Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models

Abstract

The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic progenitor cells, while EHBDs originate directly from the endoderm through a separate branching morphogenetic process. Traits that are important for cancer are often found to overlap in developmental and other processes. Therefore, it has been suggested that intrahepatic cholangiocarcinomas (iCCAs) and extrahepatic cholangiocarcinomas (eCCAs) have different developmental mechanisms. While much evidence is being gathered on the mechanism of iCCAs, the evidence for eCCA is still very limited. The main reason for this is that there are very few appropriate animal models for eCCA. We can gain important insights from these animal models, particularly genetically engineered mouse models (GEMMs). GEMMs are immunocompetent and mimic human CCA subtypes with a specific mutational pattern, allowing the development of precancerous lesions, that is, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). This review provides a summary of the pathogenesis and mechanisms of eCCA that can be revealed by GEMMs. Furthermore, we discuss several clinical questions, such as whether BilIN and IPNB really become malignant, whether the peribiliary gland is the origin of eCCAs, and others.

Biliary stem cells in health and cholangiopathies and cholangiocarcinoma

“…It has been suggested that intraductal papillary neoplasm of bile duct (IPNB) derived from PBGs are preneoplastic lesions of mucin-producing CCAs that morphologically resemble PBGs [68]. Interestingly, interleukin (IL)-33-mediated biliary epithelial injury-induced regenerative response accelerates the development of extrahepatic CCA from peribiliary glands, as demonstrated by lineage tracing models [69,70]. The role of PBGs in the genesis of ampullary tumors has been demonstrated in lineage tracing models [71].…”

Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System

“…The gallbladder, the extrahepatic biliary ducts (EHBDs), the liver, and the pancreas all develop from an outpouching of the endodermal lining of the foregut called the hepatic diverticulum. SOX17, along with Pdx1, plays a decisive role in whether Pdx1+ cells are differentiated towards the pancreas or EHBD; SOX17 expression promotes biliary tract formation, while SOX17 haploinsufficiency in mice leads to gallbladder and EHBD hypoplasia [69].…”