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Event: 378

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Tumorigenesis, Hepatocellular carcinoma

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Tumorigenesis, Hepatocellular carcinoma

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help
Process Object Action
hepatocellular carcinoma increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Mutagenic MOA for Cancer 2 AdverseOutcome Agnes Aggy (send email) Open for citation & comment EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

The AO final key event results from the processes that occur in the earlier series of key events, which for AFB1 is a mutagenic MOA—the AFB1 induction of mutations in critical cancer genes that alter the phenotype of the mutant cell and set the stage for that cell to progress to a pre-neoplastic lesion and ultimately an HCC. The biological processes described in this AO, however, are not specific to a mutagenic MOA—nor necessarily demonstrated for AFB1 exposure, but occur in development of HCC from all MOAs for HCC. Thus the final key events (AHF and HCC) represent the final stages of the pathway that leads to HCC from a mutagenic MOA or other MOAs.

Hepatocellular carcinoma (HCC) is a cancer of hepatocytes, and this disease is almost always lethal in the absence of extreme intervention measures (e.g., surgery, liver transplant). A number of factors are associated with HCC including AFB1 exposure, infection with hepatitis virus (HBV), and alcohol use. A common etiologic feature of HCC, whether produced by AFB1 intoxication, HBV, cirrhosis or something else, is the presence of oxidative damage in the liver. (Ravinayagam et al., 2012 Int J Hepatol; Kim et al., 2011 J Ginseng Res).

AFB1 produces specific pro-mutagenic adducts that are believed to lead to a mutation in the p53 gene, which affects its functioning. P53 is generally considered to be a tumor suppressor gene involved in cell cycle regulation and initiation of apoptosis. When applied in vitro to hepatocytes, AFB1 produced cellular swelling, bleb formation, and lysis. These effects may be due to lipid peroxidation affecting the cell membrane from the downstream dialdehyde metabolite of the AFB1 epoxide metabolites. (Mathijs et al., 2009, 2010) This damage is reflective of oxidative stress, a known contributor to HCC (Ravinayagam et al., 2012 Int J Hepatol; Kim et al., 2011 J Ginseng Res). As discussed elsewhere in this AOP, the Nrf2-Keap1 anti-oxidant response induced by a number of chemoprotective agents can be quite effective in preventing HCC [3-8], even in the presence of a significant burden of N7- AFB1-G adducts.

The cellular damage produced by exposure to AFB1 likely leads to chronic inflammation, also a contributor to tumor progression. (Ellinger-Ziegelbauer et al., 2004) Heme oxygenase-1 (HO-1) breaks down heme to bilirubin and biliverdin that have anti-oxidant and anti-inflammatory activities (Keum et al., 2006; Caballero et al 2004) , thus countering the inflammatory response. The induction of HO-1 is part of the Nrf2-Keap1 anti-oxidant response.

From a systems biology and biochemistry perspective, the presence of oxidative stress and inflammation, although not specific only to AFB1 exposure, are strong contributors to cancer progression.(Ohnishi et al., 2013; Zheng et al., 2013; Higgs et al., 2014).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Hepatocellular carcinoma is detected in humans by clinical examination confirmed by pathological examination, and in laboratory test species by pathological examination.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Hepatocellular carcinoma occurs in many vertebrate species including birds, fish, and mammals such as humans.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

Although not specifically used EPA for regulatory determinations vis-à-vis AFB1, HCC has been used as an adverse endpoint in many hazard assessments that can be used as input to risk management decisions. The U.S. EPA Integrated Risk Information System (IRIS database) contains 111 instances wherein HCC has been considered in hazard assessment of environmental contaminants. For example, HCC in rats formed part of the weight of evidence in categorizing polychlorinated biphenyls as probable human carcinogens. These tumors, combined with other liver tumors, also formed the basis for quantitative dose-response assessment for cancer induced by polychlorinated biphenyls by the oral route.(USEPA, 2014).

Given that AFB1 can be a contaminant in both human food and animal feed, FDA has established allowable limits. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/foodadvisorycommittee/ucm428947.pdf

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

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.

Higgs MR, Chouteau P, Lerat H (2014) 'Liver let die': oxidative DNA damage and hepatotropic viruses. J Gen Virol 95: 991-1004.

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) .

Liby KT, Sporn MB (2012) Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 64: 972-1003.

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.

Moudgil V, Redhu D, Dhanda S, Singh J (2013) A review of molecular mechanisms in the development of hepatocellular carcinoma by aflatoxin and hepatitis B and C viruses. J Environ Pathol Toxicol Oncol 32: 165-175.

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.

Roebuck BD (2004) Hyperplasia, partial hepatectomy, and the carcinogenicity of aflatoxin B1. J Cell Biochem 91: 243-249.

Shelton P, Jaiswal AK (2013) The transcription factor NF-E2-related factor 2 (Nrf2): a protooncogene? FASEB J 27: 414-423.

U.S. EPA IRIS, (2014) available at http://www.epa.gov/iris/subst/0294.htm#woe

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.

Yates MS, Kensler TW (2007) Keap1 eye on the target: chemoprevention of liver cancer. Acta Pharmacol Sin 28: 1331-1342.

Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, et al (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res 66: 2488-2494.

Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J (2008) Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2. Free Radic Res 42: 362-371.

Zheng YW, Nie YZ, Taniguchi H (2013) Cellular reprogramming and hepatocellular carcinoma development. World J Gastroenterol 19: 8850-8860.