The peroxisome proliferator class of non-genotoxic hepatocarcinogens synergize with epidermal growth factor to promote clonal expansion of initiated rat hepatocytes

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Abstract
The mechanisms by which the peroxisome proliferator (PP) class of non-genotoxic carcinogens perturb growth regulation and cause rodent liver cancer are unknown. Using a soft agar cloning assay, we have demonstrated that PPs synergize with the physiological liver mitogen epidermal growth factor (EGF) to cause the clonal expansion of rat hepatocytes associated with the early stages of tumourigenesis. In the presence of EGF (25 ng/ml), the PP nafenopin (100 µM) was able to stimulate a 5-fold increase in the number of colonies (35 colonies/50 000 hepatocytes compared to seven in the control). EGF alone or nafenopin alone gave 11 and 14 colonies respectively. TGFα, which acts through the EGF receptor, also synergized with nafenopin, whereas HGF was inactive, despite its potency as an hepatocyte growth factor. The ability to promote colony formation was shared by the potent PP Wyeth-14,643 but not by the less potent compounds methylclofenapate or trichloroacetic acid. TGFβ, a physiological negative regulator of liver growth, was able to inhibit the nafenopin/EGFstimulated colony formation at 0.25 ng/ml, a concentration below that required for TGFfi-induced hepatocyte apoptosis. The colonies formed are derived from and consist of hepatocytes, since they express the hepatocyte-specific marker albumin, although the majority are negative for the PP-induced cytochrome, P4504A1. Pre-treatment in vivo with the genotoxic carcinogen dimethylhydrazine hydrochloride (150 mg/kg) caused a doubling in the number of colonies from 35 to 75/50 000 hepatocytes. Taken together, these data suggest that some PPs act as hepatocarcinogens by synergjzing with EGF and/or TGFa to promote the clonal expansion of spontaneously initiated hepatocytes. This clonal expansion may be inhibited by TGFβ. Such a synergy may provide a mechanistic basis for the hepatocarcinogenicity of this class of non-genotoxic carcinog

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