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

The objective of this study was to compare the fine structure of presumptive preneoplastic hepatocytes at various times during liver carcinogenesis with that of normal, developing, and regenerating liver and of hepatocellular carcinomas, using transmission and scanning electron microscopy. A new model of liver carcinogenesis was used in which several of the early steps are quite well synchronized. A single initiating dose of diethylnitrosamine induced isolated islands of altered hepatocytes. The cells were characterized by persistence of glycogen despite starvation, increase in smooth endoplasmic reticulum, and hypertrophic nucleoli. Following intense selection of the altered hepatocytes by dietary 2-acetylaminofluorene plus partial hepatectomy, the affected hepatocytes proliferated rapidly to produce basophilic foci. These early hyperplastic lesions revealed stellate-shaped dilated bile canaliculi lined by blebs and abnormally thick elongated microvilli, a decreased number of microvilli on the sinusoidal surface, a marked increase in smooth endoplasmic reticulum, large nucleoli, and bundles of pericanalicular microfilaments. A majority of the proliferating lesions reacquired a normal organizational pattern within several weeks after partial hepatectomy and could not be distinguished from normal liver. A small number continued to grow and become typical persistent hyperplastic nodules. These showed significant widening of intercellular spaces between hepatocytes, elongated microvilli over large regions of the cell surface, many invaginations of the cell membrane, and irregularly shaped bile canaliculi. Sequential changes in focal hyperplastic hepatocytes during carcinogenesis could be distinguished from normal, developing, and regenerating liver. The major differences involved the cell surfaces and cytoplasmic organelles. The findings are compatible with the hypothesis that a carcinogen may act by inducing alterations in a small number of hepatocytes and that hepatocellular carcinomas arise through stepwise evolutional changes in these cells.
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PMID:Sequential analysis of hepatic carcinogenesis: a comparative study of the ultrastructure of preneoplastic, malignant, prenatal, postnatal, and regenerating liver. 22 39

The lesions that appear during hepatocarcinogenesis can be separated into morphologically distinct entities, which have been arranged into sequences believed to represent stages in carcinogenesis. Similarly, the primary and transplantable hepato-cellular carcinomas (HCC) can be arranged into a sequence of stages believed to represent the progression toward the ultimate cancer cell. Separation of morphological entities has been most successful in rat liver. Ultrastructural studies differentiate between lesions derived from hepatocytes and those originating in other cellular components of the liver. They show that there is variability and divergence in the structure of cellular organelles in the early stages of carcinogenesis, that there is simplification of cellular structure and of organelles during the progression of HCC, and that qualitative changes specific for cancer cells do not exist. Toxic changes associated with the process of carcinogenesis are loss of stacks; wrapping of cisternae around mitochondria; dilation, denudation, and vesiculation of cisternae; increase of autophagy; depletion of glycogen, and enlargement of nuclei and nucleoli. Early changes are storage of glycogen and hyperplasia of smooth endoplasmic reticulum. Subsequent alterations are increased variability in the size, shape, and structure of mitochondria and in the structure of endoplasmic reticulum, including the appearance of fingerprints. A transient stage recognizable by storage of lipid may represent a degenerative process. Ultrastructural characteristics of basophilic cells such as abundance of free ribosomes and absence of glycogen and of smooth endoplasmic reticulum suggest that they may be a stage in the formation of HCC. Progression of HCC is associated with a decrease in the number and size of mitochondria, reduction of mitochondrial cristae, decrease in the number and complexity of microbodies, reduction of the tubulovesicular form of smooth reticulum, accumulation of free ribosomes, and increase of the granular component and condensation of the fibrillar component of nucleoli. Various types of nuclear inclusions reflect the increased mitotic rate of the neoplastic tissue. Changes of the cellular surface are believed to be associated with the ability of the cells to invade and metastasize. Future investigations will require the use of single doses of potent carcinogens, application of morphometric methods at the ultrastructural level, and acceptance of primates as models for human hepatocarcinogenesis.
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PMID:Ultrastructure of hepatocellular tumors. 22 4

