Hepatic tumors induced by carbon tetrachloride in transgenic mice carrying a human c-H-ras proto-oncogene without mutations.

Hepatic tumors were generated in mice by repeated administration of carbon tetrachloride (CCl4). Eight transgenic (Tg) mice carrying a human c-H-ras proto-oncogene (rasH2 line) and 9 non-Tg mice were killed at 20 weeks. Tg mice developed more tumors than did non-Tg littermates. Most tumors were neoplastic nodules, but 1 hepatocellular carcinoma (HCC) was found in a Tg mouse at 20 weeks. Three Tg and 2 non-Tg mice were kept without further administration of CCl4. Two Tg mice died at 30 weeks of HCC with intra-abdominal bleeding, and 1 Tg mouse developed HCC with a mesenteric metastasis at 32 weeks. No HCC was found in 2 non-Tg mice at 32 weeks. Although mutations at codon 12, 13, and 61 of the H-ras gene are often found in murine hepatocarcinogenesis, neither the tumors, including one HCC, nor the normal cells revealed any such mutations. These results showed that the unmutated human c-H-ras gene facilitates malignant transformation of hepatocytes when continuous liver-cell death and regeneration is caused by repeated administration of CCl4.