Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-Hexachlorocyclohexane (alpha-HCH) was administered p.o. to female Wistar rats for periods of up to 33 months; doses were 20 mg/kg/day, 200 mg/kg every second week, or 420 mg/kg every third week. Increases of liver size, DNA, RNA, and protein (by 50 to 100%) and of drug-metabolizing enzyme activities (up to 300%) observed previously after single doses of alpha-HCH were found to persist after approximately one-third, 1, and 2 years of treatment. At 1 and 2 years, DNA synthesis was measured by [3H]thymidine uptake and was no higher than in controls. All changes regressed upon withdrawal of alpha-HCH after 1 year of treatment. These findings provide no evidence to suggest a protracted development of toxicity or of growth autonomy in the majority of liver cells. Foci of altered cells, neoplastic nodules, and in 2 animals hepatocellular carcinoma were detected histologically in the livers of 24 of 34 treated rats. In livers of 10 of 22 untreated control rats, foci of altered cells developed "spontaneously" between 12 and 34.5 months. If neoplastic lesions were induced by a single dose of diethylnitrosamine, 75 or 150 mg/kg, subsequent treatment with alpha-HCH led to the appearance of hepatocellular carcinoma with 7 months. Altogether, hepatocellular carcinoma within 7 months. Altogether, hepatocellular carcinomas were found in 18 of 21 rats treated with both agents but in only 3 of 26 animals treated with diethylnitrosamine alone. The results show that determination of tumor numbers alone in a long-term animal experiment does not allow one to decide whether alpha-HCH (and similar "xenobiotic inducers") is an initiating carcinogen or merely promotes tumorigenesis from "spontaneous" lesions. Our findings support the latter possibility by the failure to detect evidence suggesting initiating potential of alpha-HCH, by the enhanced mitotic response to alpha-HCH, by the enhanced mitotic response to alpha-HCH in foci of altered cells as reported elsewhere, and by the observation of a permanent stimulatory action on liver growth during prolonged exposure to alpha-HCH.
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PMID:Failure to discriminate initiation from promotion of liver tumors in a long-term study with the phenobarbital-type inducer alpha-hexachlorocyclohexane and the role of sustained stimulation of hepatic growth and monooxygenases. 616 34

The ubiquitous problem of cirrhosis may be complicated by the development of primary liver cell carcinoma, with rates of incidence so high in certain parts of the world as to make it a candidate for the most common cancer in humans. When cirrhosis reaches the macronodular stage, the risk of developing liver cell carcinoma increases, and at this point liver cell dysplasia may be seen in biopsy. Alcoholics, who classically have a micronodular cirrhosis, may attain the macronodular pattern through better clinical management, abstinence, and longer survival. Hepatitis B-related cirrhosis, on the other hand, is most often macronodular. Recent DNA hybridization studies strongly favor a viral role in oncogenesis, and this possibility is supported by the serologic and epidemiologic evidence complied in the last decade. Liver cell malignant tumors tend to recapitulate the characteristics of normal liver, namely, growth in cords, uniformity of cytologic appearances, and bile production, but also present distinctive histologic and immunohistochemical patterns that are unique to a malignant liver cell population. The other primary malignant tumors of the liver, arising in bile ducts, blood vessels, and mesenchymal elements, all carry their individual epidemiology and morphology, but in general invoke, as does liver cell carcinoma, the concept of a series of step by step cell-carcinogen and cell-carcinogen interactions by which normal cells give rise to malignant populations.
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PMID:The epidemiology and morphology of primary malignant liver tumors. 625 64

We identified, by anticomplement immunofluorescence, a nuclear antigen (hepatitis B virus-associated nuclear antigen [HBNA]) in two human hepatoma cell lines containing integrated hepatitis B virus DNA but not in three hepatoma cell lines lacking it. The antigen resembled neoantigens associated with the oncogenesis of certain papovaviruses, adenoviruses, and herpesviruses. Antibody to the antigen (anti-HBNA) was found in 7.3% of hepatitis B surface antigen-positive sera from patients with hepatocellular carcinoma but not in surface antigen-negative sera. The staining of HBNA was characterized by two patterns, reticular nuclear fluorescence and nucleolar fluorescence. The expression of HBNA did not parallel the production of extracellular hepatitis B surface antigen. Treatment of cells with proteinase K, RNase, DNase, or cycloheximide significantly diminished the staining of HBNA.
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PMID:Nuclear antigen detected in hepatoma cell lines containing integrated hepatitis B virus DNA. 630 93

