Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Slices of liver from CD rats were evaluated by autoradiography after exposure to N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) labeled in the acetyl moiety with tritium. These in vitro experiments showed that the incorporation of the acetyl group of N-hydroxy-AAF was a sulfate-dependent enzymatic process in livers from male rats. Livers from females, and hyperplastic nodules and carcinomas induced in the livers of males, were essentially incapable of carrying out this reaction. The results of these in vitro experiments were compared with those obtained with liver sections from a male CD rat exposed in vivo to the tritiated N-hydroxy-AAF. A close relationship between covalent binding and necrosis was demonstrated by the observation that the acetyl moiety of N-hydroxy-AAF was preferentially incorporated into the periportal area, the same area in which liver necrosis occurs after a single injection of the hydroxamic acid. These data offer a biochemical rationale for the relative sensitivities of these cells to the toxic effects of N-hydroxy-AAF and its parent amide. There were no differences in the incorporation of ring-labeled N-hydroxy-4-acetylaminobiphenyl with respect to the sex of the animal or to the morphological characteristics of the tissue. The inhibition of the formation of these adducts by paraoxon suggests that they resulted from the action of deacetylases in the endoplasmic reticulum.
Carcinogenesis 1982
PMID:Sulfotransferase and deacetylase in normal and tumor-bearing liver of CD rats: autoradiographical studies with N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl in vitro and in vivo. 696 Sep 74

Inbred male Leeds strain rats were given a diet containing 0.05% N-fluoren-4-ylacetohydroxamic acid for up to 7 months. A modified method for the synthesis of this compound is described. Rats were killed at intervals during and after treatment and their liver tissues examined by light and electron microscopy. The treated rats developed a very low incidence of (non-hepatic) tumours and hepatic clear cell foci appeared during the late stages of the experiment. The only significant fine structural changes observed were glycogenosis and alterations in the morphology of the rough endoplasmic reticulum, both of which developed only after prolonged treatment and affected a minority of hepatocytes. These changes are discussed in relation to the fine structural changes elicited by the strongly carcinogenic N-fluoren-2-ylacetamide and the non-carcinogen, N-fluoren-4-ylacetamide.
Carcinogenesis 1982
PMID:Effects of prolonged oral treatment with N-fluoren-4-ylacetohydroxamic acid on rat liver fine structure. 706 32

Male Syrian golden hamsters were given weekly s.c. injections of 250 mg/kg body weight of N-nitroso-bis(2-hydroxypropyl)amine (BHP) for up to 15 weeks. Electron microscope studies were carried out on early changes in the exocrine pancreas of these hamsters for 2 weeks to 15 weeks. The majority of observed alterations occurred in the acinar cells and included the appearance of "dark" and "light" cells, the former showing nuclear shrinkage and irregularity but maintaining a normal rough endoplasmic reticulum (ER) and zymogen content. The "light" cells exhibited a variety of early fine structural alterations including conformational changes in their rough ER, together with a reduction in zymogen granules, increased autophagic vacuoles and Golgi hypertrophy. Ducts and ductules were relatively unaffected. The observations indicate that the acinar cells were most affected, morphologically, by BHP and are consistent with the view that these cells are the primary target for BHP.
Carcinogenesis 1982
PMID:Ultrastructural analysis of pancreatic carcinogenesis. VI. Early changes in hamster acinar cells induced by N-nitroso-bis(2-hydroxypropyl)amine. 713 63

Neoplastic liver nodules were induced by a single administration of N-nitrosodiethylamine (NDEA) and selectively stimulated to growth by 2-acetylaminofluorene (2-AAF) and partial hepatectomy to provide morphological data on very early and late stages of preneoplastic development. Presumptive preneoplastic liver cells were recognizable by light and electron microscopy by 2 days after partial hepatectomy, and they developed within 2 weeks into large, solid nodules consisting of plates of 2 or 3 cell layers thick, that compressed the surrounding non-nodular tissue. The cells showed nuclei with an enlarged nucleolus, tortuously dispersed rough endoplasmic reticulum (RER) and an electron lucent cytoplasm. These features remained present throughout the first 2 weeks of growth. During this period the initially small, distinct smooth endoplasmic reticulum areas proliferated gradually. They were associated with an increasing incidence of cytoplasmic membranes whorl formation and incidentally with annulate lamellae. After withdrawal of 2-AAF the majority of the nodules regressed resulting in slowly disappearing foci of glycogen rich cells. A relatively small number of solid nodules persisted. They were characterized by large cells with a homogeneous eosinophilic cytoplasm, enlarged cells with a homogeneous eosinophilic cytoplasm, enlarged nucleoli and dispersed RER. Because these characteristics were absent in nodular cells that had reverted to normal liver cells, it is not appropriate to consider these characteristics to represent neoplastic transformation per se.
Carcinogenesis 1981
PMID:Short-term induction of neoplastic nodules in the rat liver. II. Study of their development and the effects of withdrawal of 2-acetylaminofluorene. 727 98

