Analysis of carcinogenic mechanisms of liver cancers induced by chronic exposure to alpha-particles from internally deposited Thorotrast

For the successful space traveling, the possibility for the detrimental effects on health including cancer caused by exposure to cosmic rays is a major concern. Thorotrast is a 25% colloidal solution of natural αα-emitter, thorium dioxide used as a radiological contrast medium during World War II. It caused hepatic malignant tumors by the local exposure to αα-particles decades after administration. Thorotrast-induced liver tumors consist of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and angiosarcoma (AS) at nearly the same instance. We analyzed mutations of the p53 and the K-ras genes, microsatellite instability (MSI), and loss of heterozygosity (LOH) in Thorotrast ICC. The major p53 mutation observed in Thorotrast ICC was the transition type, suggesting that reactive oxygen species are not likely involved in gene mutations of Thorotrast cancers. MSI frequency in Thorotrast ICC was significantly higher than that in non-Thorotrast ICC. MSI was partly attributed to the inactivation of the hMLH1   mismatch repair gene via methylation of the promoter region and to monoclonal expansion of cells with mutations. Thorotrast ICC shared LOH pattern with non-Thorotrast HCC and ICC. Furthermore, we could assess the distribution and the quantity of deposited thorium using an imaging plate and a BAS image analyzer. The distribution of thorium deposits was not always consistent with that of apoptotic cells. We conclude that Thorotrast ICC is developed through complex carcinogenic steps including genomic instability and mutations of crucial genes during remodeling of the liver architecture. We emphasize how pathological specimens from Thorotrast patients are valuable for assessing the relevance of long-term exposure to low dose αα-particles to radiation carcinogenesis.