Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis.

Hyperplastic liver lesions which develop following administration of hepatocarcinogens have been implicated as probable precursors for the cancers which ultimately develop. Some, and possibly all, of these putative precursor lesions are resistant to the necrogenic and growth-inhibitory action of hepatocarcinogens and other hepatotoxins. An in vivo assay system based on this resistance phenomenon has been developed which encourages the rapid selective growth of carcinogen-altered hepatocytes, facilitating their early identification. The system consists of a) single carcinogenic dose of diethylnitrosamine (DEN), b) short-term dietary exposure to 2-acetylaminofluorene (2-AAF) sufficient to suppress growth of virtually all normal hepatocytes, and c) partial hepatectomy (PH) to actuate rapid growth of DEN-altered hepatocytes not suppressed by 2-AAF. Following PH, the DEN-altered hepatocytes grow out as basophilic foci which are distributed randomly throughout the 2-AAF-suppressed parenchyma. Within 1 week they can be seen as tiny, discrete, translucent nodules on the capsular and cut surface of the remaining lobes. The lesions continue to proliferate and become histologically indistinguishable from typical carcinogen-induced hyperplastic liver nodules frequently described in the literature. These in turn appear to be precursor lesions for at least some hepatocellular carcinomas. Future experimentation based on this phenomenon of "selective resistance to cytotoxicity" should prove valuable in answering specific questions about the carcinogenic process in liver and possibly in other tissues.