Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors

Age of host and transplantation-site microenvironment influence the tumorig enic potential of neoplastically transformed liver epithelial cells. Tumori genic BAG2-GN6TF rat liver epithelial cells consistently form tumors at ect opic sites, but differentially express tumorigenicity or hepatocytic differ entiation in the liver depending on host age and route of cell transplantat ion into the liver. Direct inoculation into host livers concentrates tumor cells locally, resulting in undifferentiated tumors near the transplantatio n site in both young (3-month-old) and old (18-month old) rats. Transplanta tion-site tumors regress within 1 month in the livers of young rats, but gr ow progressively in old rats, However, inoculation of cells into the spleen distributes transplanted cells individually throughout the liver, resultin g in hepatocytic differentiation by tumor cells with concomitant suppressio n of their tumorigenicity in young rats. When transplanted into livers of o ld rats by splenic inoculation, or when young hepatic-transplant recipients are allowed to age, hepatocytic progeny of BAG2-GN6TF cells proliferate to form foci, suggesting that the liver microenvironment of old rats incomple tely regulates the proliferation and differentiation of tumor cell-derived hepatocytes. Upon removal from the liver, BAG2-GN6TF-derived hepatocytes re vert to an undifferentiated, aggressively tumorigenic phenotype, We posit t hat the spectrum between normal differentiation and malignant potential of these cells reflects the dynamic interaction of the specific transformation -related genotype of the cells and the characteristics of the tissue microe nvironment at the transplantation site. Changes in the tissue milieu, such as those that accompany normal aging, may determine the ability of a geneti cally aberrant cell to produce a tumor.