Hyperplastic nodules and
hepatocellular carcinomas were induced in livers of rats by a
low-protein diet containing 0.05% of the
carcinogen N-2-fluorenylacetamide.
Ganglioside amounts and composition were determined for histologically different
hepatocellular carcinomas and compared with those for control livers, hyperplastic nodules, and liver tissue surrounding
hepatomas and nodules as well as those for livers of fetal, newborn, 1-week-old, weanling, and adult Sprague-Dawley rats.
Ganglioside sialic acid levels were elevated above those of normal adult liver in all liver tissues following the
carcinogen treatment regimen. Livers of fetal and newborn rats contained nearly twice the amount of
ganglioside sialic acid on a
protein or
DNA basis as did livers of adult rats. Analyses of individual nodules and
hepatomas revealed two populations of
tumors in which the levels of
ganglioside sialic acid were 2.3 and 3.8 times normal.
Ganglioside sialic acid content was at
hepatoma levels in small nodules. Individual
gangliosides were evenly distributed between products of the monosialoganglioside and disialoganglioside pathways in normal liver with a ratio of [
N-acetylneuraminic acid (
sialic acid)] (NAN)-
galactose (Gal)-N-
acetylgalactosamine (GalNAc)-(NAN)-Gal-
glucose (Glc)-
ceramide (Cer) (GD1a) to Gal-GalNAc-(NAN)2-Gal-Glc-Cer (GD1b) of about one. In contrast, the
monosialogangliosides predominated in liver tissues following administration of the
carcinogen. Increased levels of specific
monosialogangliosides were present in nodules, in liver of
carcinogen-treated animals prior to the appearance of
tumors, and in the liver tissues surrounding nodules and
hepatomas. In single
hepatomas,
ganglioside patterns correlated with tumorigenicity. A well-differentiated
hepatoma had a normal
complement of most
gangliosides but was deficient in trisialogangliosides. In a poorly diferentiated but well-circumscribed
hepatoma, the relative levels of all higher
gangliosides were reduced. The monosialoganglioside
Gal-GalNAc-(NAN)-Gal-Glc-Cer (GM1) accounted for 80% of the total
ganglioside in a poorly circumscribed and poorly differentiated
hepatoma. The
ganglioside pattern of fetal livers most closely resembled that of a poorly differentiated
hepatoma. During the first week post natum, levels of all higher
monosialogangliosides and
disialogangliosides declined, but the decline was most pronounced for
gangliosides GM1 and GD1a. The ratio of GM1 + GD1a to GD1b + NAN-Gal-GalNAc-(NAN)2-Gal-Glc-Cer or (NAN)3-Gal-Glc-Cer (GT), used as an index of the relative predominance of the monoslaloganglioside and disialoganglioside pathways, fell from 2.7 for fetal liver to 0.4 for adult liver. Pools of precursor
gangliosides increased during development, transiently for GalNAc-(NAN)-Gal-Glc-Cer and for more than 3 weeks for NAN-Gal-Glc-Cer. When hyperplastic nodules and
hepatocellular carcinomas were compared, a reverse pattern was observed. The ratio of GM1 + GD1a to GD1b + GT rose steadily to values of 2.7 and 11...