Species differences in the clonal expansion of hepatocytes in response to the coaction of epidermal growth factor and nafenopin, a rodent hepatocarcinogenic peroxisome proliferator.
Peroxisome proliferators are members of the nongenotoxic family of rodent hepatocarcinogens. There exist substantial species differences in response to peroxisome proliferators among mammalian species. We have reported previously that peroxisome proliferators can synergize with epidermal growth factor (EGF) to promote the clonal expansion of rat hepatocytes associated with the early stages of hepatocarcinogenesis. The aim of the present study was to determine whether responsiveness in this in vitro assay reflected the known species differences in response to peroxisome proliferators. The process of tumorigenicity was modeled in the soft agar cloning assay since growth in soft agar is thought to reflect the early stages of tumorigenesis. This is because clonal expansion under these conditions requires the cells to survive, to undergo mitosis, and to escape from the contact-dependent growth associated with normal cell behavior. The data presented here show that mouse hepatocytes are able to undergo clonal expansion in soft agar in response to nafenopin and EGF giving a three- to fourfold increase in colony numbers over control. This result is comparable to the fivefold increase in rat hepatocyte colony numbers that we have reported previously. In contrast, hamster, guinea pig, and human hepatocytes did not respond to the concerted action of EGF and nafenopin despite their ability to respond to EGF as a mitogen in monolayer culture. These data demonstrate that the clonal expansion of rodent hepatocytes in soft agar in response to peroxisome proliferators and EGF displays the same species differences as other pleiotropic responses to these compounds and is likely therefore to be relevant to the process of hepatocarcinogenesis.
James
N H
NH
Cell Biology Group, ZENECA Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Roberts
R A
RA
D000818:Animals; D002999:Clone Cells / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000166:cytology*; D008297:Male; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D009255:Nafenopin / Q000494:pharmacology*; D013045:Species Specificity
D008934:Mitogens; D009255:Nafenopin; D004815:Epidermal Growth Factor; D004247:DNA