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Pathogenesis of intrahepatic cholangiocarcinoma.

Susumu Eguchi, MD, FACS, FEBS
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Intrahepatic cholangiocarcinoma (ICC) develops in the biliary epithelium and accounts for about 5 % of primary liver carcinoma. Although hepatectomy is the only curative treatment, patients with unresectable ICC undergo radiotherapy and/or chemotherapy with poor prognosis. Disorders such as chronic viral hepatitis causing chronic inflammation, cholangitis, and intrahepatic stones are recently drawing attention as factors causing ICC (Nakamura Y et al. IARC Press Lyon, 217-224:2010). The carcinogenesis of ICC mostly remains to be explained by molecular biology. However, various recent studies suggest that the growth of the biliary epithelium induced by chronic inflammation may play a part in carcinogenesis. [1] [2] [3] [4]

I. Mechanism of carcinogenesis due to chronic inflammation and genetic mutation

The previous studies have observed an association between chronic inflammation and carcinogenesis in patients with carcinoma. The relevant infectious inflammations include Helicobacter pylori infection associated with gastric carcinoma and human papillomavirus infection associated with cervical carcinoma as well as ulcerative colitis and Crohn’s disease with large intestine carcinoma. The clinical definition of chronic inflammation is difficult. But much evidence has recently indicated the molecular biological mechanism: inflammation triggers the activation of an inflammatory signaling pathway and the expression of transcription factors and genes, which causes uncontrolled and disorganized cell proliferation leading to carcinogenesis. [5]

Driver mutation has been observed in many patients with cholangiocarcinoma. Accumulated genomic alterations cause carcinoma to develop and become advanced. Thirty two significant drivers was identified through transcriptome analysis in 145 patients with intrahepatic cholangiocarcinoma, 86 patients with extrahepatic cholangiocarcinoma, and 29 patients with gallbladder carcinoma. FGFR2 gene fusion, IDH1/2, EPHA2, and AP-1 mutation were identified as drivers specific to intrahepatic cholangiocarcinoma, and KRAS, SMAD4, ARID1A, and GNAS mutation were identified as drivers common to both intrahepatic and extrahepatic cholangiocarcinoma (Nakamura H et al. Nature Genetics 2015;47:1003-1010). Their research indicates that the pathway of carcinogenesis varies depending on the site of carcinogenesis, which is very significant for future choice and development of a molecularly targeted drug targeting gene mutation.

The Japan and Singapore joint research project classified a total of 489 cases collected from 10 countries (Japan, Singapore, Thailand, China, Taiwan, South Korea, Romania, Italy, France, and Brazil) into 4 molecular groups through a comprehensive sequence analysis. Groups 1 to 3 were classified as the poor prognosis group. Many patients in Group 1 had clonorchis sinensis infection as background disease, activated WNT pathway in Group 2, and increased expression of an immune checkpoint (PD-1, PD-2) in Group 3 were observed. In Group 4, either IDH1 mutation and FGFR2 gene fusion was significantly higher and differences in their characteristics were observed (Jusakul A, et al. Cancer Discov 2017;7:1116-1135.) Two pathways of carcinogenesis: gene mutation caused by aberrant methylation in patients with chronic inflammation leads to carcinogenesis and driver mutation associated with aberrant methylation leads to carcinogenesis. The study indicates that both inflammation and gene mutation are significantly involved in carcinogenesis.

Possible disorders causing chronic inflammation in patients with intrahepatic cholangiocarcinoma include hepaticolithiasis and cholangitis after gastrointestinal tract surgery. Recently, it was reported that the inflammatory cytokine IL-33 induces carcinogenesis. The carcinogenic mechanism of IL-33 is that injured and peeling biliary epithelial cells release IL-33 as an alarm signal to induce a regenerative reaction by injuring the peribiliary gland (Yamada D, et al. Hepatology 2015;61:1627-1642). However, the environment allows genetically altered cells to exist in the peribiliary gland, and the regenerating reaction by IL-33 may contribute to facilitation of carcinogenesis in the peribiliary gland. Yamada et al. reported on production of a mouse model developing intrahepatic cholangiocarcinoma, with oncogenes AKT and YAP injected from the gallbladder, retained in the bile duct, and incorporated in the biliary mucosal epithelium, and intraperitoneally administered IL-33 causing inflammation. Ikegami et al. focused on the Ras-MAPK signaling pathway and the PI3K-AKT signaling pathway, which were effectively activated in patients with cholangiocarcinoma, and demonstrated spontaneous development of cholangiocarcinoma using mouse models with co-transduced KRAS gene alterations and the PTEN gene (Ikenoue T, et al. Sci Rep 2016;6:23899. doi: 10.1038/srep23899.)

II. Occupational carcinogenesis

Intrahepatic cholangiocarcinoma was reported as occupational carcinogenesis in 2012, when cholangiocarcinoma was observed in many employees working at a printing factory that used organochlorine detergent for long periods. [6] [7] [8] [9] Toyoda et al. found that dichloropropane was excreted from the liver into the bile. Dichloropropane is a candidate carcinogen produced from industrial chemical substances and is strongly suspected as the cause of occupational cholangiocarcinoma. Dichloropropane contains two chemically reactive chlorines that enter the body where they combine with glutathione, an antioxidant in the body. In the metabolic process of dichloropropane, one remaining chlorine maintains glutathione binding. In addition, the ABCC2 transporter, which is the membrane structure for biliary excretion, was found to have a function to excrete glutathione-bound dichloropropane. Dichloropropane with one remaining chlorine is excreted into the bile. Dichloropropane metabolite excreted into the bile chronically injures the biliary epithelium, leading to carcinogenesis.

These elucidation of the carcinogenesis mechanism allows prophylaxis against carcinogenesis caused by an external factor. The findings of those study contribute significantly to society. [10] It is expected that these clinical reports and establishment of corresponding animal models may allow a step up from development of in-vivo treatment to clinical study and advance research in this area including molecularly targeted drugs.

References

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