title: The direct and indirect effects of promoters may depend upon the nature of the initiated cell.
abstract: The sequence of events in carcinogenesis may be more complex than previously proposed. We cannot as yet define the nature of initiation, nor in fact the obligate aspects of promotion. Administering small doses of diethylnitrosamine (DEN) to neonatal mice genetically predisposed to hepatocarcinogenesis, or to lines that are not (with and without subsequent phenobarbital (PB) administration), gave evidence that different types of initiated cells might exist. The majority of tumors that resulted were identical in morphology and biology to those that arise spontaneously from basophilic, diploid cells. However, a second tumor type was seen only in DEN-PB treated mice. This was composed of huge eosinophilic, polyploid cells. A third tumor type, rapidly progressing to a fully malignant form, was seen only in predisposed mice that received DEN, suggesting a genetic "hit" in a genetically predisposed cell. In addition to demonstrating the spectrum of initiated cells available for the action of promoters, evidence was obtained that indicated that one major action of PB was to stimulate growth of these altered cell populations rather than to induce new phenotypic alterations commensurate with progression. Thus, characteristics of PB-expanded, altered hepatocyte populations could be identified in very early cell foci.
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004247:DNA / Q000032:analysis; D004052:Diethylnitrosamine; D008114:Liver Neoplasms, Experimental / Q000145:classification; D051379:Mice; D010634:Phenobarbital / Q000633:toxicity; D005723:gamma-Glutamyltransferase / Q000032:analysis
chemical_list: D002273:Carcinogens; D004052:Diethylnitrosamine; D004247:DNA; D015073:2-Acetylaminofluorene; D005723:gamma-Glutamyltransferase; D010634:Phenobarbital