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

Supplementary introduction of a phenobarbital (PB) promotion step after the Solt and Farber procedure dramatically increases the number of phenotypically-altered hepatocytes. These hepatocytes occupy approximately 40% of the liver volume after one week of PB treatment. These areas constitute a relatively uniform cellular population with altered histological phenotype and with distinct histochemical markers used by other authors for the detection of premalignancy. This procedure leads to the appearance of numerous hepatocellular carcinomas at approximately the 36 weeks stage. It was suggested that the early hepatocellular alterations after the initiation/selection procedure followed by PB might correspond to the hyperplasia of phenotypically-altered epidermal cells at the conversion step of mouse skin tumor promotion.
Carcinogenesis 1983
PMID:Phenobarbital as a promoter in the initiation/selection process of experimental rat hepatocarcinogenesis. 682 4

A growing body of evidence from human and animal cancer cytogenetics studies indicates that aneuploidy is an important chromosome change in carcinogenesis. To understand the role of this genetic phenomenon during the first steps of an experimental cancer model, molecular and cellular techniques were combined. A sequential cytogenetic study of a modified Solt-Farber liver cancer model in the rat was performed to identify the importance of chromosome versus genome mutations. Male Wistar rats were initiated with diethylnitrosamine (DENA), followed by a 2-acetylaminofluorene exposure to select resistant hepatocytes. Chronic phenobarbital (PB) treatment was used to induce promotion. Cell proliferation was induced by a necrogenic dose of CCl4, administered during the selection period (Gerlans protocol) or 3 days before hepatocyte isolation (experimental protocol). In order to discriminate between genetic events causing chromosome breakage (clastogenic) and those that induce chromosome loss (aneugenic), isolated micronucleated hepatocytes (MNH) were analysed for the presence of a centromere in the micronucleus (MN). Non-radioactive in situ hybridization with a rat centromere satellite 1 DNA probe was applied. Our results show that the majority of the observed genetic changes, expressed as MN during different preneoplastic stages, were of clastogenic origin. However, the number of induced aneugenic hepatocytes increased markedly during the promotion period of the Gerlans protocol (approximately 7-fold above control) and during PB exposure in the experimental protocol (approximately 4-fold above control). Additionally, these stages were also characterized by an increased level of MN expression (20.3 < % MNH < 32.8), in comparison with the initiation stage after DENA exposure (13.5 < % MNH < 17.1). Although it is not yet clear if these genetic alterations have a causative nature in neoplastic liver transformation, the use of interphase cytogenetics certainly might lead to a better understanding of the genomic changes which occur during experimental hepatocarcinogenesis.
Carcinogenesis 1995 Aug
PMID:Identification of clastogenic and/or aneugenic events during the preneoplastic stages of experimental rat hepatocarcinogenesis by fluorescence in situ hybridization. 763 10

We previously reported that LEC rats, which show a spontaneous occurrence of liver injury and hepatocellular carcinoma (HCC), are highly susceptible to chemical carcinogens such as diethylnitrosamine (DEN). Since abnormal copper accumulation in the liver of LEC rats was found to be a cause of liver injury, it is necessary to elucidate whether the carcinogen susceptibility of LEC rats is related to the accumulation of copper in the liver. In this study we have examined the relationship between the susceptibility of FI [LEC x LEA or LEC x Fischer 344 (F344)] and FI backcross rats to DEN and hepatic copper concentration, as copper accumulation has been demonstrated to be inherited as an autosomal recessive trait. The groups of F1 and F1 backcross rats were given a single intraperitoneal injection of DEN (20 mg/kg wt) and subjected to a modified Solt-Farber protocol for assaying glutathione S-transferase placental form (GST-P)-positive foci. The hepatic copper concentration was examined by atomic absorption. Although no F1 rats showed a high copper concentration in the liver, the numbers of foci were as high as those in LEC rats which accumulate copper. Backcross rats separated into high and low copper concentration groups at an almost 1:1 ratio, but there was no significant difference in the mean numbers of foci between these two groups. The results clearly indicate that the high susceptibility of LEC rats to DEN is genetically independent of copper accumulation in the liver. A possible dominant inheritance of this high carcinogen susceptibility was suggested. Biochemical measurement of cytochromes P450 and b5 in the liver of F1 rats indicated that alterations in drug metabolizing enzymes may be partially responsible for the high carcinogen susceptibility of LEC rats.
Carcinogenesis 1995 Mar
PMID:The high hepatocarcinogen susceptibility of LEC rats is genetically independent of abnormal copper accumulation in the liver. 769 3

