Non-genotoxic hepatocarcinogenesis: Suppression of apoptosis by peroxisome proliferators

Peroxisome proliferators (PPs) are potent rodent hepatocarcinogens that induce hepatocyte hyperplasia and liver enlargement.(1,2,3) It has long been accepted that the mitosis induced by this diverse group of compounds may play a role in their hepatocarcinogenicity.(3,4) However, it has become apparent more recently that liver growth regulation is controlled by the balance between cell birth by mitosis and cell death by apoptosis.(5-7) We and others have generated data to demonstrate that peroxisome proliferators can suppress hepatocyte apoptosis both in vivo and in vitro.(8-10) Thus, peroxisome proliferators can perturb both sides of the growth equation between mitosis and apoptosis. It is as yet unclear how alterations in these two processes contribute to carcinogenesis; both may be required but, individually, may not be sufficient for cancer to develop. Similarly, the mechanisms by which peroxisome proliferators perturb growth control are not clear. Our recent data have suggested that these compounds may synergize with naturally occurring liver mitogens such as epidermal growth factor (EGF) to promote clonal outgrowth of initiated hepatocytes.(11,12) In addition, peroxisome proliferators are known to activate the peroxisome proliferator-activated receptor (PPAR), a ligand-dependent transcription factor.(13-15) It is probable that the activation of this factor will lead to altered transcription of some gene(s) involved in hepatocyte growth control, although the identity of these genes remains to be determined.