This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 1171

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Clonal Expansion of Altered Hepatic Foci

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. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
hepatocyte

Organ term

Organ term
liver

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

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
PPARalpha-dependent liver tumors in rodents	KeyEvent	Chris Corton (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. 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. More help

More than 40 years ago, cancer biologists pounced on the Darwinian principles of mutation, selection, and clonal expansion to explain cancer evolution. The occurrence of altered clones of cells in the livers of animals was revealed by enzyme histochemistry with a resulting plethora of different types of clones including those positive for gamma-glutamyltranspeptidase (GGT), placental glutathione transferase and negative for APTase and glucose-6-phosphase (Glauert et al. 1986; Pitot, 1990; Scherer, 1987)

Mathematical models of clonal formation were developed soon after suffered from non-identifiability of parameters (Moolgavkar & Lubeck 2003; Connolly & Andersen 1991; Cox & Huber 2007). More recently, an examination of a clonal expansion model of cancer suggested a widely accepted model of clonal expansion appeared biologically implausible when compared to a model based on the concept of dysregulated hyperplasia (Bogen 2014).

Notwithstanding the vagaries of understanding and modeling early events in cancer pathogenesis, altered hepatic foci representing clones of presumably premalignant cells have been demonstrably observed as a precursor of rodent liver tumors. Oval cells are similar to fetal hepatoblasts and bipotential in that they can differentiate into either hepatocytes or cholantiocytes (Grompe 2013). primary oval cells from rats treated with PPARa activators differentiated into basophilic cells, similar to those in pre-neoplastic basophilic clones observed in chronic studies of PPARa activators (Kaplanski et al. 2000; Marsman & Popp, 1994). Continued activation of PPARα is necessary for focal enlargement and the formation of tumors (Grasl-Kraupp et al. 19931a, b, c; Isenberg et al. 1997; Corton et al. 2014).

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

Clonal expansion of altered hepatic foci is measure histologically as changes in the number of foci per volume of liver tissue or volume fraction of the liver (Marsman & Popp 1994; Isenberg et al. 1997; Kuwata et al. 2016)

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

The occurrence and growth of altered hepatic foci have been measured primarily rodents as part of initiation-promotion studies or two-year bioassays (Dragan et al. 1991; Hendrich et al. 1987; Pitot et al. 1989).

References

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

Conolly, R. B., & Andersen, M. E. (1991). Biologically based pharmacodynamic models: tools for toxicological research and risk assessment. Annu Rev Pharmacol Toxicol, 31, 503-523. https://doi.org/10.1146/annurev.pa.31.040191.002443

Corton, J. C., Cunningham, M. L., Hummer, T. B., Lau, C, Meek, B, Peters, JM, Popp, JA, Rhomberg, L, Seed, J., & Klaunig, J. E. (2014). Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARŒ±) as a case study. Crit Rev Toxicol, 44(1), 1-49. https://doi.org/10.3109/10408444.2013.835784

Cox, L. A., & Huber, W. A. (2007). Symmetry, identifiability, and prediction uncertainties in multistage clonal expansion (MSCE) models of carcinogenesis. Risk Anal, 27(6), 1441-1453. https://doi.org/10.1111/j.1539-6924.2007.00980.x

Dragan, Y. P., Rizvi, T., Xu, Y. H., Hully, J. R., Bawa, N., Campbell, H. A. et al. (1991). An initiation-promotion assay in rat liver as a potential complement to the 2-year carcinogenesis bioassay. Fundam Appl Toxicol, 16(3), 525-547.

Glauert, H. P., & Pitot, H. C. (1986). Influence of dietary fat on the promotion of diethylnitrosamine-induced hepatocarcinogenesis in female rats. … of the Society for Experimental Biology …. https://journals.sagepub.com/doi/abs/10.3181/00379727-181-42283.

Grasl-Kraupp B, Huber W, Just W, et al. (1993a). Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin. Carcinogenesis, 14, 1007–12.

Grasl-Kraupp B, Huber W, Timmermann-Trosiener I, Schulte-Hermann R. (1993b). Peroxisomal enzyme induction uncoupled from enhanced DNA synthesis in putative preneoplastic liver foci of rats treated with a single dose of the peroxisome proliferator nafenopin. Carcinogenesis, 14, 2435–7

Grasl-Kraupp B, Waldhor T, Huber W, Schulte-Hermann R. (1993c). Glutathione S-transferase isoenzyme patterns in different subtypes of enzyme-altered rat liver foci treated with the peroxisome proliferator nafenopin or with phenobarbital. Carcinogenesis, 14, 2407–12

Grompe, M. (2009). Adult Liver Stem Cells. In Essentials of Stem Cell Biology (pp. 285-298). Elsevier. https://www.sciencedirect.com/science/article/pii/B9780123747297000342

Hendrich, S., Campbell, H. A., & Pitot, H. C. (1987). Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis, 8(9), 1245-1250.

Isenberg JS, Kolaja KL, Ayoubi SA, et al. (1997). Inhibition of WY 14 643-induced hepatic lesion growth in mice by rotenone. Carcinogenesis, 18, 1511–9

Kaplanski, C., Pauley, C. J., Griffiths, T. G., Kawabata, T. T., & Ledwith, B. J. (2000). Differentiation of rat oval cells after activation of peroxisome proliferator-activated receptor alpha43. Cancer Res, 60(3), 580-587. https://pubmed.ncbi.nlm.nih.gov/10676640

Kuwata, K., Inoue, K., Ichimura, R., Takahashi, M., Kodama, Y., & Yoshida, M. (2016). Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice. Food Chem Toxicol, 88, 75-86.

Marsman, D. S., & Popp, J. A. (1994). Biological potential of basophilic hepatocellular foci and hepatic adenoma induced by the peroxisome proliferator, Wy-14,643. Carcinogenesis, 15(1), 111-117. https://doi.org/10.1093/carcin/15.1.111

Moolgavkar, S. H., & Luebeck, E. G. (2003). Multistage carcinogenesis and the incidence of human cancer. Genes Chromosomes Cancer, 38(4), 302-306. https://doi.org/10.1002/gcc.10264

Pitot, H. C., Campbell, H. A., Maronpot, R., Bawa, N., Rizvi, T. A., Xu, Y. H. et al. (1989). Critical parameters in the quantitation of the stages of initiation, promotion, and progression in one model of hepatocarcinogenesis in the rat. Toxicol Pathol, 17(4 Pt 1), 594-611; discussion 611.

Pitot, H. C., Dragan, Y., Xu, Y. H., & Pyron…, M. (1990). Role of altered hepatic foci in the stages of carcinogenesis. Progress in clinical …. https://europepmc.org/article/med/2196586.

Scherer, E. (1987). Relationship among histochemically distinguishable early lesions in multistep-multistage hepatocarcinogenesis. Mouse Liver Tumors. https://link.springer.com/chapter/10.1007/978-3-642-71617-1_7