Since the expression of glutathione S-transferase P-form (GST-P) has been suggested from in vitro studies to be partly regulated by the oncogene product, c-Jun and c-Fos, their distributions were compared in normal rat tissues and preneoplastic hepatic lesions induced by the Solt-Farber protocol. Immunohistochemically demonstrated GST-P protein was positively correlated with expression of both c-Jun and c-Fos in the epidermis of the skin and the smooth muscle of adult lung and with either c-Jun or c-Fos respectively in the bile ducts and bronchial epithelium. However, GST-P expression was also observed in proximal and distal straight segments of the kidney and other tissues negative for c-Jun and c-Fos and both c-Jun and c-Fos were present in the renal proximal and distal convoluted tubules, where GST-P was lacking. Thus, the localization of GST-P was in some cases clearly separable from those of c-Jun or c-Fos. GST-P was found to be focally expressed from an early stage of hepatocarcinogenesis, when c-Jun was not detectable. At later stages, this oncogene product was stained in 35.7% of GST-P-positive foci, with a clear relation to the degree of GST-P staining. Since GST-P is not always accompanied by appreciable c-Jun or c-Fos, these oncogene products are apparently not prerequisites for its expression. However, c-Jun may be partly responsible for maintaining high levels of GST-P in hepatic foci at later stages of hepatocarcinogenesis.
Carcinogenesis 1995 Mar
PMID:Lack of correlated expression between the glutathione S-transferase P-form and the oncogene products c-Jun and c-Fos in rat tissues and preneoplastic hepatic foci. 769 15

The early cellular changes in the Solt-Farber resistant hepatocyte model of carcinogenesis have been studied to clarify the relationship of oval cell proliferation to the development of early hepatocyte nodules. Cellular proliferation, intermediate filament profiles and the expression of specific cytochrome P450 enzymes were examined. At 24 h after partial hepatectomy (PH) many of the bile ductular cells were in S phase, but over the next few days DNA synthesis progressively decreased in the portal bile ducts and was more common in arborizing ductules (oval cells) radiating from the portal areas. These cells strongly expressed cytokeratins 8 and 19 and vimentin, and from 1 week after PH they frequently underwent differentiation either into hepatocytes, expressing cytochrome P450 enzymes, or into intestinal-type cells. Five days after PH, numerous basophilic foci were discernible, and these expanded rapidly. The ductular cells swirled around the foci, but their antigenic profile clearly indicated that these cells were not involved in the development of these early nodules. In normal hepatocytes, cytokeratin 8 immunoreactivity was distinctly membranous in location, and could only be readily detected in periportal hepatocytes. In the basophilic hepatocyte foci, overexpression of cytokeratin 8 was consistently associated with cells organizing into acini, with expression reminiscent of authentic bile ducts, possibly indicating a structure-function relationship. In conclusion, early foci and nodules in this model are derived from resistant hepatocytes and not ductular oval cells, the latter being a facultative multipotential stem cell compartment.
Carcinogenesis 1995 Apr
PMID:The resistant hepatocyte model of carcinogenesis in the rat: the apparent independent development of oval cell proliferation and early nodules. 772 66

