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

As previously demonstrated, chronic administration of phenobarbital (0.05% in the drinking water) and of nafenopin (0.1% in the diet) increases the incidence and the kinetics of appearance of liver cancers. If bile acids play a key role in liver carcinogenesis, it might thus be expected that treatments like phenobarbital or nafenopin, which positively modulate that process, also modify their hepatic pool. The aim of the present study was to analyze the modifications of the liver bile acid pool during the modulation of liver carcinogenesis by phenobarbital and nafenopin. The animals were submitted to the hepatocarcinogenic initiation-selection (IS) procedure adapted from Solt and Farber. As compared to basal diet, the chronic feeding of phenobarbital significantly increased the total concentrations of liver bile acids both at weeks 9 and 17. That increase was mainly due to a change in the concentration of beta-muricholic acid and hyodeoxycholic acid and, to a lesser extent, of chenodeoxycholic acid and alpha-muricholic acid. In contrast, feeding a diet containing nafenopin led to a significant decrease in the concentration of liver bile acids, due to a complete disappearance of chenodeoxycholic acid and muricholic acid, and a decrease in the concentration of hyodeoxycholic acid. Carcinomas appearing in IS phenobarbital-treated rats contain fewer bile acids than the surrounding parenchyma (because of the decrease in deoxycholic acid and ursodeoxycholic acid) whereas the malignant tumors appearing in IS nafenopin-treated rats have essentially the same pattern of bile acids as the surrounding parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modifications of liver bile acids pool during modulation of rat hepatocarcinogenesis by phenobarbital and nafenopin. 809 30

Mutations of p53 and Ki-ras exon 1 were investigated in rat hepatic lesions induced by four kinds of hepatocarcinogenic protocols: continuous feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), daily intraperitoneal injection of aflatoxin B1 (AFB1), and the Solt and Farber regimen (Nature 236:701-703, 1976), in which diethylnitrosamine (DEN) or nitrosomethylurea (NMU) was used as initiating agents. DNA from microdissected tissue sections was amplified by the polymerase chain reaction (PCR) directly using primers for p53 exons 5-8 and Ki-ras exon 1 and analyzed for mutations by denaturing gradient gel electrophoresis (DGGE) or constant denaturant gel electrophoresis (CDGE). One or both of the p53 PCR primers were located within introns to prevent amplifying the p53 processed pseudogenes. In a total of 59 hepatocellular carcinomas (HCCs), no p53 aberrations were detected, indicating that p53 mutations are not very important in rat hepatic carcinogenesis. On the other hand, Ki-ras codon 12 mutations were found at low frequency in HCCs, hyperplastic foci, and cholangiofibroses induced by 3'-Me-DAB and by AFB1 but not in the lesions induced by the Solt and Farber regimen. Although Ki-ras codon 12 mutations are generally infrequent in rat hepatic tumors, their incidence thus appears to vary depending on the carcinogen used for their induction.
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PMID:Absence of p53 mutations and various frequencies of Ki-ras exon 1 mutations in rat hepatic tumors induced by different carcinogens. 818 29

Liver carcinogenesis is considered to be a good experimental model to study the sequential changes leading to cancer and was applied here for the analysis of chromosome/genome mutations. Since the micronucleus test was shown to be an adequate method to detect and analyse chromosome changes in dividing cells, the frequency of micronuclei (MN) together with their relative DNA content (DNA content of the MN divided by the DNA content of the corresponding nucleus) were analysed in hepatocytes isolated from rats at different stages of experimentally induced hepatocarcinogenesis. The protocol used for the induction of liver cancer was based on the triphasic 'Gerlans protocol', a Solt-Farber procedure supplemented with a phenobarbital (PB) promotion step. Male Wistar rats were initiated by a single i.p. dose of diethylnitrosamine (DENA), followed by selection of the resistant hepatocytes by 2-acetylaminofluorene (2-AAF). Subsequent promotion was accomplished by chronic exposure to phenobarbital. For each group of rats a mitotic stimulator (CCl4) is necessary at the end of their treatment period to express the clastogenic and/or aneugenic lesions which may lead to micronuclei. The results of these experiments do confirm that genetic alterations are occurring at the chromosome level (MN expression) during the different steps of experimental rat liver carcinogenesis. DNA measurements seem to be a good genetic parameter to detect eventual differences between the chromosomal content (whole chromosome or chromosome fragments) of MN populations appearing in different stages of the carcinogenic process. Moreover, a comparison between the mono- and bi-nucleated cell population showed that the frequency of micronuclei is higher in mononuclear parenchymal liver cells.
Carcinogenesis 1993 Nov
PMID:Frequency and DNA content of micronuclei in rat parenchymal liver cells during experimental hepatocarcinogenesis. 824 71

