EARLY EVENTS IN CHEMICALLY INDUCED RAT HEPATOCARCINOGENESIS

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The project was initiated to study the sequence of events during chemically induced neoplasia using the rodent hepatoma model in combination with quantitative two-dimensional electrophoresis (2-D). Results obtained to date include: 1) demonstration that 2-D could reliably detect and quantitate changes in known polypeptide markers for hepatocarcinogernesis (albumin, alpha-fetoprotein, aldehyde dehydrogenase, the individual subunits [Yc, Yb, Ya, and Yp] of the glutathione-S-transferases [B, A, ligandin and P] and DT-diaphorase). 2) Using the Solt-Farber initiation promotion protocol, preneoplastic and neoplastic liver nodules were induced in male Fischer F344 rats. Individual nodules were dissected and classified histologically as being either early preneoplastic, preneoplastic, or neoplastic. One cytosolic polypeptide (pI 6.8/57 kDa) and three membrane-associated polypeptides (pI 6.25/41 kDa; 6.75/26 kDa; 6.05/21 kDa) were expressed in both preneoplastic and neoplastic nodules but not in control liver. In addition to quantitation of the above known markers, numerous quantitative changes were also detected in as yet unidentified polypeptides among the various cell types. Twenty-one membrane and 10 cytosolic polypeptides were down-regulated, while 14 membrane and 6 cytosolic polypeptides were up-regulated during hepatocarcino-genesis. In all but three polypeptides, the direction and magnitude of change were the same in both preneoplastic and neoplastic nodules. 3) Investigation of the homogeneity and heterogeneity of polypeptide expression among individual nodules isolated from separate animals have revealed marked similarities among the individual preneoplastic and neoplastic nodules from the same animal and among nodules isolated from different animals.