Butylated hydroxytoluene (BHT) is a synthetic, food-use, phenolic antioxidant. It has previously been demonstrated to be operationally non-genotoxic and, in addition, failed to induce biologically significant increases in cellular proliferation in the liver, urinary bladder and thyroid gland on feeding to young adult Wistar rats. Nevertheless, it has been reported to enhance the yield of liver tumors when fed to rats or mice that developed an appreciable background incidence of these tumors without treatment. In order to resolve this situation, cell proliferation in response to BHT treatment was studied in enzyme-altered foci (EAF) induced in male Fischer 344 rats using the Solt-Farber procedure. It was demonstrated that feeding 0.5% dietary BHT for 30 days after the induction of EAF led to a 20- to 30-fold increase in the gamma-glutamyltranspeptidase-positive areas in both DEN- and saline-initiated rat livers, but to no major effects in glutathione S-transferase placental form (GSTP)-positive foci. Cell proliferation rates within EAF and surrounding normal liver were measured using different histological techniques. Nuclear labeling with [3H]thymidine and proliferating cell nuclear antigen (PCNA) over the total hepatocyte population indicated that BHT approximately doubled nuclear labeling in rats initiated with DEN. PCNA labeling in GSTP-positive foci was not affected by BHT. In GSTP-positive foci, evaluation of nucleolar organizer regions (AgNOR), which reflect cell proliferative in addition to transcriptional activity of ribosomal RNA, was achieved using a novel double staining technique. BHT diet did not affect the number of AgNOR per nucleus or the percentage AgNOR area/nucleus. Nevertheless, both PCNA labeling and the AgNOR area per nucleus were significantly greater in GSTP-positive foci compared with non-focal regions in rats fed either BHT or control diets. These results are discussed in the light of further experimental work required to determine the relevance of these data to possible human risk assessment for BHT.
Carcinogenesis 1995 May
PMID:The effect of butylated hydroxytoluene on the growth of enzyme-altered foci in male Fischer 344 rat liver tissue. 776 67

The profiles of the calcium-dependent protein kinase C (PKC) isozymes alpha, beta, and gamma were examined in subcellular fractions from Fischer 344 rat liver during the early stages (48 h, 96 h, 7 d, and 60 d) of diethylnitrosamine (DEN)-induced carcinogenesis, using the Solt-Farber "resistant hepatocyte" model (DEN-2-acetylaminofluorene-partial hepatectomy; DEN-AAF-PH), and then related to the presence of focal or nodular gamma-glutamyl transpeptidase (GGT)-positive morphologic changes in the liver. After DEAE and hydroxyapatite column chromatography, two peaks, immunologically identified as PKC-alpha and -beta isoforms, were detected in the liver of normal (alpha/beta ratio = 4.0) and treated rats. In DEN-AAF-PH hepatocarcinogenesis an increase in PKC-alpha expression was found after PH (+43 +/- 19% at 48 h, alpha/beta ratio = 5.1; +125 +/- 25% at 96 h, alpha/beta ratio = 4.8), whereas the PKC-beta isoform appeared less significantly modified (+11 +/- 3% at 48 h and +89 +/- 17% at 96 h). Seven and 60 days after PH, a marked increase in the PKC-alpha (+96 +/- 20% and +150 +/- 48%, respectively) and PKC-beta isoforms (+158 +/- 41%, alpha/beta ratio = 3.1 and +130 +/- 26%, alpha/beta ratio = 4.4, respectively), occurred along with the appearance of GGT-positive altered hepatic foci and nodules in the liver sections. Sham hepatectomy caused PKC-alpha and -beta isoform activities similar to those of normal controls. In contrast, saline-AAF-PH-treated rats had downregulation of PKC-alpha after PH (alpha/beta ratio = 1.8 at 96 h), possibly due to the mitoinhibitory effect of the carcinogen AAF on normal uninitiated hepatocytes. Immunohistochemical analysis with monoclonal antibodies to PKC-alpha and -beta revealed diffuse positive cytoplasmic signals in GGT-positive foci and nodules in rat liver. Taken together, these preliminary results, using the Solt-Farber model of liver carcinogenesis, suggest a role for PKC in tumor promotion. They also suggest that the PKC-alpha isoform may play a specific role in clonal expansion of DEN-initiated hepatocytes after PH.
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PMID:Analysis of calcium-dependent protein kinase C isoforms in the early stages of diethylnitrosamine-induced rat hepatocarcinogenesis. 790 65