Electron and high resolution light microscope studies were made of the pseudoductular structures that develop in the pancreas of the Syrian hamster during chronic treatment with the pancreatocarcinogen, N-nitroso-bis(2-hydroxypropyl)amine (BHP). These pseudoductules, which precede the development of tumours, arise from acini, whose cells undergo dedifferentiation by selective autophagy of their zymogen granules and granular endoplasmic reticulum. It is proposed that the pseudoductules develop into the ultrastructurally similar cystic foci that appear to be the immediate precursors of pancreatic tumours in this experimental model. The possibility is discussed that the acinar cells are the primary target for BHP carcinogenesis.
Carcinogenesis 1981
PMID:Ultrastructural analysis of pancreatic carcinogenesis. IV. Pseudoductular transformation of acini in the hamster pancreas during N-nitroso-bis(2-hydroxypropyl)amine carcinogenesis. 732 24

Morphologically atypical cells were first detected on the 98th day after subcutaneous implantation to rats of a paraffin pellet containing 2 mg of 7,12-dimethylbenz(a)anthracene (DMBA). These cells subsequently formed groups and finally gave rise to malignant fibrous histiocytomas. Early atypical cells were located between proliferating fibroblasts and histiocytes in the center of a fibrous capsule surrounding the DMBA-pill. They exhibited a smooth cell surface, dilated rough endoplasmic reticulum, multiple Golgi complexes, and were often associated with newly formed collagen. These cells incorporated 3H-thymidine and 3H-proline intensively, and showed weak acid phosphatase activity, but no features typical for macrophages (microvilli, numerous lysosomes, high activity of acid phosphatase, nonspecific esterases, antigens recognized by monoclonal antibodies ED1 and OX-42, vital staining with trypan blue). Atypical cells also did not differentiate into muscle cells (no expression of desmin and the alpha-sarcomeric form of actin), nor into Schwann cells (no expression of S-100 protein). No point mutation of the neu gene at nucleotide 2007, which is specific for N-ethyl-N-nitrosourea and DMBA-induced malignant rat schwannoma cells, was detected by polymerase chain reaction-restriction fragment length polymorphism analyses of microscopically selected regions of individual 7 micron cryostat sections. These results support the view that malignant fibrous histiocytoma is derived from immature fibroblasts exhibiting pronounced phenotypic diversity during later stages of carcinogenesis.
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PMID:[The early stages of the morphogenesis and tissue lineage of an experimental malignant fibrous histiocytoma]. 769 95

Morphologically atypical cells were first detected in the adjacent connective tissue 98 days after implanting a paraffin pill containing 2 mg of 7,12-dimethylbenz[a]anthracene (DMBA) into the subcutaneous tissues of rats. These cells subsequently formed groups and finally produced gross malignant fibrous histiocytomas (MFH). Early atypical cells were located between proliferating fibroblasts and histiocytes in the center of a fibrous capsule surrounding the DMBA pill. They exhibited a smooth cell surface, dilated rough endoplasmic reticulum, multiple Golgi complexes, and were often associated with newly formed collagen. These cells incorporated [3H]thymidine and [3H]proline intensively, and showed weak acid phosphatase activity but no features diagnostic of macrophages (microvilli, numerous lysosomes, high acid phosphatase and non-specific esterase activities, antigens recognized by monoclonal antibodies ED1 and OX-42 and vital staining with trypan blue). There was no evidence that atypical cells differentiated into muscle cells (no expression of desmin or the alpha-sarcomeric form of actin) or Schwann cells (no expression of S-100 protein). No point mutation in the neu gene at nucleotide 2007, specific for N-ethyl-N-nitrosourea- and DMBA-induced malignant rat schwannomas, was detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analyses. These results support the view that malignant fibrous histiocytoma is derived from immature fibroblasts exhibiting pronounced phenotypic diversity during the later stages of carcinogenesis.
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PMID:Development of malignant fibrous histiocytoma induced by 7,12-dimethylbenz[a]anthracene in the rat: characterization of early atypical cells. 790 72

