Hepadnaviral hepatocarcinogenesis: in situ visualization of viral antigens, cytoplasmic compartmentation, enzymic patterns, and cellular proliferation in preneoplastic hepatocellular lineages in woodchucks

Radaeva, Svetlana; Li, Yanhua; Hacker, Hans Jörg; Burger, Vera; Kopp‐Schneider, Annette; Bannasch, Peter

doi:10.1016/s0168-8278(00)80010-0

Cited by 30 publications

(33 citation statements)

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“…While virus-free FAH and foci of virus-free, but morphologically normal hepatocytes [20,21,[36][37][38] would appear to fulfill the role described in the model (Fig. 3), it…”

Section: Introductionmentioning

confidence: 96%

“…2). As in humans, some of the foci of virus-free hepatocytes in the woodchuck liver clearly represent FAH, often considered to be preneoplastic [34][35][36][37][38], whereas virus-free hepatocytes in other foci appear to have a normal morphology [36]. In contrast, virtually all hepatocytes can be infected during a typical transient WHV infection [7,10].…”

Section: Introductionmentioning

confidence: 99%

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Immune selection during chronic hepadnavirus infection

2007

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Purpose Late-stage outcomes of chronic hepatitis B virus (HBV) infection, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) result from persistent liver injury mediated by HBV antigen specific cytotoxic T lymphocytes (CTLs). Two other outcomes that often accompany chronic infection, the emergence of mutant viruses, including HBe-antigen negative (HBeAg (-)) HBV, and a reduction over time in the fraction of hepatocytes productively infected with HBV, may also result from persistent immune attack by antiviral CTLs. To gain insights into how these latter changes take place, we employed computer simulations of the chronically infected liver. Methods Computational programs were used to model the emergence of both virus-free hepatocytes and mutant strains of HBV. Results The computer modeling predicted that if cell-tocell spread of virus is an efficient process during chronic infections, an HBV mutant that replicated significantly more efficiently than the wild type would emerge as the prevalent virus in a few years, much more rapidly than observed, while a mutant that replicated with the same or lower efficiency would fail to emerge. Thus, either cell-tocell spread is inefficient or mutants do not replicate appreciably more efficiently than wild type. In contrast, with immune selection and a higher rate of killing of hepatocytes infected with wild-type virus, emergence of mutant virus can be explained without the need for a higher replication rate. Immune selection could also explain the emergence of virus-free hepatocytes that are unable to support HBV infection, since they should have a lower turnover rate than infected hepatocytes.

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“…While virus-free FAH and foci of virus-free, but morphologically normal hepatocytes [20,21,[36][37][38] would appear to fulfill the role described in the model (Fig. 3), it…”

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Immune selection during chronic hepadnavirus infection

2007

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“…Hepatic glycogenosis, which is usually focal but may also occupy almost the whole liver parenchyma, has been induced in different species, including human and nonhuman primates, by hepatocarcinogenic chemicals (Bannasch 1968;Bannasch, Mayer, and Hacker 1980;Cattan et al 2000;Hacker et al 1982;Moore and Kitagawa 1986;Nehrbass, Klimek, and Bannasch 1998;Williams et al 1976), by oncogenic hepadnaviridae or subgenomic fragments of these viruses (Bannasch et al 1995;Kim et al 1991;Radaeva et al 2000;Toshkov, Chisari, and Bannasch 1994), and by intrahepatic transplantation of pancreatic islets producing local hyperinsulinemia in the liver under diabetic conditions (Dombrowski, Bannasch, and Pfeifer 1997;Dombrowski, Mathieu, and Evert 2008). Compelling evidence for the preneoplastic nature of the focal hepatic glycogenosis (appearing as clear cell lesions in conventional, H&E-stained tissue sections) has been provided by many laboratories (Bannasch 1968;Bannasch, Mayer, and Hacker 1980;Bannasch et al 1995;Cattan et al 2000;Dombrowski, Bannasch, and Pfeifer 1997;Dombrowski, Mathieu, and Evert 2008;Hacker et al 1982;Kim et al 1991;Moore and Kitagawa 1986;Nehrbass, Klimek, and Bannasch 1998;Radaeva et al 2000;Toshkov, Chisari, and Bannasch 1994;Williams et al 1976; see the preceding for further literature). It has been demonstrated by biochemical approaches in situ in animal models of chemical, viral, and hormonal hepatocarcinogenesis, and in acquired human liver diseases, that the focal hepatic glycogenosis is regularly associated with a reduction in the activity of the two key enzymes involved in glycogen breakdown, namely, the glycogen phosphorylase and the glucose-6-phosphatase (Bannasch et al 1984Hacker et al 1982;Kitagawa 1986, Toshkov, Chisari, ...…”