Expression of transforming growth factor alpha (TGF alpha) was investigated immunohistochemically in preneoplastic and neoplastic hepatocytes induced by the Solt-Farber regimen. Although TGF alpha was almost negative in early lesions comparing carcinogen-altered hepatocytes, it was expressed in approximately 65% of the late lesions. Growth factor localization was predominantly in the cytoplasm or at the bile canalicular membrane within individual lesions, both types being observed at various ratios. Hyperplastic nodules (HPN) predominantly consisting of cells with cytoplasmic type staining showed expansive growth with more abundant expression of EGF receptors (EGFR) and proliferating cell nuclear antigen (PCNA) than those with the membranous localization. The staining patterns of TGF alpha, EGFR and PCNA in hepatocellular carcinomas (HCC) were similar to those of cytoplasmic type growth factor-positive HPN. Western blotting analysis for TGF alpha demonstrated a single 30 kDa protein in lysates of HPN and HCC. Since this protein was broken down to the 6 kDa mature TGF alpha via 20, 16 and 14 kDa forms by treatment with bovine pancreatic elastase, it may represent a physiological precursor. No mature TGF alpha was detected in the conditioned medium of cultured HPN cells, although a small amount of the 30 kDa form was identified. These results suggest that this form of TGF alpha may have an important role in the growth of preneoplastic and neoplastic hepatocytes during rat hepatocarcinogenesis.
Carcinogenesis 1994 Aug
PMID:Abundant TGF alpha precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogen-induced preneoplastic and neoplastic hepatocytes in rats. 791 77

We followed the expression of several glutathione S-transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt-Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S-transferase subunits Yf (pi-class), Ya (alpha-class) and Yb1 (mu-class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S-transferase Yb2 (mu-class) subunit expression, 5% of Yf-positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S-transferase subunits Yf, Ya and Yb1, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S-transferase subunit expression were confirmed by quantitative analysis by reverse-phase HPLC of S-hexylglutathione affinity-purified glutathione S-transferases from advanced tumors. Cytosolic glutathione S-transferase activity for trans-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S-transferase activities for 1-chloro-2,4-dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S-transferase subunits are induced is associated with the loss of a major constitutive mu-class hepatic glutathione S-transferase. Although the mechanism and role of the reduction or loss of glutathione S-transferase Yb2 during malignant progression are unknown, we propose that loss of glutathione S-transferase Yb2 in some preneoplastic populations of hepatocytes might be conducive to further DNA damage by presently unknown environmental or endogenous compounds that are normally detoxified preferentially by glutathione S-transferase isoenzymes containing this subunit.
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PMID:Reduced expression of glutathione S-transferase Yb2 during progression of chemically induced hepatocellular carcinomas in Fischer 344 rats. 802 Aug 84

The activity and expression of Ca(2+)-dependent cPKC alpha and beta isoenzymes in the particulate, soluble (cytosolic) and nuclear fractions of rat liver and the expression of Ca(2+)-independent nPKC delta and aPKC zeta were examined during the early stages (30 and 60 min, 24 and 96 h and 7 and 60 days post-hepatectomy) of the Solt-Farber 'resistant hepatocyte' model of diethylnitrosamine (DENA)-induced hepatocarcinogenesis in Fischer 344 rats and related to the presence of gamma-glutamyl transpeptidase (GGT)-positive hyperplastic cell foci and persistent nodules in rat liver. Total PKC activity was unmodified by the carcinogenic treatment. In contrast, the PKC activity in the particulate, as well as nuclear fractions increased with time, reaching a maximum 60 days post-hepatectomy, with a decrease in the cytosolic activity. In carcinogen-treated animals maximal expression of cPKC alpha and beta isoenzymes was present 7 days post-hepatectomy, while no changes in nPKC delta and aPKC zeta immunoreactivity were detected. In the nucleus, no cPKC alpha isoform expression was observed, the cPKC beta expression being maximal at 60 days. Seven and 60 days post-hepatectomy GGT-positive hyperplastic cell foci and persistent nodules were present in rat liver respectively. Taken together, the results of this study suggest a role for nuclear cPKC beta and for cPKC alpha in promoting the selective growth of carcinogen-initiated hepatocytes in rat liver. No evidence for a role of Ca(2+)-independent nPKC delta and aPKC zeta isoenzymes in the early stages of DENA-induced liver carcinogenesis could be demonstrated.
Carcinogenesis 1994 Aug
PMID:Membrane and nuclear protein kinase C activation in the early stages of diethylnitrosamine-induced rat hepatocarcinogenesis. 805 57


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