Biomedical subjects

Peter Bannasch

Publications and source records attributed to Peter Bannasch.

5 recordsLinked to original sources

PubMed2003

WY-14,643-mediated promotion of hepatocarcinogenesis in connexin32-wild-type and connexin32-null mice.

Connexin32 (Cx32) is the major gap junction forming protein in liver and lack of functional Cx32 enhances hepatocarcinogenesis. Many tumour-promoting agents block gap junctional intercellular communication, which may favour clonal expansion of neoplastic cells. We recently demonstrated that liver tumourigenesis is accelerated in Cx32-wild-type but not in Cx32-null mice by the model tumour promoter phenobarbital (PB). In the present study, male Cx32-wild-type and Cx32-null mice were treated with a single injection of 90 micro g/g body wt of N-nitrosodiethylamine (DEN) at 6 weeks of age and were subsequently kept on a diet containing the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) or on control diet. Thirty-eight weeks after DEN treatment, mice were killed, frozen liver sections were prepared and (pre)-neoplastic lesions were identified by alterations in glucose-6-phosphatase (G-6-Pase) and glutamine synthetase (GS) staining. G-6-Pase-deficient lesions were generally small in size and were observed in all groups of mice. Large focal pre-neoplastic and benign neoplastic lesions, however, which demonstrated increased rather than decreased activity in G-6-Pase were exclusively present in DEN/Wy-14,643-treated mice. G-6-Pase-positive lesions were strongly promoted by Wy-14,643, both in Cx32-wild-type and Cx32-null mice without significant difference in response between mice of the two genotypes. This contrasts G-6-Pase-negative lesions and lesions over-expressing GS, which were both increased by WY-14,643 treatment in number and size in Cx32-wild-type but not in Cx32-null mice. GS-positive lesions from WY-14,643-treated mice harboured beta-catenin mutations, a hallmark of lesions selected during promotion by PB, while G-6-Pase-positive lesions, which displayed negative or diffuse GS staining, did not show beta-catenin mutations. Our results demonstrate significant differences between mouse liver lesions of differing phenotype and genotype in their response towards selection by Wy-14,643 during the promotional phase of hepatocarcinogenesis.

Animals↗

PubMed2002

Woodchuck hepatitis virus replication and antigen expression gradually decrease in preneoplastic hepatocellular lineages.

BACKGROUND/AIMS: Hepatocellular carcinomas elicited in woodchucks by the woodchuck hepatitis virus (WHV) emerge gradually from parenchymal areas of minimal structural deviation via two predominant preneoplastic hepatocellular lineages, composed of either glycogenotic/basophilic or amphophilic/basophilic cell foci. In this study we analyzed WHV replication during neoplastic development in both lineages. METHODS: In minimal deviation areas, preneoplastic hepatocellular foci, and hepatocellular neoplasms, developing in 16 WHV-carriers 31-38 months after WHV-inoculation, the proportion of hepatocytes containing WHV replicative intermediates (as detected by in situ hybridization for WHV DNA) and immunoreactive for WHV core and surface antigens was assessed. RESULTS: Appearance of WHV replicative intermediates and expression of antigens were limited to the cytoplasm of hepatocytes and were strongly correlated (P<0.0001), both showing high levels in minimal deviation areas, but markedly reduced amounts in all types of preneoplastic hepatic focus (P<0.0001), and in hepatocellular adenomas. Most hepatocellular carcinomas were negative for WHV replicative intermediates and antigens. CONCLUSIONS: In both the glycogenotic-basophilic and the amphophilic-basophilic preneoplastic hepatocellular lineage, WHV replication and antigen expression gradually decrease early during the preneoplastic phase. The close correlation of these changes with metabolic aberrations characterizing preneoplastic hepatocellular lineages suggests that oncogenic effects mimicking insulin/glucagon imbalances may be responsible for the repression of hepadnaviral replication.

Adenoma, Liver Cell↗

PubMedDate not supplied

Prevalidation of a rat liver foci bioassay (RLFB) based on results from 1600 rats: a study report.

A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.

2-Acetylaminofluorene↗

PubMedDate not supplied

Relevance of hepatic preneoplasia for human hepatocarcinogenesis.

Different lesions have been suggested to represent preneoplastic conditions in human liver. They include liver cell dysplasia, separated in large-cell change (LCC) and small-cell change (SCC), adenomatoid hyperplasia, and the more recently identified foci of altered hepatocytes (FAH) and nodules of altered hepatocytes (NAH). FAH have been demonstrated to represent preneoplastic lesions in various animal models of hepatocarcinogenesis. To demonstrate prevalence and significance of FAH in the human liver, the cellular composition, size distribution, and proliferation kinetics of these lesions were studied in 163 explanted and resected human livers with or without hepatocellular carcinoma (HCC). FAH including glycogen-storing foci (GSF), mixed cell foci (MCF), and basophilic cell foci were found in 84 of 111 cirrhotic livers, demonstrating higher incidences in cases with than without HCC. MCF, predominant in cirrhotic livers of the high-risk group, were more proliferative, larger and more often involved in formation of NAH than GSF. The results suggest that the FAH are preneoplastic lesions, MCF being more advanced than GSP. We also investigated the relationship of FAH to liver cell dysplasia. Occurrence of SCC, rather than that of LCC, confers FAH an increased proliferation activity and higher risk to nodular transformation, and, hence, should be considered a precancerous condition. Histological detection of FAH and SCC through needle-aspiration liver biopsy can be used for monitoring HCC development in high-risk populations, such as HBV carriers with chronic hepatitis and/or cirrhosis.

Cell Division↗

PubMedDate not supplied

Significance of hepatic preneoplasia in risk identification and early detection of neoplasia.

Among the different types of liver tumor, hepatocellular neoplasms predominate by far in both animals and man. Consequently, preneoplastic foci of altered hepatocytes (FAH), preceding both hepatocellular adenomas and carcinomas, represent the most prevalent form of hepatic preneoplasia observed in animals for a long time, and identified in human chronic liver diseases associated with, or predisposing to, hepatocellular carcinomas more recently. Morphological, microbiochemical, and molecular biological approaches in situ revealed striking similarities in specific changes of the cellular phenotype of preneoplastic FAH developing in experimental and human hepatocarcinogenesis, irrespective of whether this was elicited by chemicals, hormones, viruses or radiation. The advantage of using FAH for risk identification (aiming at primary cancer prevention) in long-term and medium-term carcinogenesis bioassays has been well documented, but quantitative morphometric approaches appear to be indispensable for an appropriate evaluation of both bioassays. The detection of phenotypically similar FAH in various animal models and in humans prone to develop or bearing hepatocellular carcinomas favors the extrapolation from data obtained in animals to humans. Moreover, the recently reported frequent finding of FAH in fine-needle biopsies of patients suffering from chronic liver diseases opens new perspectives for secondary prevention of human hepatocellular carcinoma.

Animals↗