Peroxisome proliferators: potential role of altered hepatocyte growth and differentiation in tumor development

Continued, exposure-dependent proliferation of hepatocytes in basophilic proliferative lesions appears to be critical to the mechanism of peroxisome proliferator carcinogenesis in rodents. Identification of the growth regulatory pathway(s) involved in the exaggerated hepatocellular proliferation observed in these lesions is proceeding. So far, regulatory pathways involving cyclophilin and IGFII/M6P receptor have been implicated, while no evidence for involvement of HGF-R, TGF alpha, or PPAR is available. Clearly, this work is preliminary and additional information is needed. Exposure/dose response relationships for hepatocellular proliferation in the basophilic proliferative lesions, as well as species differences in regulation of hepatocellular proliferation, will be important information for development of realistic assessments of cancer risk in humans exposed to peroxisome proliferators. Given the traditional reliance on theoretical models of carcinogenesis that assume carcinogen-DNA interaction and mutation, utilization of newer information on hepatocellular growth and differentiation is expected to significantly change the estimated human risk of peroxisome proliferator-induced cancer.