Neither immunologic nor genetic concepts of carcinogenesis have yet been decisively confirmed, and epigenetic theories, as formulated so far, are either non-predictive or insufficiently consistent with morphologic and experimental evidence. Computing data, concerned with carcinogenic mechanisms and neoplastic changes at the level of the endoplasmic reticulum, may lead to a new coherent understanding of tumor pathogenesis. Carcinogenic agents initiate biophysical perturbations, chemical alterations and conformational transitions in the membrane lattice of the endoplasmic reticulum. Foremost among the resulting neoplastic changes is an increased, irreversible separation of polyribosomes from membranes of the ergastoplasm. The carcinogenic process, apparently, deletes a protein required for polysome attachment. Since microsomal cytochromes can be synthesized by membrane-bound polysomes only, the translation of genetic information for their biosynthesis is irreversibly restricted. A similar, self-perpetuating deficiency may be postulated for the polysome attachment protein. Activities, depending on cytochromes P-450 and b5, are hampered, e.g. those of the monoxygenase system. Cholesterogenesis is derepressed. Ratios of phospholipids/cholesterol are decreased, and lipid-protein complexes, altered both in structure and function. Another distinct effect of the membrane-polysome separation is the unmasking of thiol-disulfide exchange enzymes which, in turn, stimulate the biosyntehsis of proteins and of deoxyribonucleotides involved in cell replication.
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PMID:Microsomal aspects of carcinogenesis and neoplasia. 37 54

In the control animals of thyroid peroxidase is localized within the membrane of rough endoplasmic reticulum, perinuclear cisternae, microvilli, lamellar structures of the GOLGI apparatus and dispersed through the cytoplasm small vesicles. 3 weeks treatment of the animals with MTU leads to disappearance of the peroxidase activity from the follicular cells. However, a prolongation of MTU administration until the 6th month and latter causes a reappearance of the peroxidase activity within the same structures of the proliferating cells as in the control animals. In the epithelial cells of follicular and papillary carcinomas the reaction product is observed predominantly within the membrane of the rough endoplasmic reticulum, perinuclear space and outher membrane of the microvilli. The changes in the inhibitory effect of MTU on the peroxidase activity during thyroid carcinogenesis are discussed.
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PMID:Cytochemical localization of peroxidase activity in normal, proliferating and neoplastic thyroid tissues of rats. An ultrastructural study. 40 41

During diethylnitrosamine (DEN) administration, a distinctive difference was observed between rats and guinea-pigs in the sequence of ultrastructural changes in the hepatic endoplasmic reticulum (ER). In DEN-induced hepatic tumour cells in the guinea-pig there was extensive proliferation of the rough ER, while the smooth ER was quite sparse; in the premalignant liver the opposite was noted. This is in contrast to the rat, in which administration of either DEN or 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) brings about, in both premalignant and malignant hepatic tissue, proliferation of the smooth ER and sparsity of the rough ER. Yet, as in the rat, the number of ribosomes on the outer surface of the guinea-pig liver rough ER is greatly reduced and this is paralleled by a 49% decrease of the RNA/protein ratio as early as 4 weeks of nitrosamine administration. The decrease of RNA/protein ratio and ultrastructurally observed loss of ribosomes from the ER, following nitrosamine administration, correlate with a decrease of photometric response of microsomal suspensions to the sulphydryl probe, p-chloromercuribenzoate. While azo-dye-reductase activity is higher in untreated rats than in untreated guinea-pigs, feeding 3'-Me-DAB for 6 weeks brings about a 76% decrease in the rat, but no significant decrease in the guinea-pig, which is refractory to azo-dye carcinogenesis. Thus, the ability of the liver to inactivate the dye is greatly decreased in the rat, but not in the guinea-pig, as administration progresses toward the threshold dose for tumorigenesis. On the other hand, constitutive levels of nitrosamine dealkylase are identical in the 2 species and remain essentially unchanged following administration of DEN for 10 weeks. Inasmuch as nitrosamine dealkylation represents activating metabolism, this provides a rationale for the comparable susceptibility of the rat and guinea-pig to DEN carcinogenesis. Of the 2 enzymes in the 2 species, it is only azo-dye reductase in the guinea-pig which appears to be unregulated by glucose repression, since starvation brings about no change in this activity. Starvation-induced increase of azo-dye reductase in the rat is not influenced by administration of 3'-Me-DAB and only slightly by DEN. The starvation-induced increase of nitrosamine dealkylation is abolished, however, in both species by administration of DEN but only slightly decreased by 3'-Me-DAB.
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PMID:Ultrastructural and metabolic determinants of resistance to azo-dye susceptibility to nitrosamine carcinogenesis of the guinea-pig. 41 61