In two recently reported cases, integrated hepatitis B virus (HBV) DNAs cloned from hepatocellular carcinoma were found to express a transcriptional transactivator from 3'-terminally truncated HBV surface (preS/S) genes. In this study, we characterized the transactivator at the protein level. Expression of a 3'-truncated preS2/S gene in Spodoptera frugiperda (Sf9) insect cells resulted in a C-terminally truncated middle surface protein of 76 amino acids (MHBst76), which was found to be associated with membranes of the endoplasmic reticulum and retained from Golgi processing and secretion. Accordingly, the microsome fraction of MHBst76-expressing Sf9 cells displayed transactivator activity after electric field-mediated transfer into Chang liver cells. In contrast to full-length MHBs, MHBst76 is unglycosylated, and glycosylation is not required for transactivation as shown by mutation of the glycosylation site at asparagine-4. Since highly purified MHBst76 derived from an E. coli expression system also showed transactivator activity, it is concluded that unglycosylated MHBst76 protein is the authentic transactivating factor. As the transactivator protein derives from inactive MHbs by rearrangements of integrated HBV DNA, it may be important for HBV-associated liver carcinogenesis.
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PMID:ER-localization and functional expression of the HBV transactivator MHBst. 824 38

A positive association between the incidence of hepatocellular carcinoma and the consumption of alcoholic beverages has been reported from some countries. The possible mechanistic nature of the association remains unclear, however. The effects of alcohol, as ethanol and as ethanol in various complex mixtures in the many different alcoholic beverages, were compared with the effects of well-known genotoxic and nongenotoxic or epigenetic carcinogens in carcinogenesis. There is no convincing evidence that alcohol can initiate the long multistep process of development of hepatocellular carcinoma. Thus, it appears that alcohol cannot be considered as a complete carcinogen. The effects of alcohol were also compared with known promoting agents for liver cancer. Although the available data are less clear, nevertheless it appears that alcohol cannot be considered as a bona fide promoting agent for liver cancer development. The most likely roles of alcohol in the genesis of liver cancer are: (1) to induce a well-known precancerous liver lesion, cirrhosis, and (2) to modulate, in an as yet ill-defined manner, the process of cancer development with known human carcinogenic influences such as hepatitis due to hepatitis B and hepatitis C viruses. Alcohol is well known to induce several enzymes in the liver and, thus, could theoretically modulate one or more steps in the carcinogenic process. Because alcohol has been found to alter cell membranes in well-defined ways and cell membrane changes, especially in the liver endoplastic reticulum, appear to be common in the later steps in liver cancer development, it is suggested that one site of alcohol action might be in the modulation of the biophysical composition of the liver endoplasmic reticulum and plasma membrane, favoring the cellular evolution to neoplasia.
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PMID:Alcohol and other chemicals in the development of hepatocellular carcinoma. 879 78

One of the most important processes controlling cellular detoxification is carried out in the endoplasmic reticulum by glucuronidation, and most likely plays an important role in the defense mechanism against chemical-induced carcinogenesis. The human UDP-glucuronosyltransferase UGT1A locus encodes up to 12 unique transferases that are transcribed through selective exon sharing. Little is known about how this locus is regulated in human tissues. We present evidence that the UGT1A gene products are differentially expressed in normal liver tissue, which is composed of hepatocellular and biliary tissue, as well as in malignant and premalignant tumor tissue. In liver, UGT1A1, UGT1A3, UGT1A4, and UGT1A9 are expressed, and are all significantly down-regulated in malignant hepatocellular carcinoma and its premalignant precursor, hepatic adenoma, but not in benign focal nodular hyperplasia. UGT1A6, which is expressed abundantly in liver, is not significantly regulated in liver tumors. UGT1A10, a newly discovered UGT1A gene product, is expressed only in biliary and not hepatocellular tissue and is also significantly down-regulated in cholangiocellular carcinoma. Differential regulation between normal biliary tissue and tumor is also observed with UGT1A4. These findings implicate the regulation of the UGT1A locus as a putative early event in hepatocarcinogenesis that discriminates between benign and malignant hepatotumorigenesis and indicates that a complex mode of cellular control underlies the regulation of this locus.
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PMID:Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer. 923 Feb 12


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