Transforming Growth Factor-α in Carcinogen- Induced F344 Rat Hepatic Foci

Abstract

Transforming growth factor-α (TGFα) is a positive growth regulator in epithelial cells, including hepatocytes. Overexpression of TGFα has been associated with increased growth and malignancy of end-stage cancers in humans and rodents. The overall aim of this study was to characterize TGFα staining in diethylnitrosamine-induced hepatic 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 TGFα was also examined. Hepatic foci were identified as eosinophilic, basophilic, clear cell, or mixed cell. Of these foci, 37.5% labeled positive for TGFα. There were distinct differences in the pattern of TGFα labeling between the different H and E histological phenotypes. Intense, uniform TGFα labeling was observed in eosinophilic foci. Basophilic foci labeled for TGFα diffusely uniform throughout the cytoplasm. In clear-cell foci, TGFα labeling occurred primarily along the periphery of the cell membrane. In mixed-cell foci, labeling occurred 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 approximately half of the basophilic and clear-cell foci stained for GSTP. The presence of GSTP in a focus was not always associated with the presence of increased TGFα protein. All rat hepatic adenomas and the one carcinoma labeled positive for TGFα. Increased levels of TGFα protein were associated with increased DNA synthesis labeling index. The number of TGFα-positive foci with the highest DNA synthesis labeling indices were statistically higher than those with lower levels of DNA synthesis labeling. Although characteristic staining patterns for TGFα were associated with specific histological subtype, the role that TGFα plays in the progression of focal lesions to neoplasia requires further definition. High levels of TGFα protein appear to be acquired sometime during the hepatocarcinogenic process. It may be that early lesions that acquire high levels of TGFα are the ones to develop into hepatocellular carcinoma (e.g., hepatocellular carcinoma is determined very early in the carcinogenic process). It is apparent that further work is needed to delineate the role of TGFα in both rodent and human hepatocarcinogenesis.