Abstract
The identification of the cellular origin of cancer is important for our understanding of the mechanisms regulating carcinogenesis, thus the cellular origin of cholangiocarcinoma (CCA) is a current topic of interest. Although CCA has been considered to originate from biliary epithelial cells, recent studies have suggested that multiple cell types can develop into CCA. With regard to the hilar and extrahepatic bile ducts, peribiliary glands (PBGs), a potential stem cell niche of biliary epithelial cells, have attracted attention as the cellular origin of biliary tract cancer. Recent histopathological and experimental studies have suggested that some kinds of inflammation-induced CCA and intraductal papillary neoplasms of the bile duct are more likely to originate from PBGs. During inflammation-mediated cholangiocarcinogenesis, the biliary epithelial injury-induced regenerative response by PBGs is considered a key process. Thus, in this review, we discuss recent advances in our understanding of cholangiocarcinogenesis from the viewpoint of inflammation and the cellular origin of CCA, especially focusing on PBGs.
Highlights
Cholangiocarcinoma (CCA) is a highly malignant tumor exhibiting feature of biliary epithelial differentiation
CCA is classified, according to its anatomical location, as intrahepatic CCA, perihilar CCA, or distal CCA. pCCA and dCCA are distinguished by the insertion site of the cystic duct, and iCCA is defined as CCA arising from the second-order bile duct in the liver [1,2]
Biliary tract cancer has been considered to originate from biliary epithelial cells (BECs), recent mouse genetic lineage-tracing experiments have suggested that multiple cell types, including mature hepatocytes, can give rise to iCCA [9,10]
Summary
Cholangiocarcinoma (CCA) is a highly malignant tumor exhibiting feature of biliary epithelial differentiation. Many studies using mouse models have identified tissue-resident, long-lived stem cells in various organs and suggested that these cells are the main cellular origin of cancer [7]. Biliary tract cancer has been considered to originate from biliary epithelial cells (BECs), recent mouse genetic lineage-tracing experiments have suggested that multiple cell types, including mature hepatocytes, can give rise to iCCA [9,10]. We established a new mouse model of extrahepatic CCA whose malignant progression depends on biliary epithelial injury and inflammation. This mouse model has suggested that PBGs are the cellular origin of extrahepatic CCA [12]. In this review, we first provide a brief overview of CCA, and discuss recent advances in the understanding of cholangiocarcinogenesis from the viewpoint of the inflammation and cellular origin of CCA, especially focusing on PBGs
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