Abstract
Background: Cadmium (Cd) is reported to have antitumor effects against chemical-induced liver tumors. Antitumor effects of Cd are not completely understood, but may be related to metallothionein-deficiency in tumors, which makes tumor vulnerable to necrotic effects of Cd. Methods: Eight-week old male C57BL/6 mice were given injections of diethylnitrosamine (DEN, 90 mg/kg, and 50 mg/kg two weeks later), followed by promotion with CCl4. CdCl2 was administered in the drinking water (500 ppm) from 21-40 weeks after DEN initiation. Body weights were recorded and liver tumor formation was monitored via ultrasound. At the end of experiments, livers were removed, weighed, and the tumor incidence, tumor numbers and tumor size scores were recorded. Liver histology and metallothionein immunostaining were performed. Results: After DEN injection, animal body weight decreased, and slowly recovered afterwards. Cd treatment did not affect animal body weight gain. Ultrasounds detected liver tumors 35 weeks after DEN injection. Animals were necropsied at 40 weeks. Liver/body weight ratios increased in DEN and DEN+Cd groups. Cd treatment decreased tumor incidence (71% vs 17%), tumor numbers (15 vs 2), and tumor scores (22 vs 3). Histopathology showed hepatocyte degeneration in all groups, and immunohistochemistry showed metallothionein-deficiency in liver tumors, while metallothionein stain was intensified in tumor surrounding tissues. RT-qPCR showed increases of alpha-fetoprotein in DEN-treated livers, and increases of metallionein-2 and TNFα in Cd-treated livers. Conclusion: Cd is effective in suppression of DEN-induced liver tumors, and the mechanisms may be related to metallothionein-deficiency in tumors and induction of TNFα to kill tumor cells.