In continuation of earlier studies on murine neoplastic liver lesions, we characterized by histochemical methods the phenotype of
hepatocellular adenomas and
carcinomas induced by single
injections of
diethylnitrosamine (1.25, 2.5, or 5.0 micrograms/g of
body weight) in 15-day-old C57BL/6 x male C3H F1 mice. The
hepatocellular adenomas were composed predominantly of basophilic cells but stored excessive amounts of fat and
glycogen in large portions of the
tumors. Irrespective of the carcinogenic dose, the
adenomas showed a consistent histochemical pattern.
Glycogen synthase and
phosphorylase were highly active in the hepatocytes that stored
glycogen. In cells poor in, or free of, this
polysaccharide, these
enzymes were only moderately active or even inactive. In
glycogen-storing parts of the
adenomas, the activity of
adenylate cyclase was reduced compared with normal liver parenchyma, but in fat-storing portions it was elevated. In a few
adenomas, uniform increase in
adenylate cyclase activity could be encountered. The levels of
ATPase,
acid phosphatase, and
glucose-6-phosphatase were either increased or decreased.
Glucose-6-phosphate dehydrogenase and
glyceraldehyde-3-phosphate dehydrogenase showed an increased activity in all
adenomas compared with preneoplastic foci, which in turn exhibited a higher
glucose-6-phosphate dehydrogenase and
glyceraldehyde-3-phosphate dehydrogenase activity than the surrounding parenchyma or the liver of untreated controls. The
hepatocellular carcinomas showed remarkable histochemical changes compared with
adenomas. The levels of fat and
glycogen and the activities of
glycogen synthase,
phosphorylase, and in most cases also that of
glucose-6-phosphate dehydrogenase, were reduced significantly. In contrast,
adenylate cyclase,
glucose-6-phosphatase,
glyceraldehyde-3-phosphate dehydrogenase, and also
alkaline phosphatase showed a striking elevation in developing
carcinomas. Similar, although more pronounced, histochemical changes were seen in the advanced
hepatocellular carcinomas. These observations indicated that progression from
adenomas to
hepatocellular carcinomas was associated with a change in the activity of several
enzymes involved in cell membrane function,
glycogen metabolism, the oxidative pentose phosphate pathway, and glycolysis.