TGF-ALPHA IS DIFFERENTIALLY EXPRESSED IN LIVER FOCI INDUCED BY DIETHYLNITROSAMINE INITIATION AND PEROXISOME PROLIFERATOR PROMOTION

Transforming growth factor alpha (TGF alpha) is a mitogenic growth fac tor for hepatocytes that may play a role in the development of liver c ancer in rodents and humans. Epidermal growth factor receptor (EGFR) i s the receptor for TGF alpha; its expression is also altered in mitoge nic and carcinogenic processes. Homogeneous basophilic foci (HBF), the precursor lesion to hepatocellular carcinomas in peroxisome prolifera tor (PP)-treated rats, have labeling indices much greater than surroun ding liver (similar to 5- to 20-fold) and other types of foci (similar to 2-fold greater than eosinophilic foci; EF). To test the hypothesis that PP-induced HBF over-express TGF alpha and/or EGFR, male F344 rat s 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 initiati on (150 mg/kg body wt i.p.). Serial paraffin sections of liver were st ained for TGF alpha or EGFR and with hematoxylin and eosin. DEN-WY and WY abrogated the small amount of centrilobular TGF alpha staining obs erved in livers from control rats. Increased staining for TGF alpha wa s not observed in HBF induced by WY (0/22) or DEN-WY (0/101). Addition ally, 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 unexpe ctedly 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 (0/1 3) or DEN-WY (0/11) over-expressed TGF alpha. All 13 WY-induced tumors also lacked increased expression of EGFR. TGF alpha over-expression n oted in a significant proportion of EF was associated only with those regimens including HEN initiation. In conclusion, TGF alpha or EGFR ov erexpression is not associated with early appearing, rapidly prolifera ting HBF or tumors induced by PP.