The ultrastructure of primary hepatocytes cultured for 2 to 17 days on floating collagen membrane was evaluated. A pellet of the hepatic cell suspension used to inoculate the collagen membranes contained some single cells and many aggregates of two, three, or four cells. Desmosomes were split during the perfusion, but tight junctions and gap junctions remained intact. By 2 days in culture, the hepatocytes had formed a monolayer of cells of polygonal shape with newly synthesized desmosomes between cells. Since the flexible floating collagen membrane decreases in size as the monolayer forms, the hepatocytes do not flatten out, as is characteristic of cells cultured on a rigid substrate. Hepatocytes in culture for 10 days or less exhibited large lamellar arrays of rough endoplasmic reticulum, well developed Golgi complexes, and structures resembling bile canaliculi, which possess tight junctions and desmosomes separating them from the intercellular space. Microfilaments oriented parallel to the plasma membranes of adjoining cells and in an intermeshed network at the edge of the monolayer and beneath the plasma membrane bordering the medium increased in size and number in older cultures. After 17 days in culture, the cells maintained tight junctions, desmosomes, Golgi complexes, and rough endoplasmic reticulum in small lamellar stacks and in small vesicles. Since hepatocytes on the floating collagen membrane retain most of the subcellular structural elements characteristic of normally functioning hepatocytes for 2.5 weeks, this system may be valuable for future experiments involving drug metabolism and carcinogenesis in vitro.
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PMID:Ultrastructure of adult rat hepatocytes cultured on floating collagen membranes. 56 78

Pituitaries of mammary tumor-bearing mice (C3H) were examined by quantitative electron microscopy. The results indicate that considerable modifications occur in mammotropic and somatotropic cells. Both types show an increase of the surface of the endoplasmic reticulum and a decrease of the volume of secretory granules (in percent of cytoplasmic volume), suggesting a heightened secretory activity of these cells during mammary carcinogenesis.
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PMID:[Mammotropic and somatotropic pituitary cells in spontaneous mammary tumor bearing C3H female mice. A quantitative electron microscope study]. 62 Jul 55

There were found certain changes in the total content of phospholipids as well as in the content of their separate fractions in the membranes of endoplasmic reticulum in the rat liver at early stages of carcinogenesis. In the first week under the carcinogen DENA exposure a considerable reduction of the total phospholipids content was noted in the fraction of granular endoplasmic reticulum, while in agranular reticulum during this period of embryogenesis the total content of phospholipids is not changed, but subsequently the former increases as compared with normal values. During the whole period of carcinogenesis under study changes in the phospholipid content are observed in both fractions of endoplasmic reticulum membranes, the greatest changes being noted in the fractions of lysophosphatidicholines, phosphatidilcholines, and phosphatidilinosites.
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PMID:[Membrane phospholipids of the rat liver endoplasmic reticulum normally and in the early stage of carcinogenesis]. 71 16

Livers of 6- to 7-week-old male C3H/He, CBA, A, and BALB/c mice were examined by electron microscopy for the presence of intracisternal A particles (ICAP) after administration of diethylnitrosamine (DEN) in drinking water. In control mice, ICAP were extremely rare; they were found in the livers of only 2 mice (strains C3H/He and A; none in the other strains). By contrast, the treatment of mice with DEN greatly enhanced the appearance of ICAP in the liver cells of all strains. Within 2 weeks of the treatment, ICAP were found in 8-26% of liver cells examined in all mice and the number of ICAP/cell ranged from 3 to 12. Aside from mild disorganization of the rough endoplasmic reticulum, such as segmentation and vesiculation, liver cells of carcinogen-treated mice showed none of the consistent abnormalities that characterize the appearance of ICAP. The reactivation of ICAP (which are usually suppressed in adult mice) by DEN may become a useful marker for analysis of the sequential alterations of the liver that lead to the development of hepatoma during carcinogenesis.
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PMID:Activation of intracisternal A particles in mouse liver by diethylnitrosamine. 84 86

Male rats were given single doses p.o. of 3'-methyl-4-dimethylaminoazobenzne (3'-MeDAB), either alone or at the same time as single s.c. injections of cycloheximide. They were killed either 24 or 48 hr after treatment or at intervals up to 21 months, and their hepatic tissues were examined by electron density, combined treatment with both chemicals failed to produce this acute toxic effect. However, the fine structure of the hepatic cells of rats given this combined treatment with cycloheximide and 3'-MeDAB closely resembled that obtained by chronic exposure to carcinogenic azo dyes. Of the changes thus produced, the granular endoplasmic reticulum in particular became permanently altered, both quantitatively and morphologically. Other persistent changes included mitochondrial abnormalities and glycogen depletion. Cycloheximide appears to protect the liver cell against the nonspecific acute toxic action of 3'-MeDAB, while facilitating the expression of effects that may possibly be associated with the carcinogenic action of this azo dye. Although this experimental model does not result in the appearance of tumors, it demonstrates that a single exposure to a carcinogen may induce permanent changes that are similar to those observed during carcinogenesis.
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PMID:Fine structural changes in hepatocytes after simultaneous treatment with single doses of 3'-methyl-4-dimethylaminoazobenzene and cycloheximide. 127 25


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