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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The localization of DNA and RNA adducts was studied at the ultrastructural level using antibodies directed against O6-methylguanine (O6-metG) and the protein A-gold technique. Primary rat hepatocyte cultures were exposed for 2 h to 5 mM N-nitrosodimethylamine (NDMA). In NDMA-treated cells, the O6-metG-induced immunoreactive sites do not appear at random but seem to be concentrated in the nucleus, and in the cytoplasm, in areas rich in rough endoplasmic reticulum (RER) elements. Mitochondria were not significantly labelled. Untreated control preparations showed no specific immunogold labelling. After RNase digestion of ultrathin sections obtained from cells exposed to NDMA and subsequent immunogold labelling, most of the immunolabelling in the cytoplasm had disappeared, and that over the nucleus had only been slightly reduced, as compared to undigested specimens from NDMA-treated cultures. After similar digestion with DNase, a strong reduction of the labelling of the nucleus was observed, but labelling of the cytoplasm was practically unaffected by this enzymatic treatment, as compared to what was observed in undigested preparations of NDMA-treated hepatocytes. The results provide evidence of preferential formation of O6-metG at the DNA and RNA levels, in the nucleus and cytoplasm RER, respectively. Furthermore, this study demonstrates the applicability of the high-resolution protein A-gold technique for ultrastructural detection of nucleic acid adducts in NDMA-treated hepatocytes using affinity-purified anti-O6-metG polyclonal antibodies.
Carcinogenesis 1992 Dec
PMID:Colloidal gold ultraimmunocytochemical localization of DNA and RNA adducts in rat hepatocytes. 128 95

Numerous hepatic cell lineage pathways have been proposed for the development of hepatocarcinogensis induced by chemical carcinogens in rats. The roles of bile ductule cells and hepatocytes in the development of carcinogenesis were investigated using light and electron microscopic procedures to detect differences in morphology and in the phenotypic expression of antigens that are associated with each cell type. In early stages of hepatocarcinogenesis (4-10 weeks after initiation of feeding of a choline-deficient ethionine containing diet), both bile ductulelike (BDL) cells and hepatocytes were seen in mitosis. At the light microscope level, BDL cells showed intense cytoplasmic pyronin (RNA) staining and were positive for the antigens defined by monoclonal antibody 270.38 (bile ductule cells and "oval" cell marker) and glutathione-S-transferase (Yp isoform), whereas hepatocytes were positive for the antigens defined by monoclonal antibodies 270.26 and 258.26 (liver parenchymal cell markers), catalase activity (peroxisome marker) and adenosine triphospatase activity (bile canalicular marker). The authors frequently encountered BDL cells and hepatocytes in close proximity. Ultrastructural examination showed extensive plasma membrane appositions between a subset of BDL cells and hepatocytes. Desmosome structures, tight junctions, microvilli interdigitations and ATPase-positive bile canalicularlike structures were present along the contiguous plasma membrane domains of BDL cells and hepatocytes. Many of the BDL cells attached to hepatocytes were also attached to other BDL cells that had retained a basal lamina. In many cases, BDL cells connected to both hepatocytes and other BDL cells were no longer completely surrounded by basal lamina and had acquired a dual polarity as a consequence of their sharing apical and lateral membrane domains with both BDL cells and hepatocytes. BDL cells showed increased numbers of microperoxisomes (catalase positive organelles) and numerous free ribosomes. Hepatocytes showed a prominent development of the smooth endoplasmic reticulum, a feature prominent in hepatocytes within hyperplastic nodules. Since BDL cells and hepatocytes proliferate and BDL cells and hepatocytes develop intercellular junction sites, the authors propose that both cell types in early stages of carcinogenesis have the capacity to enter the cell lineage pathway leading to the development of hepatocarcinoma. Furthermore, the finding that BDL cells and hepatocytes form multiple attachment sites at the level of the plasma membrane, suggests the possibility that at some stage convergence of separate hepatic cell pathways may occur.
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PMID:Characterizations of and interactions between bile ductule cells and hepatocytes in early stages of rat hepatocarcinogenesis induced by ethionine. 175 May 8