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confidence: 99%

“…Compelling evidence for the preneoplastic nature of the focal hepatic glycogenosis (appearing as clear cell lesions in conventional, H&E-stained tissue sections) has been provided by many laboratories (Bannasch 1968;Bannasch, Mayer, and Hacker 1980;Bannasch et al 1995;Cattan et al 2000;Dombrowski, Bannasch, and Pfeifer 1997;Dombrowski, Mathieu, and Evert 2008;Hacker et al 1982;Kim et al 1991;Moore and Kitagawa 1986;Nehrbass, Klimek, and Bannasch 1998;Radaeva et al 2000;Toshkov, Chisari, and Bannasch 1994;Williams et al 1976; see the preceding for further literature). It has been demonstrated by biochemical approaches in situ in animal models of chemical, viral, and hormonal hepatocarcinogenesis, and in acquired human liver diseases, that the focal hepatic glycogenosis is regularly associated with a reduction in the activity of the two key enzymes involved in glycogen breakdown, namely, the glycogen phosphorylase and the glucose-6-phosphatase (Bannasch et al 1984Hacker et al 1982;Kitagawa 1986, Toshkov, Chisari, andBannasch 1994;Radaeva et al 2000;Dombrowski, Bannasch, and Pfeifer 1997;Dombrowski, Mathieu, and Evert 2008). It would be of great interest to know whether the activity of glucose-6-phosphatase is reduced in addition to that of glycogen phosphorylase in the model presented by Floettmann and colleagues.…”

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confidence: 99%

“…It would be of great interest to know whether the activity of glucose-6-phosphatase is reduced in addition to that of glycogen phosphorylase in the model presented by Floettmann and colleagues. In all experimental models of hepatocarcinogenesis, the transformation of the glycogenotic preneoplastic into the neoplastic cell populations requires a long lag period and is characterized by a fundamental metabolic shift resultingamong many other subcellular changes-in a gradual reduction of the glycogen initially stored in excess (Bannasch 1968;Bannasch, Mayer, and Hacker 1980;Bannasch et al 1984Bannasch et al , 1995Moore and Kitagawa 1986;Radaeva et al 2000;Toshkov, Chisari, Toxicologic Pathology, 38: 1000-1002, 2010 Copyright # 2010 by The Author(s) ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1177/0192623310378026 and Bannasch 1994;Dombrowski, Bannasch, and Pfeifer 1997;Dombrowski, Mathieu, and Evert 2008). This metabolic shift is often accompanied by a transient accumulation of neutral fat.…”

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confidence: 99%

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Hepatocellular Glycogenosis and Hepatic Neoplasms

Bannasch¹

2010

Toxicol Pathol

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In a recent issue of Toxicologic Pathology, Floettmann et al. (2010) published an article titled ''Prolonged Inhibition of Glycogen Phosphorylase in Liver of Zucker Diabetic Fatty Rats Models Human Glycogen Storage Diseases.'' I have read these well-described observations, dealing with Zucker rats treated with the test compound GPi921 (2,3-, which has been designed to inhibit glycogen phosphorylase in patients afflicted with type 2 diabetes mellitus, with great interest. I do not disagree with the presentation of the results obtained, and I endorse the conclusion that ''although glycogen phosphorylase inhibitors are efficacious agents for the control of hyperglycemia, prolonged treatment might have the potential to cause significant clinical hepatic complications that resemble those seen in GSD and hepatic glycogenosis.'' This statement is certainly correct, but in their discussion and conclusion, the authors did not take into consideration a possible lifethreatening additional complication: the well-documented high risk of patients and experimental animals suffering from inborn or acquired hepatocellular glycogenosis (glycogen storage disease, GSD) to develop hepatocellular adenomas and carcinomas. I would like to bring this possible serious complication to your attention and ask you to further spread this knowledge by the publication of this letter in Toxicologic Pathology.

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Models for Liver Cancer

Feo

Pascale

Calvisi

2007

The Cancer Handbook

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Primary liver tumours include hepatocellular carcinomas (HCCs), cholangiocarcinomas, and hepatoblastomas. HCC is the most frequent liver tumour, whose development is preceded, both in humans and rodents, by the appearance in the liver of foci of altered hepatocytes (FAHs) and dysplastic nodules. Bipotential hepatic progenitor cells (HPCs), which may differentiate into hepatocytes or cholangiocytes, are liver tumour precursors. Several rodent models have been developed to study the aetiology, evolution, and pathogenesis of preneoplastic and neoplastic liver lesions. They include the woodchuck hepatitis model, chemical models in which hepatocyte initiation by a carcinogen is followed by a growth stimulus inducing clonal expansion of initiated cells, diet‐linked models based on induction of methyl donor deficiency, and transgenic/knockout models, particularly useful to study in vivo role(s) of genes favouring or suppressing neoplastic cell growth. Furthermore, in vitro growing liver tumour cell lines have been used to study the role of single genes or signal transduction pathways, the effect of inhibitor compounds and genome engineering on tumour growth, and gene expression profiles. Transplants of in vitro growing cells are currently used for chemopreventive and therapeutic approaches to hepatocarcinogenesis. Animal models of liver cancer allowed investigation of the molecular alterations involved in early stages and in the progression phase of hepatocarcinogenesis, thus evidencing the interspecies commonalties of the basic mechanisms of hepatocarcinogenesis, and strongly contributing to understanding the molecular bases of the disease. Finally, animal models allowed investigation of genetic predisposition to liver cancer and contributed to map predisposition genes, understanding the genetic model, and some effector mechanisms of cancer modifier genes.

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Hepadnaviral hepatocarcinogenesis: in situ visualization of viral antigens, cytoplasmic compartmentation, enzymic patterns, and cellular proliferation in preneoplastic hepatocellular lineages in woodchucks

Cited by 30 publications

References 48 publications

Immune selection during chronic hepadnavirus infection

Immune selection during chronic hepadnavirus infection

Hepatocellular Glycogenosis and Hepatic Neoplasms

Models for Liver Cancer

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