Upstream eventClonal Expansion/Cell Proliferation, to form Altered Hepatic Foci (AHF)
Tumorigenesis, Hepatocellular carcinoma
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)||adjacent||Moderate||Moderate|
Life Stage Applicability
Key Event Relationship Description
While there is no direct evidence addressing how AFB1 exposure affects cellular proliferation and the clonal expansion of mutant cells to ultimately form HCC, there are multiple biological processes that are generally involved in tumor development. These are discussed in a previous section and include effects on apoptosis, inflammation, the development of a tumor microenvironment, interference with the anti-oxidant response, and likely others.
Evidence Supporting this KER
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; 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. Cell proliferation appears to be six- to seven-fold greater in AHF than in surrounding liver parenchyma (Dragan et al., 1994). In tree shrews, the apoptosis-related genes p53, bcl-2, bax and survivin were expressed to a much greater extent at 30 and 60 weeks in rats treated with AFB1 than in control rats (Duan et al., 2005). However, the measurements were made from liver biopsies, and whether the increased expression was associated with foci is not known. The Nrf2-Keap1 pathway activated by chemoprotectants appears to be a large factor in preventing hepatocellular carcinoma (HCC). Hence, the oxidative environment and resulting cellular stress that are the targets of this pathway likely contribute to tumor development from AHF.
A large number of initiation-promotion studies have been conducted in rats, and it is clear from these that AHF occur earlier in time than liver tumors, establishing the expected temporal sequence (Pitot et al., 1990a, 1990b, 1991; Dragan et al., 1995; Grasl-Kraupp et al. 1997).
Uncertainties and Inconsistencies
A seemingly strong relationship exists between AHF and tumors; AHF have been considered as pre-neoplastic lesions for a number of years (Bannasch et al., 1986; Ikeda et al., 2004; Ribback et al., 2013).
Quantitative Understanding of the Linkage
One might obtain a quantitative understanding of this linkage from studies with AFB1 that reported both AHF in terms of volume fraction of the liver and HCC tumor incidence. However, no such data were identified. Most initiation-promotion studies used a highly artificial system with chemical initiation with an alkylating agent and promotion with phenobarbital, TCDD, or some other compound, coupled with partial hepatectomy to further stimulate rapid cell proliferation (Xu et al., 1990a, 1990b). Chemoprotection studies such as Johnson et al. (2014) indicate that a strong relationship likely exists between AHF and tumors, but insufficient data exist for quantification or definitive dose-response determination.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
AHF have been observed essentially universally in AFB1-treated mammals, birds, and fish examined (Pottenger et al., 2014; Kensler et al., 2011; Kimura et al., 2004; Cullen et al., 1900; Kirby et al., 1990).
1. Olden K, Vulimiri SV (2014) Laboratory to community: chemoprevention is the answer. Cancer Prev Res (Phila) 7: 648-652.
2. Liby K, Yore MM, Roebuck BD, Baumgartner KJ, Honda T, et al (2008) A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res 68: 6727-6733.
3. Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, et al (2007) Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther 6: 154-162.
4. Yates MS, Kensler TW (2007) Keap1 eye on the target: chemoprevention of liver cancer. Acta Pharmacol Sin 28: 1331-1342.
5. Kensler TW, Egner PA, Wang JB, Zhu YR, Zhang BC, et al (2004) Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas. Gastroenterology 127: S310-S318.
6. 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) .
7. Dragan YP, Hully J, Crow R, Mass M, Pitot HC (1994) Incorporation of bromodeoxyuridine in glutathione S-transferase-positive hepatocytes during rat multistage hepatocarcinogenesis. Carcinogenesis 15: 1939-1947.
8. Duan XX, Ou JS, Li Y, Su JJ, Ou C, et al (2005) Dynamic expression of apoptosis-related genes during development of laboratory hepatocellular carcinoma and its relation to apoptosis. World J Gastroenterol 11: 4740-4744.
9. Pitot HC, Dragan Y, Sargent L, Xu YH (1991) Biochemical markers associated with the stages of promotion and progression during hepatocarcinogenesis in the rat. Environ Health Perspect 93: 181-189.
10. Pitot HC, Dragan Y, Xu YH, Pyron M, Laufer C, Rizvi T (1990) Role of altered hepatic foci in the stages of carcinogenesis. Prog Clin Biol Res 340D: 81-95.
11. Pitot HC (1990) Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu Rev Pharmacol Toxicol 30: 465-500.
12. 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.
13. 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.
14. 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.
15. Ikeda H, Nishi S, Sakai M (2004) Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem J 380: 515-521.
16. 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.
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. 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.
19. Pottenger LH, Andrews LS, Bachman AN, Boogaard PJ, Cadet J, et al (2014) An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride. Crit Rev Toxicol 44: 348-391.
20. Kensler TW, Roebuck BD, Wogan GN, Groopman JD (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicol Sci 120 Suppl 1: S28-S48.
21. Kimura M, Lehmann K, Gopalan-Kriczky P, Lotlikar PD (2004) Effect of diet on aflatoxin B1-DNA binding and aflatoxin B1-induced glutathione S-transferase placental form positive hepatic foci in the rat. Exp Mol Med 36: 351-357.
22. Cullen JM, Marion PL, Sherman GJ, Hong X, Newbold JE (1990) Hepatic neoplasms in aflatoxin B1-treated, congenital duck hepatitis B virus-infected, and virus-free pekin ducks. Cancer Res 50: 4072-4080.
23. 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.