Ultrastructural changes were investigated and quantified, using a stereological approach, in early gamma-glutamyltranspeptidase (GGT)-positive focal lesions, induced in the rat liver by treatment with a single initiating dose of diethylnitrosamine (DENA) followed by promotion with phenobarbitone (PB) for 30 weeks. Within the extra-hepatocyte environment of focal tissue, the mean volume occupied by Ito cells was markedly decreased, whilst that occupied by endothelial and Kupffer cells was increased, when compared to uninvolved tissue from the same rat livers. The bile canaliculi were dilated, but no significant differences in the mean volume occupied by the sinusoidal and Disse spaces were noted. In focal hepatocytes there was a striking overproduction of lipid droplets and proliferation of smooth endoplasmic reticulum (sER). Whorls of concentrically arranged, parallel ER membranes were found only in the hepatocytes of preneoplastic foci, in association with the proliferated sER, and never in the surrounding, uninvolved tissue. The increase in mean volume of the sER, lipid droplet and cytoplasmic matrix compartments, together with the appearance of whorls, were the major contributing factors to the marked hypertrophy seen in focal hepatocytes. The mean volume of the rough endoplasmic reticulum, mitochondrial, lysosomal, peroxisomal and nuclear compartments per hepatocyte also increased, but contributed to a lesser extent to the cellular hypertrophy. It is speculated that whorls may be structural adaptations, resulting from a possible alteration in the normal feedback control of cholesterol synthesis, for the production of sterols and the biogenesis of sER in eosinophilic-type focal cells. The significance of changes observed in focal tissue, and the high biological variation noted between foci, is discussed in relation to the hepatocarcinogenic process.
Carcinogenesis 1990 Sep
PMID:Ultrastructural changes in chemically induced preneoplastic focal lesions in the rat liver: a stereological study. 197 47

Aflatoxin B1 (AFB1) is thought to be an occupational risk factor for airway carcinogenesis where exposure to AFB1-laden grain dusts is common. Since activation of AFB1 is catalyzed by cytochromes P-450 associated with the smooth endoplasmic reticulum, we compared the response to AFB1 in cultured tracheal epithelium from species with abundant (rabbit and hamster) and scarce (rat and monkey) distributions of smooth endoplasmic reticulum in nonciliated tracheal epithelial cells. Explants from each species, incubated in medium containing 0.5 microM [14C]-AFB1 for selected intervals up to 24 h, were compared on the basis of binding of [14C]-AFB1 to tracheal DNA, amount and type of AFB1 metabolites in the medium, ultrastructurally determined population densities of epithelial cells, and distribution of bound material in epithelium as determined by autoradiographic grain densities. Cultures derived from rabbits were most active in metabolic conversion and formation of AFB1-DNA adducts, followed by those from hamsters, rats, and monkeys. Rabbit tracheal epithelium formed a significantly greater proportion of glutathione conjugates, while that from hamster formed a greater amount of AFB1-dihydrodiol, compared to rats and monkeys. The monkey formed significantly greater proportions of aflatoxin Q1 and the rabbit more aflatoxicol, compared to other species. There was selective degeneration and accumulation of labeled material in nonciliated cells in both rabbits and hamsters but not in rats or monkeys. Explants from rabbit tracheas were much more susceptible to cytotoxic injury and had higher autoradiographic grain densities than explants from hamsters. We conclude that the presence of smooth endoplasmic reticulum-containing nonciliated epithelial cells is qualitatively associated with the activation and toxicity of AFB1.
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PMID:Comparative action of aflatoxin B1 in mammalian airway epithelium. 210 74

