from the latter by centrifugal elutriation. Normal, isolated hepatocytes responded to amino acid deprivation by increasing their rates of autophagic sequestration (measured with electroinjected (14C)sucrose as a probe) and endogenous protein degradation, the resulting protein loss eventually leading to cell death. Hepatocytes from carcinogen-treated rats were much less responsive to amino acid deprivation, preserved their protein better, and survived for longer periods of time in culture than did normal cells. The reduced autophagic responsiveness may conceivably give carcinogen-altered cells a survival advantage even in vivo, that could contribute to their outgrowth during carcinogenesis.
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PMID:Changes in cellular ploidy and autophagic responsiveness during rat liver carcinogenesis. 378 17

Treatment of mouse fibroblast BALB/c 3T6 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate or the antipromoter retinoic acid affects the release of several glycoproteins into the medium. The phorbol ester decreases the secretion of a 180-kd and 160-kd glycoprotein and increases the release of a 38-kd glycoprotein. In contrast, retinoic acid affects these glycoproteins in the opposite way. Moreover, retinoic acid enhances the level of a 55-kd and 60-kd glycoprotein. The 180-kd and 160-kd glycoproteins appear sensitive to collagenase and after pepsin treatment are converted to bands which comigrate with collagen alpha 1 (I) and alpha 2 (I). These glycoproteins are tentatively identified as being pro alpha 1 (I) and pro alpha 2 (I). The 38-kd glycoprotein appears to comigrate with the major excreted protein. Retinoic acid appears to reduce significantly the incorporation of mannose into secreted glycoproteins whereas treatment with the phorbol ester induces an enhancement in mannose incorporation. Our results indicate that both phorbol esters and retinoids alter the release of several glycoproteins from 3T6 mouse fibroblasts. These changes appear to relate to the influence of these compounds on the expression of the transformed phenotype of these cells.
Carcinogenesis 1985 Mar
PMID:Retinoic acid and 12-O-tetradecanoylphorbol-13-acetate alter release of glycoproteins from mouse fibroblast BALB/C 3T6 cells. 391 54


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