TGF alpha differentially expressed in liver foci induced by diethylnitrosamine initiation and peroxisome proliferator promotion.

Transforming growth factor alpha (TGF alpha) is a mitogenic 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 TGF alpha; its expression is also altered in mitogenic 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 (approximately 5- to 20-fold) and other types of foci (approximately 2-fold greater than eosinophilic foci; EF). To test the hypothesis that PP-induced HBF over-express TGF alpha 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 TGF alpha or EGFR and with hematoxylin and eosin. DEN-WY and WY abrogated the small amount of centrilobular TGF alpha staining observed in livers from control rats. Increased staining for TGF alpha 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 TGF alpha-positive. None of the tumors induced by WY (0/13) or DEN-WY (0/11) over-expressed TGF alpha. All 13 WY-induced tumors also lacked increased expression of EGFR. TGF alpha over-expression noted in a significant proportion of EF was associated only with those regimens including DEN initiation. In conclusion, TGF alpha or EGFR over-expression is not associated with early appearing, rapidly proliferating HBF or tumors induced by PP.