A growth-constrained environment drives tumor progression in vivo

We recently have shown that selective growth of transplanted normal hepatoc ytes can be achieved in a setting of cell cycle block of endogenous parench ymal cells. Thus, massive proliferation of donor-derived normal hepatocytes was observed in the liver of rats previously given retrorsine (RS), a natu rally occurring alkaloid that blocks proliferation of resident liver cells. In the present study, the fate of nodular hepatocytes transplanted into RS -treated or normal syngeneic recipients was followed. The dipeptidyl peptid ase type IV-deficient (DPPIV-) rat model for hepatocyte transplantation was used to distinguish donor-derived cells from recipient cells. Hepatocyte n odules were chemically induced in Fischer 344, DPPIV+ rats; livers were the n perfused and larger (>5 mm) nodules were separated from surrounding tissu e. Cells isolated from either tissue were then injected into normal or RS-t reated DPPIV- recipients. One month after transplantation, grossly visible nodules (2-3 mm) were seen in RS-treated recipients transplanted with nodul ar cells. They grew rapidly, occupying 80-90% of the host liver at 2 months , and progressed to hepatocellular carcinoma within 4 months. By contrast, no liver nodules developed within 6 months when nodular hepatocytes were in jected into the liver of recipients not exposed to RS, although small clust ers of donor-derived cells were present in these animals. Taken together, t hese results directly point to a fundamental role played by the host enviro nment in modulating the growth and the progression rate of altered cells du ring carcinogenesis. In particular, they indicate that conditions associate d with growth constraint of the host tissue can drive tumor progression in vivo.