Administration of a single oral dose (20 mg/kg) of [U-14C]3,3'-dichlorobenzidine to rats resulted in the in vivo covalent binding of the compound to hepatic lipids. More than 70% of the lipid-3,3'-dichlorobenzidine adducts were accounted for in microsomes. Loss of the lipid-bound 3,3'-dichlorobenzidine residues from either total liver or endoplasmic reticulum occurred in at least two phases--an initial fast phase and a terminal slow phase. In vitro studies with hepatic microsomes in the presence of antibodies to specific P450 isozymes and chemical inhibitors to determine the enzymes that activate 3,3'-dichlorobenzidine to the lipid-binding derivative(s) implicated cytochrome P450d. The 3,3'-dichlorobenzidine-bound microsomal lipids were not mutagenic to Salmonella TA98 in the Ames test. The results suggest that adduct formation between 3,3'-dichlorobenzidine and membrane lipids may provide a measure of 3,3'-dichlorobenzidine activation. It is speculated that covalent interaction of the compound with membrane lipids may modify cellular processes, leading to either enhancement or attenuation of carcinogenesis by the chemical.
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PMID:Covalent interaction of 3,3'-dichlorobenzidine with hepatic lipids. Enzymic basis and stability of the adducts. 211 1

The ACI rat constitutes a unique model for human prostatic carcinogenesis. A high percentage of these animals spontaneously develop prostatic carcinomas in the ventral lobe as they age. The light microscopic appearance of these tumors is similar to the cribriform pattern of adenocarcinoma in human prostate. In order to further characterize this useful model, we carried out light and electron microscopy studies of the morphology of carcinomatous lesions developing in these animals. Sixteen rats ranging in age from 25 to 43 months were examined histologically, and ultrastructural studies were performed on eight of these cases. The neoplastic cells showed features of well-developed secretory epithelium including prominent Golgi apparatus, abundant rough endoplasmic reticulum, and numerous secretory vacuoles. Microvilli were numerous in some cells and focal apocrine secretory activity was present. Intraluminal crystals similar to those associated with human prostate carcinoma were observed in one of our cases. Prostate carcinomas developing in the ACI rat share many of the ultrastructural features of human prostatic carcinoma.
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PMID:Morphologic characterization of early prostatic carcinomas in the ACI rat: a light and electron microscopic study. 233 37

The carcinogenic properties of styrene and styrene oxide were investigated using C3H/10T1/2C18 cells as a test system. In vitro transformation was not observed for either of the two chemicals; however, styrene oxide at three different concentrations enhanced the morphological transformation in the two-stage transformation assay. 0.1, 1 and 10 microM styrene oxide added twice weekly resulted in 32.4, 26.8 and 31.4 per cent of the dishes with one or more type III foci. Styrene and styrene oxide were only slightly toxic to the cells at the concentrations used. Styrene oxide did not affect the growth rate of the C3H/10T1/2 cells at 10 microM. However, 100 microM styrene oxide added to logarithmically growing cells caused a significant decrease in growth rate within 24 to 48 h. The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate inhibited DNA synthesis approximately 60% 8 h after initiation of treatment. When styrene oxide at concentrations up to 100 microM was tested in a similar experiment, however, no significant effect was observed. Total RNA synthesis increased by 70% 1.5 h after initiation of treatment at 1 microM styrene oxide; this effect was not seen after 24 h. Styrene oxide at concentrations of 1 and 0.1 microM stimulated the incorporation of [3H]choline into cells by approximately 20% during a 2 h incubation, the major site of incorporation being the nuclear-associated endoplasmic reticulum.
Carcinogenesis 1985 Sep
PMID:In vitro transformation and tumor promotion studies of styrene and styrene oxide. 241 41

