Hepatocyte cell cycle transitions during the age-related development of type I hepatic adenomas in the genetically predisposed C3H mouse

Normal aging in the mammalian liver is associated with the progressive establishment of a predominant G1Q (quiescent G1) substate in the diploid hepatocyte population and a marked reduction in the cycling G1 compartment (G1A and G1B stage cells) (Higgins, Age 8:122–126, 1985). The C3H mouse, however, exhibits a genetic predisposition to the development of age-related proliferative lesions (adenomas) in the liver. Multiparameter flow cytometric computer models of the cell division cycle of normal young, normal old, and adenoma-derived liver cells were constructed using data obtained from acridine orange-based cytochemical measurements of hepatocyte RNA and DNA content. Compared to normal hepatocytes from young and age-matched old animals, liver cells derived from hepatic adenomas were characterized by an increased growth fraction (% cells involved in DNA synthesis), an increase in the proportion of cells in the immediate pre-DNA synthetic (G1B) phase of the cell cycle, and, most dramatically, the complete absence of a cytochemically-defined G1Q substate. Identical results were obtained by contour mapping of the RNA and DNA content of the isolated nuclear fraction of normal and adenomatous liver cells. Particularly evident was the fact that adenomas generally were comprised of a hepatocyte population with a predominantly tetraplold DNA content. The combined analyses on both intact hepatocytes and isolated nuclei clearly indicated that the G1 compartment of adenomatous hepatocytes in aged C3H mice consists solely of liver cells of the G1A and G1B phenotypes. In contrast, the uninvolved distal normal liver tissue in adenoma-bearing mice exhibited a predominant G1Q condition in the diploid hepatocyte complement as is characteristic of normal aging in this organ. Cell cycle distributions in adenomas, thus, appear to reflect the proliferative potential of such lesions.