Since 1973, a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material, we have examined the histology of over 250 cases of hepatic neoplasia, mostly in patients receiving steroids. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for nodular focal hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of the patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in those who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Significant is the young age of these patients and the lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophillic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations.
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PMID:Human liver tumors in relation to steroidal usage. 630 79

HBeAg has been detected in the peripheral lymphocytes of chronic hepatitis B patients who were seronegative for HBeAg. Nearly 50% of these patients (males, aged 41-66) had histology confirmed hepatocellular carcinoma while the normal carriers (males, aged 22-37) showed histological changes of chronic persistent or chronic active hepatitis. The HBeAg was also demonstrated in the lymphocytes of eight voluntary blood donors who were found to be seropositive for HBsAg and HBeAg. The lymphocyte HBeAg exists in two subentities; a soluble and a particulate form. These observations suggest that the peripheral blood lymphocytes are hosts for HBV replication and production of infectious virus particles. Such processes may lead to an impaired immune defence mechanism, and explain the chronicity of the disease, and hepatic oncogenesis.
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PMID:Detection of HBeAg in the lymphocytes of sero-HBeAg negative patients with chronic hepatitis B and primary hepatocellular carcinoma. 632 1

Mitochondria isolated from rapidly growing, poorly differentiated Morris hepatoma 3924A have been found to export the citrate they generate from pyruvate, at a rate greater than four times that of control liver preparations. These 3924A mitochondria fail to exhibit state 3 respiration when either pyruvate or citrate are supplied as respiratory fuels. Nevertheless, substrates that join the Krebs cycle beyond citrate (viz. isocitrate, glutamate, alpha-ketoglutarate, and succinate) are readily oxidized by tumor 3924A mitochondria. Blocking the tricarboxylate anion exchange carrier with the citrate transport inhibitor 1,2,3-benzenetricarboxylate restores the ability of tumor 3924A mitochondria to respire with pyruvate or citrate. Slowly growing, minimally deviated Morris hepatoma 16 possesses mitochondria that do not display discernably altered respiratory patterns with pyruvate or citrate, but they do exhibit a 30% increase in the rate of citrate export relative to control liver preparations. Paralleling the preferential citrate export from tumor mitochondria is a dramatic enrichment of the tumor mitochondrial membranes with cholesterol. Hepatoma 3924A mitochondria possess a more than 5-fold enrichment in cholesterol, and those from tumor 16 display a 2-fold enrichment. When normal mitochondria, isolated from ACI strain rat liver, were enriched with cholesterol in vitro via a solid-state molecule transfer method employing Sephadex G-10 beads coated with cholesterol, they exhibited altered patterns of Krebs cycle metabolism that were qualitatively identical to those obtained with isolated Morris hepatoma mitochondria (which become enriched in membrane cholesterol endogenously during tumorigenesis). The enrichment of mitochondrial membranes with cholesterol, either by experimental manipulation in vitro or during the proliferation of the tumor in the host animal, promotes these metabolic changes directly, apparently by effecting a functional alteration in the operation of the tricarboxylate (citrate) exchange carrier of the inner mitochondrial membrane. These results highlight two related but incompletely understood phenomena as follows: 1) a functionally truncated Krebs cycle in cholesterol-rich tumor mitochondria, and 2) a mechanism for providing higher cytoplasmic levels of precursor metabolite intermediates which help sustain deregulated cholesterogenesis in hepatomas and other malignant neoplasms.
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PMID:Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol. 646 76

Woodchuck hepatocellular carcinoma has been successfully transplanted into nude (athymic) mice. The morphology of heterotransplanted tumor is similar to that of naturally occurring hepatocellular carcinoma before transplantation. The growth rate of transplanted tumor was very slow compared with those of other transplanted tumors. During the first month, only two tumors appeared. However, definitive tumor growth was noted in 6 of 20 nude mice about 3 months later. Seventeen of 20 nude mice exhibited sustained tumor growth after 6 months. The woodchuck hepatocellular carcinoma in nude mice provides an in vivo model for the study of oncogenesis of human hepatocellular carcinoma related to hepatitis B virus.
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PMID:Transplantation of woodchuck hepatocellular carcinoma in nude mice. 661 33