The question of a possible precursor--product relationship between oval cells and hepatocytes was examined in rats treated for 2 weeks with 2-acetylaminofluorene (2-AAF) with a two-thirds partial hepatectomy (PH) performed after the first week of 2-AAF treatment (modified Solt-Farber model). Liver cells were pulse-chase labelled with bromodeoxyuridine (BrdU) on day 6 post PH. On day 7 post PH the nonparenchymal (NPC) fraction, which contains the oval cells, exhibited a labelling index (LI) approximately 10 times higher than that of the hepatocytes as analysed by flow cytometry (FCM), the majority of the proliferating cells being oval cells. At later time points, there was no significant increase in the LI of diploid hepatocytes, and no detectable shift of BrdU-labelled cells from the NPC fraction to the hepatocyte fraction, suggesting that no extensive conversion of BrdU-labelled oval cells to hepatocytes was taking place. Throughout the experimental period there was a significant increase in the diploid hepatocyte cell fraction, from 12% on day 7 to 25% on day 13 post PH. Diploid hepatocytes pulse-labelled on days 7 or 9 post PH had a high LI (7-8%), in contrast to the low LI (1%) of tetra- and octoploid cells. Proliferation of diploid hepatocytes may thus explain the large increase in the diploid hepatocyte fraction observed from days 9 through 15 post PH. Our results, therefore, provide no reason to invoke oval cells as precursors of hepatocytes in the modified Solt-Farber carcinogenesis model.
Carcinogenesis 1994 Jan
PMID:Flow cytometric investigation of a possible precursor--product relationship between oval cells and parenchymal cells in the rat liver. 829 49

Analbuminemic rats differ from Sprague-Dawley rats (SD), their strain of origin, with respect to carcinogenic susceptibility of various organs. We compared hepatic changes after carcinogenic treatments in two kinds of analbuminemic rats with different genetic backgrounds (NAR isolated from outbred SD and F344-alb F344-congenic analbuminemic rats) as well as in their parent strains. After the rats were treated according to the Solt-Farber protocol [a single dose of diethylnitrosamine (DEN) followed by dietary 2-acetylaminofluorene (2-AAF) plus partial hepatectomy], F344 and F344-alb demonstrated similar numbers of much larger hyperplastic hepatic nodules (HPN) than SD or NAR, while in the latter two cases, sizes are approximately the same, NAR had a greater number of HPN. When HPN cells of F344 rats were infused into the portal vein of F344 and F344-alb, followed by treatment with the Solt-Farber protocol, the transplanted cells formed almost the same numbers of colonies of almost equal size within the livers in these two strains of rats. With continuous administration of a 2-acetylaminofluorene (2-AAF) diet, which can change the normally albumin-negative hepatocytes of analbuminemic rats to albumin-positive cells, this process occurred earlier in F344-alb than NAR, but almost the same numbers were reached after 30 days. The results demonstrate responses to significantly differ between NAR and F344-alb, with both resembling their parent strains to a large extent, indicating that genetic background has the major influence on susceptibility to hepatic carcinogenesis, rather than analbuminemia itself.
Carcinogenesis 1994 Feb
PMID:Analbuminemia does not significantly influence hepatocarcinogenesis on comparing F344 rats and a congenic line carrying the analbuminemic mutation. 831 13

