Radiation pathology: From thorotrast to the future beyond radioresistance

Abstract

The effects of radiation on human health have been a major concern, especially after the Fukushima Daiichi Nuclear Power Plant (FNPP) accident. We can determine these effects only from radiological disasters. The radiological contrast medium Thorotrast is known to induce hepatic cancers decades after injection. Using archival materials from Thorotrast patients, we performed molecular pathological studies to elucidate carcinogenic mechanisms of internal radiation exposure. It is emphasized here that radiation-induced cancers are a complex consequence of biological response to radiation and ingested radionuclides. We further expanded the study to establish clinically relevant radioresistant cancer cells in order to develop more effective and less harmful radiation therapy. We also found that cancer cells can acquire radioresistance by low-dose fractionated radiation within one month. The FNPP accidents prompted us to collect tissue samples from animals in and around the evacuation zone in order to construct a tissue bank. The final goal of the bank is to enable research that will contribute to the common understanding of radioprotection.

History note: tragedy of Thorotrast

“…Malignancy associated with Thorotrast deposition is various, including malignancy in the liver, biliary tracts, hematopoietic system, lymphoma, lung, peritoneum, bone and others [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. According to Ito and his associates [15] the hepatic tumors after Thorotrast deposition comprised cholangiocarcinoma (CCA) (44 cases, 43.1 %), angiosarcoma (AS) (39 cases, 38.3 %), hepatocellular carcinoma (HCC) (16 cases, 15.7 %), triple cancers (CCA + AS + HCC) (1 case, 1 %), and double cancers (CCA + HCC) (2 cases, 2 %).…”

“…Thorium dioxide suspension, trade name "Thorotrast", used to be considered an apparently innocent contrast medium that was used for angiography with adequate radiodensity and no significant acute or subacute adverse reactions at the clinical standard in the past. However, it was an alpha emitter which was deposited in the reticuloendothelial system, including the liver, spleen and lymph nodes, and it irradiated such organs for a lifelong period [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Presented here is a tragic case that may be known to radiologists of older generations, but such experiences may not have been shared by younger radiologists, since almost all victims of Thorotrast injection are now dead.…”

Inhibition of livin overcomes radioresistance in nasopharyngeal carcinoma cells

“…Based on the notion that cancer cells can acquire radioresistance by low-dose fractionated radiation within a short period [8,18], we developed a radioresistance model. NPC cells were PLOS ONE role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.…”

Introduction and Overview

“…of angiosarcoma is negligible. These differences show how Thorotrast-induced liver cancer is crucial to understand the oncogenic mechanisms of persistent LDR internal radiation in humans [3]. Supported by the War Victims' Relief Bureau, former Ministry of Health and Welfare of Japan, approximately 400 Thorotrast patients underwent the postmortem pathological examination.…”

“…This systematic archive is valuable for elucidating the molecular mechanisms of human cancers induced by internal radiation exposure, particularly as it is composed of the world's largest number of related cases with the highest quality of radiological and pathological information [4]. The profile of cancer induction is quite different between Hibakusha and Thorotrast patients, indicating that the mechanisms underlying the carcinogenic effect of radiation vary between external and internal exposure and, therefore, have to be analyzed differently [3]. LSS revealed that the likelihood of cancer is different depending on the originating organ [5].…”