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 rod ent hepatocarcinogens. There exist substantial species differences in response to peroxisome proliferators among mammalian species. We have reported previously that peroxisome proliferators can synergize with e pidermal growth factor (EGF) to promote the clonal expansion of rat he patocytes associated with the early stages of hepatocarcinogenesis. Th e aim of the present study was to determine whether responsiveness in this in vitro assay reflected the known species differences in respons e to peroxisome proliferators. The process of tumorigenicity was model ed 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 und ergo mitosis, and to escape from the contact-dependent growth associat ed with normal cell behavior. The data presented here show that mouse hepatocytes are able to undergo clonal expansion in soft agar in respo nse to nafenopin and EGF giving a three- to fourfold increase in colon y numbers over control. This result is comparable to the fivefold incr ease in rat hepatocyte colony numbers that we have reported previously . In contrast, hamster, guinea pig, and human hepatocytes did not resp ond to the concerted action of EGF and nafenopin despite their ability to respond to EGF as a mitogen in monolayer culture. These data demon strate that the clonal expansion of rodent hepatocytes in soft agar in response to peroxisome proliferators and EGF displays the same specie s differences as other pleiotropic responses to these compounds and is likely therefore to be relevant to the process of hepatocarcinogenesi s. (C) 1995 Society of Toxicology.