Structural alterations of the p53 gene were investigated in chemically induced rat hepatocellular carcinomas (HCCs), hyperplastic hepatic nodules (HPNs), and cell lines derived from rat neoplastic and normal liver cells. The mutations were detected by GC-clamped denaturing gradient gel electrophoresis using DNA that had been amplified from p53 mRNA by the reverse transcriptase-polymerase chain reaction. This method enabled us to find single-base changes within the p53 gene without using radioisotopes. The presence of mutations was subsequently confirmed by DNA sequencing. No mutations were detected in six primary HCCs and 12 HPNs induced by the Solt and Farber regimen (Nature 236: 701-703, 1976), suggesting that p53 gene mutations do not play a major role in rat hepatic carcinogenesis. However, five of seven HCC cell lines and one of two cell lines derived from normal liver cells had the mutated p53 gene and had lost the normal p53 gene. Five cell lines had a G-->T transversion at various codons, whereas one line had a 21-base deletion in exon 5. Therefore, we conclude that p53 gene mutations may occur in vitro during establishment of the cell lines or may be derived from very small populations within the primary tumors.
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PMID:Detection of p53 gene mutations in rat hepatocellular carcinoma cell lines by denaturing gradient gel electrophoresis. 835 84

Glutathione transferase P (GST-P; glutathione transferase, EC 2.5.1.18) is known to be specifically expressed at high levels in precancerous lesions and in hepatocellular carcinomas from a very early phase of chemically induced hepatocarcinogenesis in the rat. The almost invariable occurrence of this phenotype in these lesions strongly suggests a mechanism by which GST-P gene is activated together with a crucial transforming gene of liver cells. To distinguish the two alternative possibilities--either the GST-P gene is coactivated with a closely located transforming gene by a cis mechanism or it is activated in trans by a common trans-acting factor--we carried out carcinogenesis experiments using transgenic rats harboring the bacterial chloramphenicol acetyltransferase reporter gene ligated to the upstream regulatory sequence of the GST-P gene. In each of three independent lines tested, liver foci and nodules produced by chemical carcinogens (Solt-Farber procedure) were found to express high levels of chloramphenicol acetyltransferase activity, indicating clearly that the GST-P gene is activated by a trans mechanism during hepatocarcinogenesis.
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PMID:Trans-activation of glutathione transferase P gene during chemical hepatocarcinogenesis of the rat. 844 29

While glutathione S-transferase P form (GST-P), a reliable marker for preneoplastic lesions induced by mutagenic hepatocarcinogens, is generally not expressed in rat liver foci, hyperplastic nodules and hepatomas induced by peroxisome proliferators (PPs), such lesions can be detected due to their peroxisomal enzyme-negative nature. For comparative purposes we examined the inducibility of enoyl CoA hydratase (ECH), a key peroxisomal enzyme, in rat hepatic preneoplastic lesions induced by mutagenic carcinogens. Clofibrate (CF) was therefore administered for 2 or 4 weeks following performance of the Solt-Farber protocol using diethylnitrosamine and 2-acetylaminofluorene. Immunohistochemical examination revealed no or only very weak expression of ECH within the induced foci in clear contrast to the strong staining of surrounding parenchyma. ECH expression was thus diametrically opposed to that of GST-P which was found only in foci. Although ECH was completely lacking in GST-P-strongly positive foci, it was expressed in GST-P-negative hepatocytes inside some foci otherwise positive for GST-P. CF administration resulted in a significant decrease in the numbers and areas of foci exhibiting strongly positive or positive GST-P staining; this being reflected in a lowering of GST-P protein levels. Furthermore, in primary cultured rat hepatocytes, clofibric acid as well as dexamethasone suppressed the expression of both GST-P and the oncogene, c-jun. These results taken together suggest that possible interaction of the PP receptor with JUN might be involved in loss of ECH expression in GST-P-strongly positive foci.
Carcinogenesis 1993 Mar
PMID:Lack of peroxisomal enzyme inducibility in rat hepatic preneoplastic lesions induced by mutagenic carcinogens: contrasted expression of glutathione S-transferase P form and enoyl CoA hydratase. 845 14

