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 (CCI₄). 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 I 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 CCI₄. Two Tg mice died at 30 weeks of HCC with intra‐abdominal bleeding, and I 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 CCI₄. © 1994 Wiley‐Liss, Inc.