Further evidence for promoter-dependent development of hepatoblastoma in the mouse.

In previous studies, we found that male D2B6F1 mice fed phenobarbital (PB) for 53 weeks following N-nitrosodiethylamine (NDEA) initiation developed a high (70-80%) incidence of malignant hepatoblastomas. A very low (3.3%) incidence of such tumors occurred in the absence of promoter treatment in NDEA-initiated mice observed for 60 weeks, although nearly 50% of these animals developed hepatocellular lesions. To investigate whether hepatocellular lesions in NDEA-initiated mice or spontaneous hepatocellular lesions promoted by PB in mice given PB but no NDEA, progress to hepatoblastomas later in life, mice exposed to NDEA alone and PB alone were maintained for 110 weeks. Hepatocellular tumors (adenomas and carcinomas) occurred in almost all (97%) mice given NDEA alone. However, only 10% of NDEA-treated mice developed hepatoblastomas. Thus, despite its ability to induce hepatocellular neoplasms, NDEA treatment alone was rarely sufficient to induce hepatoblastomas in these mice. In contrast, PB treatment in the absence of NDEA initiation promoted the development of spontaneously occurring hepatocellular lesions, a significant number (37%) of which progressed to hepatoblastomas. Our observations clearly show that in this animal model the development of hepatoblastoma from its precursor cells (hepatocellular adenoma and carcinoma cells) occurs predominantly in the presence of promoting agents such as PB.