It is widely believed that abnormal production of polypeptide growth factors, together with other molecular alterations, play an important role in neoplastic development. Transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major growth factors that contribute to liver regeneration occurring via both hepatocyte replication and oval cell proliferation. It is not clear, however, whether and to what extent these growth factors are also involved in hepatocarcinogenesis. In the present study, the gene expression of TGFalpha, HGF and aFGF and their corresponding receptors was examined by Northern blotting and in situ hybridization during hepatocarcinogenesis induced by the Solt-Farber protocol. All three growth factor/receptor systems, TGFalpha/epidermal growth factor receptor (EGFR), HGF/c-met and aFGF/FGF receptors (flg and bek) were significantly elevated at early time points when oval cells were proliferating. Their respective expression decreased after 1 month and remained at a low level until the development of liver tumors. In all hepatocellular carcinomas (HCC) examined, the transcripts of TGFalpha and aFGF were highly expressed, while those of HGF were low. With regard to the receptor expression in the tumors, EGFR was present at varying levels, c-met was expressed at higher levels and flg increased significantly, whereas bek remained at low levels. These data suggest that TGFalpha and aFGF are the major growth factors involved in the progression of HCC, and that the signal of aFGF is mainly transduced by the receptor flg in HCC. Furthermore, HCC cells were phenotypically very similar to oval cells with regard to the gene expression of growth factor/receptor systems. These results, along with the finding that all the HCC cells are positive for the oval cell antigen OV6, and that cytokeratin 19 is heavily expressed in both tumor and oval cells, strongly suggest that at least some of the HCC induced by the Solt-Farber protocol may be derived from oval cells.
Carcinogenesis 1996 May
PMID:Expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis. 864 Sep 40

In a previous paper (Barboro et al., 1993, Biophys. J. 65, 1690-1699) we have shown that cancer development in the resistant hepatocyte model of Solt and Farber is characterized by the progressive unfolding of the higher-order structure of chromatin. A possible functional role of decondensation phenomena in cell transformation cannot be ruled out. Genetic activation involves the relaxation of the superstructure of chromatin, which may be, at least in part, modulated by its interaction with the nuclear matrix. Moreover, recent observations suggest that gene expression can be stimulated by alterations in the organization of the cytoskeleton. Therefore, we have characterized the changes in composition that the nuclear matrix-intermediate filament complex undergoes during the evolution of rat hepatocyte nodules. Dramatic changes in the expression of both the nuclear matrix and intermediate filament proteins occur during transformation; they are, however, related in a different way to the stages of carcinogenesis. Several new nuclear matrix proteins appear in early nodules, isolated 9 weeks after initiation. The subsequent evolution of persistent nodules is also characterized by discrete changes in the composition. Thus, the new synthesis of nuclear matrix proteins reflects the emergence of successive cellular populations, in line with the recent finding that a subset of components of the nuclear matrix is cell type-specific. In contrast, intermediate filament proteins undergo continuing changes. A new keratin with apparent molecular weight of 39 kDa, analogous to human keratin 19, appears in early nodules, and its expression steadily increases up to the 32nd week from initiation; at the same time, the amount of the proteolytic fragments of keratins A and D increases sharply. These findings suggest that the inappropriate expression of keratin 19 may be involved in the epigenetic activation of new cellular programs, through the rearrangement of the cytoskeleton which in turn may perturb nuclear matrix function.
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PMID:Changes in the cytoskeletal and nuclear matrix proteins in rat hepatocyte neoplastic nodules in their relation to the process of transformation. 866 Sep 20


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