Heterogeneity of hepatocyte antigen expression in rat liver carcinogenesis: concordance between neoplastic nodules...

Fischer F344 rats were given a cyclical diet of 0.06% 2-acetylaminofluorene (AAF), which progressively induced oval cell proliferation, cirrhosis and hyperplastic (or neoplastic) nodules. Primary liver tumours developed from 7 months after ceasing the diet. Liver samples taken during and after AAF administration and specimens of primary tumours were processed into frozen sections and examined microscopically for morphological changes in cell populations, stained histochemically for gamma-glutamyl transpeptidase (GGTase) and four phosphatases, and stained by the immunoperoxidase technique for the presence of antigens detected by seven anti-liver cell monoclonal antibodies and monoclonal antibodies to six oncoproteins. During and after AAF treatment several of the anti-liver antibodies revealed foci of aberrantly or heterogeneously-stained cells, although anti-oncoprotein antibodies showed no consistent changes. Foci of cells positive for GGTase and heterogeneous for adenosine triphosphatase (ATPase) were also seen. Nodules invariably showed heterogeneous antigenicity, raised GGTase and abnormal ATPase expression. Primary tumours exhibited varying degrees of positivity, negativity and heterogeneity with the anti-liver monoclonal antibodies, and all were positive for GGTase. Comparison between various parameters and different lesions showed the greatest concordance between nodules and tumours, suggesting that nodules are probably the precursors of malignant tumours in this system.