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Event: 384

Key Event Title

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Increased, Clonal Expansion / Cell Proliferatin to form Pre-Neoplastic Altered Hepatic Foci

Short name

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Biological Context

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Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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The occurrence of altered hepatic foci (AHF) as precursors to liver tumors in AFB1-treated rats has been recognized for decades. Originally, these foci were observed as histologically different from the surrounding parenchyma. (Harada et al, 1989, 1990; Gil et al., 1988; Bannasch et al., 1985) In addition, enzyme alterations were used to identify AHF foci, most notably, the occurrence of a placental form of glutathione-S-transferase (GSTP+). (Godlewski et al., 1985; Dragan et al., 1994a, 1995; Kirby et al., 1990) The growth and occurrence of foci are expressed as the number of AHF in a volume of liver, possibly the entire liver, and the volume fraction of the liver occupied by AHF. (Dragan et al., 1997) Both of these reflect focal growth because single cell foci are not detectable with the immunohistochemical staining technique. The assumption is that single transformed cells in which apoptosis is blocked by tumor-critical mutations will grow into AHF. (Grassl-Kraupp et al., 1997). A number of agents regarded as tumor promoters appear to enhance the growth of foci, acting to further inhibit apoptosis and also creating an overall proliferative stimulus. (Angsubhakorn et al., 2002; Wyde et al., 2002).

AFB1 appears to be a “complete” carcinogen in that the toxin acts as an initiator through the formation of pro-mutagenic DNA adducts (the MIE) and as a promoter through increasing oxidative stress and inflammation. (Ohnishi et al., 2013; Caballero et al., 2004).

Evidence Supporting Essentiality

Strong

Chemoprevention studies, reviewed in another section of this AOP, suggest a strong relationship between altered hepatic foci (AHF) and HCC tumor formation (Olden and Vulimiri, 2014; Liby et al., 2008; Yates et al., 2007; Yates and Kensler, 2007; Kensler et al., 2004). For example, Johnson et al. (2014) observed background levels of AHF along with a complete absence of tumors in rats treated with a triterpenoid chemoprotectant CDDO-Im, despite maintaining a significant burden of AFB1-induced adducts. (Johnson et al., 2014) Cell proliferation appears to be six- to seven-fold greater in AHF than in surrounding liver parenchyma. (Dragan et al., 1994) However, the measurements were made from liver biopsies, and whether the increased expression was associated with foci is not known.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Quantitative stereology has been used to quantify the growth of AHF.(Pitot et al., 1996; Dragan et al., 1995; Xu et al., 1990). Growth of foci appears to follow the Moolgavkar-Venzon-Knudson model of initiation and promotion. (Dewanji et al., 1991; Dragan et al, 1995) Most recently, Johnson et al. (2014) have shown that a chemoprotective agent reduces the occurrence of AHF to background levels and completely protects against tumors, although pro-mutagenic adducts are still present at easily quantifiable levels.

Domain of Applicability

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The occurrence of AHF appears to be universal and has been observed in mammals, including humans, as well as in birds and in fish. (Ribback et al., 2013; Thoolen et al., 2012; Kirby et al., 1990).

References

List of the literature that was cited for this KE description. More help

Angsubhakorn S, Pradermwong A, Phanwichien K, Nguansangiam S (2002) Promotion of aflatoxin B1-induced hepatocarcinogenesis by dichlorodiphenyl trichloroethane (DDT). Southeast Asian J Trop Med Public Health 33: 613-623.

Bannasch P, Benner U, Enzmann H, Hacker HJ (1985) Tigroid cell foci and neoplastic nodules in the liver of rats treated with a single dose of aflatoxin B1. Carcinogenesis 6: 1641-1648.

Caballero F, Meiss R, Gimenez A, Batlle A, Vazquez E (2004) Immunohistochemical analysis of heme oxygenase-1 in preneoplastic and neoplastic lesions during chemical hepatocarcinogenesis. Int J Exp Pathol 85: 213-222.

Dewanji A, Moolgavkar SH, Luebeck EG (1991) Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions. Math Biosci 104: 97-109.

