Cell suspensions or tissue fragments from primary hepatocellular carcinomas and benign neoplastic nodules, induced by treating rats with chemical carcinogens, were transplanted by intraportal injection or subcapsular implantation in the livers of syngeneic host rats. Both nodule and carcinoma transplants produced high numbers of hepatocellular carcinomas in the hosts 2 to 5 mo after transplantation. Treatment of the host rats with liver tumor promoters (phenobarbital or 2-acetylaminofluorene) greatly stimulated tumor outgrowth, demonstrating that even established carcinoma cells can be promoter-sensitive. Tumor outgrowth was also stimulated by partial hepatectomy of the hosts, the regenerative stimulus interacting synergistically with the tumor promoters. (€~ATOL.OGY 1990;12:295-300.)
Tumor promoters are usually defined as agents that selectively stimulate the proliferation of tumor precursor cells during the early stages of carcinogenesis (1). The tumor promoters show great diversity in chemical structure and activity, ranging from activation of protein kinase C by the skin-tumor promoter tetradecanoylphorbol acetate (2) to activation of a DNA-binding, transcription-regulatory protein (the Ah receptor) by a liver tumor-promoting dioxin (3, 4). However, the ability of tetradecanoyl-phorbol acetateactivated protein kinase C to phosphorylate and activate, directly or indirectly, various transcriptional regulator proteins suggests a final common mechanism of tumor-promoter action at the level of activation of growth-regulatory genes (5,s). Promoters usually induce a limited proliferative response in the normal cells and a strong, sustained response in the preneoplastic (initiated) cells of the target tissue (7,8). The basis for the selective hyperresponsiveness of the tumor precursor cells is not known. In experimental initiation-promotion protocols,