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Key Event Title
Increase, Clonal Expansion of Altered Hepatic Foci
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
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
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
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).
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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