The role of stem cells/progenitor cells in liver carcinogenesis in glycine N-methyltransferase deficient mice

Regeneration of the liver is inhibited as a result of a sustained increase in S-adenosylmethionine levels in glycine N-methyltransferase (GNMT)−/− mice. This sets the stage for normally dormant stem cells/progenitor cells to replicate and differentiate to replenish the liver parenchyma with liver cells. With time the stem cells/progenitor cells may aggregate and ultimately form liver tumors. This transformation of stem cells persists within the tumors that form in order to maintain the growth of the tumors that have formed. To test this hypothesis, GNMT−/− mice were maintained for 18 months and their livers were studied at intervals, in order to document the process of tumors formation and the identification of stem cells/progenitor cells involved in the process. Progenitor cell (OV-6 positive cells) hyperplasia was already established at 8 months in the livers of the GNMT−/− mice. This process was expanded at 18 months when liver tumors had formed. Stem cells which stained positive in the livers at 8 months and within tumors at 18 months (Oct 4 and CK 19 positive cells) were found. Fat 10, a marker for progenitor liver cells, was uniformly expressed by all tumors that developed at 8 and 18 months in GNMT−/− mice.