Dragan Y, Teeguarden J, Campbell H, Hsia S, Pitot H (1995) The quantitation of altered hepatic foci during multistage hepatocarcinogenesis in the rat: transforming growth factor alpha expression as a marker for the stage of progression. Cancer Lett 93: 73-83.

Dragan YP, Campbell HA, Baker K, Vaughan J, Mass M, Pitot HC (1994) Focal and non-focal hepatic expression of placental glutathione S-transferase in carcinogen-treated rats. Carcinogenesis 15: 2587-2591.

Dragan YP, Hully J, Baker K, Crow R, Mass MJ, Pitot HC (1995) Comparison of experimental and theoretical parameters of the Moolgavkar-Venzon-Knudson incidence function for the stages of initiation and promotion in rat hepatocarcinogenesis. Toxicology 102: 161-175.

Dragan YP, Campbell HA, Xu XH, Pitot HC (1997) Quantitative stereological studies of a 'selection' protocol of hepatocarcinogenesis following initiation in neonatal male and female rats. Carcinogenesis 18: 149-158.

Gil R, Callaghan R, Boix J, Pellin A, Llombart-Bosch A (1988) Morphometric and cytophotometric nuclear analysis of altered hepatocyte foci induced by N-nitrosomorpholine (NNM) and aflatoxin B1 (AFB1) in liver of Wistar rats. Virchows Arch B Cell Pathol Incl Mol Pathol 54: 341-349.

Godlewski CE, Boyd JN, Sherman WK, Anderson JL, Stoewsand GS (1985) Hepatic glutathione S-transferase activity and aflatoxin B1-induced enzyme altered foci in rats fed fractions of brussels sprouts. Cancer Lett 28: 151-157.

Grasl-Kraupp B, Ruttkay-Nedecky B, Müllauer L, Taper H, Huber W, et al (1997) Inherent increase of apoptosis in liver tumors: implications for carcinogenesis and tumor regression. Hepatology 25: 906-912.

Harada T, Maronpot RR, Morris RW, Boorman GA (1990) Effects of mononuclear cell leukemia on altered hepatocellular foci in Fischer 344 rats. Vet Pathol 27: 110-116.

Harada T, Maronpot RR, Morris RW, Stitzel KA, Boorman GA (1989) Morphological and stereological characterization of hepatic foci of cellular alteration in control Fischer 344 rats. Toxicol Pathol 17: 579-593.

Johnson NM, Egner PA, Baxter VK, Sporn MB, Wible RS, et al (2014) Complete protection against aflatoxin B1-induced liver cancer with triterpenoid: DNA adduct dosimetry, molecular signature and genotoxicity threshold. Cancer Prev Res (Phila) .

Kirby GM, Stalker M, Metcalfe C, Kocal T, Ferguson H, Hayes MA (1990) Expression of immunoreactive glutathione S-transferases in hepatic neoplasms induced by aflatoxin B1 or 1,2-dimethylbenzanthracene in rainbow trout (Oncorhynchus mykiss). Carcinogenesis 11: 2255-2257.

Ohnishi S, Ma N, Thanan R, Pinlaor S, Hammam O, et al (2013) DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev 2013: 387014.

Pitot HC, Dragan YP, Teeguarden J, Hsia S, Campbell H (1996) Quantitation of multistage carcinogenesis in rat liver. Toxicol Pathol 24: 119-128.

Ribback S, Calvisi DF, Cigliano A, Sailer V, Peters M, et al (2013) Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis. J Hepatol 58: 1147-1156.

Thoolen B, Ten Kate FJ, van Diest PJ, Malarkey DE, Elmore SA, Maronpot RR (2012) Comparative histomorphological review of rat and human hepatocellular proliferative lesions. J Toxicol Pathol 25: 189-199.

Wyde ME, Cambre T, Lebetkin M, Eldridge SR, Walker NJ (2002) Promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in male Sprague-Dawley rats. Toxicol Sci 68: 295-303.

Xu YH, Maronpot R, Pitot HC (1990) Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. Carcinogenesis 11: 267-272.

Xu YH, Campbell HA, Sattler GL, Hendrich S, Maronpot R, et al (1990) Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. Cancer Res 50: 472-479.