Oreochromis mossambicus, commonly known as tilapia, is a freshwater teleost with a wide tolerance to environmental conditions. Multiple focal lesions in the liver were observed 2 months after cessation of a one-month long treatment with 100 p.p.m. diethylnitrosamine. Cells were small and compact and arranged in sheets. Ultrastructurally, these cells have abundant endoplasmic reticulum, round mitochondria, less conspicuous golgi apparatus and fat droplets. Other organs like the intestines, spleen, kidneys, ovaries and pituitary appeared normal. Two liver inducible enzymes, gamma-glutamyl transferase and tyrosine aminotransferase were elevated by 5- and 3-fold respectively. Aggressive migration of hepatocytes was observed in tumorigenic liver explants. Vitellogenesis and early embryological development appeared unaffected as the female fish spawned during hepatocarcinogenesis. However, their fry were stunted and short-lived. To compare the susceptibility of tilapia to another hepatocarcinogen, the fish were also treated with methylazoxymethanol acetate at 10 p.p.m. for 0.5-1 h. However, methylazoxymethanol acetate was too toxic and 75% of the fish succumbed 1 day after treatment. Moreover, after 2 months post-treatment, neither tumors nor change in enzyme activities were observed in any organ. These results suggest that tilapia could be a useful model for screening and differentiating carcinogens since they could develop liver tumors within only 2 months after treatment with diethylnitrosamine.
Carcinogenesis 1989 Mar
PMID:Differential susceptibility of a fish, tilapia Oreochromis mossambicus (Teleostei, Cichlidae) to hepatocarcinogenesis by diethylnitrosamine and methylazoxymethanol acetate. 256 20

Adult rat liver gamma-glutamyltransferase (GGT) has been poorly characterized because of its very low concentration in the tissue. In contrast with the kidney, the liver enzyme is inducible by some xenobiotics, and its relationship to hepatic ontogeny and carcinogenesis seems to be important. Liver GGT polypeptides were identified by immunoblot analysis in subcellular fractions (rough endoplasmic reticulum, smooth endoplasmic reticulum, Golgi membranes and plasma membranes). Rat liver GGT appeared as a series of polypeptides corresponding to different maturation steps. Polypeptides related to the heavy subunit of GGT were detected in rough endoplasmic reticulum at 49, 53 and 55 kDa, and in Golgi membranes at 55, 60 and 66 kDa. Two polypeptides related to the light subunit of GGT were also observed in Golgi membranes. In plasma membranes GGT was composed of 100 kDa, 66 kDa and 31 kDa polypeptides. The 66 kDa component could correspond to the heavy subunit of the rat liver enzyme, and if so has a molecular mass higher than that of the purified rat kidney form of GGT (papain-treated). These data suggest different peptide backbones for the heavy subunits of liver GGT and kidney GGT.
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PMID:Electrophoretic mobility of gamma-glutamyltransferase in rat liver subcellular fractions. Evidence for structure difference from the kidney enzyme. 257 20

In rats treated orally with a single dose of aflatoxin B1 (5 mg/kg body weight) characteristic focal and nodular liver lesions developed which differed in their fine structure, enzyme histochemical pattern and growth behaviour from other types of carcinogen-induced hepatic foci and nodules described earlier. The foci were composed of a distinct cell population which showed specific structural changes of the cytoplasm. Typically, unusually large and abundant basophilic bodies consisting of highly ordered stacks of cisternae of the rough endoplasmic reticulum (ER) were arranged in long, striped bands and stood out against an acidophilic background which was due to hypertrophy of the smooth ER. We propose the descriptive terms 'tigroid cells', and 'tigroid cell foci' for this population of altered hepatocytes. Correlative cytochemical investigations on the tigroid cell foci revealed characteristic changes in carbohydrate metabolism, such as a decrease in the activity of glycogen synthetase and glycogen phosphorylase and an increase in the activity of glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The activity of glucose-6-phosphatase and ATPase was normal (or partially reduced) and that of the gamma-glutamyl-transpeptidase was always lacking. A progressive increase in the number and size of the tigroid cell foci and transitions from tigroid cell foci to neoplastic nodules with similar morphological and cytochemical features were observed during the time period of 104 weeks. The mitotic index within tigroid cell foci and nodules was approximately 100 times higher than that of the surrounding hepatic tissue or the liver parenchyma of untreated control animals. The important question whether the tigroid cell foci represent a specific pre-neoplastic or early neoplastic cell population requires further investigations.
Carcinogenesis 1985 Nov
PMID:Tigroid cell foci and neoplastic nodules in the liver of rats treated with a single dose of aflatoxin B1. 286 15


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