Mechanisms of liver carcinogenesis by chronic exposure to alpha-particles form internally deposited Thorotrast

We analyzed mutations of the p53 and the K-ras genes, microsatellite instability (MSI), in Thorotrast intrahepatic cholangiocarcinoma (ICC) and loss of heterozygosity (LOH) in Thorotrast ICC and angiosarcoma (AS). The major p53 mutation suggested that reactive oxygen species are not likely involved in gene mutations of Thorotrast ICC. MSI in Thorotrast ICC was significantly more frequent than that in non-Thorotrast ICC and was partly attributed to the inactivation of the hMLH1 mismatch repair gene via methylation. LOH pattern of Thorotrast ICC was partly shared with non-Thorotrast ICC but was different from that of AS. A BAS image analyzer revealed that the distribution of thorium deposits was always in living macrophages. We conclude that Thorotrast-induced cancers are developed through complex carcinogenic steps by the biological reaction during remodeling of the liver architecture.