Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)||KE||Strong|
Level of Biological Organization
How this Key Event works
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. [1-4] In addition, enzyme alterations were used to identify AHF foci, most notably, the occurrence of a placental form of glutathione-S-transferase (GSTP+). [5-8] 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.  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.  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. [11,12] 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. [13,14]
How it is Measured or Detected
Quantitative stereology has been used to quantify the growth of AHF. [6,15-17] Growth of foci appears to follow the Moolgavkar-Venzon-Knudson model of initiation and promotion. [18,19] 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.
Evidence Supporting Taxonomic Applicability
The occurrence of AHF appears to be universal and has been observed in mammals, including humans, as well as in birds and in fish. [8,21,22].
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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. 11. 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. 12. 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. 13. 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.
14. 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.
15. Pitot HC, Dragan YP, Teeguarden J, Hsia S, Campbell H (1996) Quantitation of multistage carcinogenesis in rat liver. Toxicol Pathol 24: 119-128.
16. 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.
17. 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.
18. Dewanji A, Moolgavkar SH, Luebeck EG (1991) Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions. Math Biosci 104: 97-109.
19. 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.
20. 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) .
21. 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.
22. 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.