TGFα is differentially expressed in liver foci induced by diethylnitrosamine initiation and peroxisome proliferator promotion

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Abstract
Transforming growth factor α (TGFα) is a mitogenlc growth factor for hepatocytes that may play a role In the development of liver cancer in rodents and humans. Epidermal growth factor receptor (EGFR) is the receptor for TGFα; its expression is also altered in mltogenic and carcinogenic processes. Homogeneous basophilic foci (HBF), the precursor lesion to hepatocellular carcinomas in peroxisome proliferator (PP)-treated rats, have labeling Indices much greater than surrounding liver (˜5- to 20-fold) and other types of foci (˜.2-fold greater than eosino philic foci; EF). To test the hypothesis that PP-induced HIBF over-express TGFα and/or EGFR, male F344 rats were treated with the PP WY-14, 643 for 22 weeks (1000 p.p.m. in the diet) with (DEN-WY) and without (WY) prior diethylnitrosamine initiation (150 mg/kg body wt i.p.). Serial paraffin sections of liver were stained for TGFα or EGFR and with hematoxylin and eosin. DEN-WY and WY abrogated the small amount of centrilobular TGFα staining observed in livers from control rats. Increased staining for TGFα was not observed in HBF induced by WY (0/22) or DEN-WY (0/101). Additionally, Increased EGFR expression was not observed in HBF Induced by WY (0/22) or DEN-WY (0/19) or in EF induced by DEN-WY (0/30). An unexpectedly large proportion of EF induced by DEN-WY (6/38) and DEN-control (3/11) were TGFα-positive. None of the tumors Induced by WY (0/13) or DEN-WY (0/11) over-expressed TGFα. All 13 WY-induced tumors also lacked increased expression of EGFR. TGFα overexpression noted in a significant propor tion of EF was associated only with those regimens including DEN Initiation. In conclusion, TGFα or EGFR overexpression is not associated with early appearing, rapidly proliferating HBF or tumors induced by PP.

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