Energy-dispersive X-ray microanalysis was carried out on normal and regenerating liver as well as on 3924 A hepatoma cells. Specimens were quickly removed from the sacrificed animals, frozen in liquid isopentane, fractured still in the frozen state and freeze-dried under vacuum. The dried samples were examined in secondary electron image mode, and the X-ray spectra were recorded by means of an EDAX 707A system. Sodium and chlorine contents were higher both in nuclei and cytoplasms of regenerating and tumor hepatocytes than in normal liver. Moreover, hepatoma cells showed higher sodium and chlorine contents than did normal proliferating hepatocytes. Potassium contents did not show any differences among the experimental models. The increased sodium content and the resulting increased Na:K ratios of proliferating normal and tumor cells were not due to a generalized increase of these parameters in all the cells, but to the presence of new cell populations with high Na content and high Na:K ratios. Findings of present work are consistent with the hypothesis that high sodium content is associated with mitogenesis. Moreover, the much higher concentration of sodium in tumor cells as compared with normal proliferating hepatocytes supports the hypothesis that the concentration of this ion is related to oncogenesis of hepatocytes.
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PMID:X-ray microanalysis of monovalent electrolyte contents of quiescent, proliferating as well as tumor rat hepatocytes. 665 71

When Chinese hamster lung (CHL) cells were cultured in medium containing 25 microM cadmium chloride, resistant cells appeared at a frequency of 0.04%. When one of three tumor promoters, 12-O-tetradecanoylphorbol-13-acetate (TPA), aplysiatoxin and dihydroteleocidin B, was added during selection with cadmium chloride, the frequency of appearance of resistant cells increased more than 50-fold. Two of the resistant clones obtained were characterized. Both clones produced much higher levels of metallothionein I mRNA than the parental CHL cells. Southern blot analysis showed that in these resistant cells, metallothionein I genes were amplified approximately 5-fold. Therefore, it seems that tumor promoters can enhance the frequency of gene amplification. One possible mechanism of the action of tumor promoters in oncogenesis is amplification of activated c-onc genes. Consistent with this idea, it has been reported that c-onc genes are amplified in various cancer cells. We also found that the c-Ha-ras and c-myc genes were amplified in a bladder cancer removed surgically and in a transplanted rat hepatocellular carcinoma, Morris hepatoma 7794A, respectively.
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PMID:Increase in frequency of appearance of cadmium-resistant cells induced by various tumor promoters; evidence for the induction of gene amplification. 668 Jul 25

The effects of 2-acetylaminofluorene (2-AAF), sodium phenobarbital (PB) and 4,4'-diaminodiphenylmethane (DDPM) on the developmental sequence of N-nitrosomorpholine (NNM) induced changes in the rat liver was investigated using a histological, histochemical and morphometric approach. Male Sprague-Dawley rats were treated with NNM for 3 weeks, maintained on basal diet for 1 week and then fed on diets containing either 0.005% 2-AAF, 0.05% PB, 0.08% DDPM or, as carcinogen controls, no addition (basal diet, BD) for a further 48 weeks. Control and experimental groups were sacrificed at weeks 4, 16, 28, 40 and 52 of the investigation. The incidence of the hepatocellular carcinomas observed at weeks 40 and 52 was markedly enhanced by 2-AAF treatment and slightly increased after PB administration. 2-AAF also exerted a positive influence on the development of angiosarcomas, benign hemangioendotheliomas and cystic cholangiomas. DDPM did not show clear effects on the development of liver cell carcinoma but enhanced the induction of cholangiofibromas, cholangiofibrosis and, very markedly, spongiosis hepatis. No neoplastic lesions were observed in animals treated with 2-AAF, PB or DDPM without prior application of NNM. Morphometric analysis of enzyme-altered foci revealed contrasting effects of 2-AAF, PB and DDPM, not only on number and size of lesion but also on their histochemical phenotype. Thus whilst 2-AAF administration was primarily linked with increase in number of lesions, PB appeared to stabilise their phenotypic cellular changes and increased the activity of G6PDH. DDPM did not significantly influence the number of focal lesions but seemed to effect a decrease in phenotypic alteration within foci. The results suggest that changes in the nature of enzyme-altered foci may be correlated with enhancement or inhibition of tumorigenesis.
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PMID:Modification of the development of N-nitrosomorpholine-induced hepatic lesions by 2-acetylaminofluorene, phenobarbital and 4,4'-diaminodiphenylmethane: a sequential histological and histochemical analysis. 670 39


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