Relationship: 343



Increased, Proliferation/Clonal Expansion of Mutant Cells (Pre-Neoplastic Lesions/Altered H leads to Tumorigenesis, Hepatocellular carcinoma

Upstream event


Increased, Proliferation/Clonal Expansion of Mutant Cells (Pre-Neoplastic Lesions/Altered H

Downstream event


Tumorigenesis, Hepatocellular carcinoma

Key Event Relationship Overview


AOPs Referencing Relationship


Taxonomic Applicability


Sex Applicability


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


Biological Plausibility


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.

Empirical Evidence


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.

Response-response Relationship




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).



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