TRANSFORMING GROWTH-FACTOR-ALPHA IN CARCINOGEN-INDUCED F344 RAT HEPATIC FOCI

Transforming growth factor-alpha (TGF alpha) is a positive growth regu lator in epithelial cells, including hepatocytes. Overexpression of TG F alpha has been associated with increased growth and malignancy of en d-stage cancers in humans and rodents. The overall aim of this study w as to characterize TGF alpha staining in diethylnitrosamine-induced he patic foci from male F344 rats with the hematoxylin and eosin (H and E ) histological phenotype. The association between the individual focal DNA synthesis labeling index and the presence of TGF alpha was also e xamined. Hepatic foci were identified as eosinophilic, basophilic, cle ar cell, or mixed cell. Of these foci, 37.5% labeled positive for TGF alpha. There were distinct differences in the pattern of TGF alpha lab eling between the different H and E histological phenotypes, Intense, uniform TGF alpha labeling was observed in eosinophilic foci, Basophil ic foci labeled for TGF alpha diffusely uniform throughout the cytopla sm. In clear-cell foci, TGF alpha labeling occurred primarily along th e periphery of the cell membrane. In mixed-cell foci, labeling occurre d both along the periphery and diffusely throughout the cytoplasm. On those slides stained, glutathione-S-transferase (placental; GSTP) was detected in almost all eosinophilic and mixed-cell foci, whereas appro ximately half of the basophilic and clear-cell foci stained for GSTP, The presence of GSTP in a focus was not always associated with the pre sence of increased TGF alpha protein. All rat hepatic adenomas and the one carcinoma labeled positive for TGF alpha. Increased levels of TGF alpha protein were associated with increased DNA synthesis labeling i ndex. The number of TGF alpha-positive foci with the highest DNA synth esis labeling indices were statistically higher than those with lower levels of DNA synthesis labeling. Although characteristic staining pat terns for TGF alpha were associated with specific histological subtype , the role that TGF alpha plays in the progression of focal lesions to neoplasia requires further definition. High levels of TGF alpha prote in appear to be acquired sometime during the hepatocarcinogenic proces s. It may be that early lesions that acquire high levels of TGF alpha are the ones to develop into hepatocellular carcinoma (e.g., hepatocel lular carcinoma is determined very early in the carcinogenic process). It is apparent that further work is needed to delineate the role of T GF alpha in both rodent and human hepatocarcinogenesis. (C) 1996 Acade mic Press, Inc.