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Key Event Title
Increase, Clonal Expansion of Altered Hepatic Foci
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Key Event Components
Key Event Overview
AOPs Including This Key Event
|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 Do not cite||Under Development|
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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