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Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTαß transgenic mice as well as TAK1LPC-KO and Mcl-1Δhep mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/19, glutamine synthetase) in mouse and n = 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLTαß transgenic mice and TAK1LPC-KO models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTαß murine livers. CGH profiles from the Mcl-1Δhep model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity). IMPLICATIONS: Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.

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The prevalence (percent of animals with a tumor) and multiplicity (number of tumors per animal) of hepatocellular neoplasia in the male B6C3F1 mouse exposed to trichloroacetic acid (TCA) in the drinking water were determined. Male mice were exposed to 0.05, 0.5, and 5 g/L TCA for 60 wk (Study 1), to 4.5 g/L TCA for 104 wk (Study 2) and to 0.05 and 0.5 g/L TCA for 104 wk (Study 3). Time-weighted mean daily doses measured for the low, medium, and high dose groups were consistent over the three studies, 6-8, 58-68, and 572-602 mg/kg-d for the 0.05, 0.5, and the 4.5-5 g/L treatment groups, respectively. No significant changes in animal survival were noted across the studies. A significant increase in the prevalence and multiplicity of hepatocellular tumors was found in the 58-68 and 572-602 mg/kg/d TCA dose groups. Nonhepatoproliferative changes (cytoplasmic alterations, inflammation, and necrosis) in mice treated with TCA were mild and dose related. A TCA-induced increase in liver palmitoyl CoA oxidase activity, a marker of peroxisome proliferation, correlated with tumor induction. A linear association was found between peroxisome proliferation and tumor induction. Sporadic increases in the labeling index of nuclei outside of proliferative lesions were observed at carcinogenic doses throughout the studies. Given that there are no compelling data demonstrating genotoxic activity of either TCA or any metabolite, data are consistent with an epigenetic mode of action. The studies provide dose-response data on the development of hepatocellular neoplasia in male mice over a lifetime exposure to TCA. A no-observed-effect-level (NOEL) of 6 mg/kg/d was calculated for neoplastic and nonproliferative liver pathology.

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Over the years, the most appropriate classification scheme for nodular proliferative lesions of the hepatocyte has been heavily debated. In the most recent guidelines there appears to be a consensus for classifying these lesions as hepatocellular adenoma, hepatocellular carcinoma, or regenerative hyperplasia. Also, large foci of cellular alteration may appear somewhat nodular. Some nodular hepatocellular lesions from a group of 7 studies of dioxin and dioxin-like compounds conducted by the National Toxicology Program did not readily fit into these categories. Some of these lesions had morphologic features consistent with hyperplasia. However, there was not sufficient morphological or biological evidence to conclude that the entire response was regenerative. In other instances, these lesions had some features resembling adenoma, but contained a prominent component of biliary epithelium and/or oval cells. This component does not appear to be well described in the literature, and while its presence suggested a nodule to be nonneoplastic, this is inconclusive. This paper describes the morphology of these lesions, as well as the diagnostic approach taken in this series of studies.

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Karbe and Kerlin have questioned the classification of spongiosis hepatis as a preneoplastic lesion or even a benign neoplasm, designated as spongiotic pericytoma, and have proposed to use the term cystic degeneration for this lesion in rats and fish. However, the reclassification of spongiosis as cystic degeneration is unwarranted for several reasons. In the rat, spongiosis hepatis represents a specific pathomorphologic entity, originating from the perisinusoidal (Ito) cells; it may occur spontaneously in aged animals but its number and size increases significantly after exposure to various (hepato)carcinogens. Comparative morphological, immunohistochemical, and autoradiographic studies in rats exposed to N-nitrosomorpholine revealed that spongiosis hepatis is an integral part of larger proliferative Ito-cell aggregates showing an autonomous, progressive growth. The classification of spongiosis hepatis as a benign neoplasm is based on these findings that endorse and extend previous considerations on the preneoplastic or neoplastic nature of this lesion. Irrespective of the classification of spongiosis hepatis as a benign neoplastic or a preneoplastic lesion, there is compelling evidence for its reliability as a sensitive marker for (hepato)carcinogenic effects in rats and fish. The data collected by Karbe and Kerlin support rather than contradict the reliability of spongiosis hepatis as an effect marker for carcinogens.

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Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.

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We compared the ultrastructure of a well-differentiated rat hepatoma line (H4II) and its clonal progeny, including dedifferentiated variant cells, and revertants of the variants in which the spectrum of hepatocyte-specific functions is again expressed. The cells of the original differentiated lines and the revertants were very similar to one another. In addition, they exhibited some of the characteristics of fetal and neonatal hepatocytes. Variant cells which fail to express hepatocyte functions showed a wide range of morphological alterations accompanied by generalized disorganization. It is concluded that the loss of hepatocyte differentiation in the variants is not associated with a uniform morphological type, and that a wide range of ultrastructural phenotypes can be generated in the progeny of a single neoplastic but well-differentiated hepatocyte. Also, the expression of hepatocyte functions only occurs within a limited and organized morphological framework that includes features of young hepatocytes.

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The sequence of events in carcinogenesis may be more complex than previously proposed. We cannot as yet define the nature of initiation, nor in fact the obligate aspects of promotion. Administering small doses of diethylnitrosamine (DEN) to neonatal mice genetically predisposed to hepatocarcinogenesis, or to lines that are not (with and without subsequent phenobarbital (PB) administration), gave evidence that different types of initiated cells might exist. The majority of tumors that resulted were identical in morphology and biology to those that arise spontaneously from basophilic, diploid cells. However, a second tumor type was seen only in DEN-PB treated mice. This was composed of huge eosinophilic, polyploid cells. A third tumor type, rapidly progressing to a fully malignant form, was seen only in predisposed mice that received DEN, suggesting a genetic "hit" in a genetically predisposed cell. In addition to demonstrating the spectrum of initiated cells available for the action of promoters, evidence was obtained that indicated that one major action of PB was to stimulate growth of these altered cell populations rather than to induce new phenotypic alterations commensurate with progression. Thus, characteristics of PB-expanded, altered hepatocyte populations could be identified in very early cell foci.

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A morphologic classification of neoplastic, proliferative and related hepatic lesions in the mouse is presented. The classification includes lesions of the hepatocyte, biliary system, sinusoidal lining cells, hematopoietic cells and metastatic neoplasms.

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The organochlorine chemicals comprise a large number of pesticides that are used widely throughout the world. The organochlorine pesticides given in the diet to mice are carcinogenic for the liver. They induce not only carcinomas of the liver, particularly at the higher doses, but also carcinomas and sarcomas in other organs in rats. They cause acute and chronic liver and kidney injury, which interferes with the development of carcinomas and sarcomas in rats. The testing of chemicals for carcinogenicity, with particular reference to organochlorine pesticides, includes discussions on the following topics: classification of hepatic lesions in mice and rats, toxicity versus carcinogenicity in the testing of chemicals, a comparison of carcinomas and cirrhosis of the liver in experimental animals and humans, and the significance of laboratory carcinogenicity findings to human health.

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