RESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares , Conductos Biliares Extrahepáticos , Colangiocarcinoma , Animales , Ratones , Humanos , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Conductos Biliares Extrahepáticos/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Pigmentos BiliaresRESUMEN
The two main biliary pathologies in paediatric practice, biliary atresia and choledochal malformations (CM), have their origins within prenatal life. Nevertheless, the actual mechanisms remain elusive with many unanswered questions. The extrahepatic bile duct develops as a funnel-like structure emerging from the foregut from about 3-4 weeks of gestation into the mesenchyme of the septum transversum. The cranial elements of this contain hepatoblasts - the precursors to the two key cell lines that will become hepatocytes and biliary epithelial cells. The intrahepatic bile ducts develop separately and emerge from a complex process involving the ductal plate surrounding the in-growing portal venous system from about the 7-8th week of gestation. A developmental defect at some point(s) in this process may be the cause of at least some variants of BA - the Biliary Atresia Splenic Malformation syndrome particularly - though evidence in the more common isolated BA is much more circumstantial. Similarly, some types of choledochal malformation, specifically the cystic type of CM, are invariably present during prenatal life although again an actual aetiological mechanism remains elusive.
Asunto(s)
Conductos Biliares Extrahepáticos , Atresia Biliar , Embarazo , Femenino , Humanos , Niño , Atresia Biliar/etiología , Atresia Biliar/patología , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/anomalías , Conductos Biliares Intrahepáticos/patologíaRESUMEN
Significant efforts have advanced our understanding of foregut-derived organ development; however, little is known about the molecular mechanisms that underlie the formation of the hepatopancreatic ductal (HPD) system. Here, we report a role for the homeodomain transcription factor Hhex in directing HPD progenitor specification in zebrafish. Loss of Hhex function results in impaired HPD system formation. We found that Hhex specifies a distinct population of HPD progenitors that gives rise to the cystic duct, common bile duct, and extra-pancreatic duct. Since hhex is not uniquely expressed in the HPD region but is also expressed in endothelial cells and the yolk syncytial layer (YSL), we tested the role of blood vessels as well as the YSL in HPD formation. We found that blood vessels are required for HPD patterning, but not for HPD progenitor specification. In addition, we found that Hhex is required in both the endoderm and the YSL for HPD development. Our results shed light on the mechanisms directing endodermal progenitors towards the HPD fate and emphasize the tissue specific requirement of Hhex during development.
Asunto(s)
Hepatopáncreas/embriología , Hepatopáncreas/crecimiento & desarrollo , Proteínas Represoras/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente/metabolismo , Tipificación del Cuerpo/fisiología , Sistema Digestivo/metabolismo , Embrión no Mamífero/metabolismo , Endodermo/metabolismo , Células Endoteliales/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Hepatopáncreas/metabolismo , Proteínas de Homeodominio/genética , Proteínas Represoras/genética , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
The hepatopancreatic ductal system is the collection of ducts that connect the liver and pancreas to the digestive tract. The formation of this system is necessary for the transport of exocrine secretions, for the correct assembly of the pancreatobiliary ductal system, and for the overall function of the digestive system. Studies on endoderm organ formation have significantly advanced our understanding of the molecular mechanisms that govern organ induction, organ specification and morphogenesis of the major foregut-derived organs. However, little is known about the mechanisms that control the development of the hepatopancreatic ductal system. Here, we provide a description of the different components of the system, summarize its development from the endoderm to a complex system of tubes, list the pathologies produced by anomalies in its development, as well as the molecules and signaling pathways that are known to be involved in its formation. Finally, we discuss its proposed potential as a multipotent cell reservoir and the unresolved questions in the field.
Asunto(s)
Sistema Digestivo/crecimiento & desarrollo , Endodermo/crecimiento & desarrollo , Hígado/crecimiento & desarrollo , Páncreas/crecimiento & desarrollo , HumanosRESUMEN
BACKGROUND AND AIMS: It is necessary to study about extrahepatic bile duct (EHD) lesions in cases with abnormal liver function test (LFT) and clinical symptoms, even though abdominal ultrasonography could not find out the bile duct lesions. It is unclear however, whether the precise examination of EHD lesions are necessary in asymptomatic patients with normal liver function showing EHD dilatation without any lesions on abdominal ultrasonography (US). METHODS: We examined prospectively about EHD using endoscopic ultrasonography (EUS), followed by endoscopic retrograde cholangiopancreatography (ERCP) in fifty-three patients with normal LFT showing only EHD dilatation on US. The mean EHD diameter on US was 9.1 1.4 mm. RESULTS: The EHD dilatations alone on EUS were 41.5% and the EHD dilatations with lesions were 58.5%. The observed lesions of EHD by EUS were bile duct stones in 32.1%, thickening or stricture of distal bile duct in 17.0%, ampullary mass in 5.7% and CBD polyps in 3.8%. Three cases of ampullary mass were confirmed as 2 cases of T1 ampullary cancer and 1 case of papillitis. Examination by ERCP revealed EHD dilatation alone in 49.1% and bile duct lesions in 50.9%. ERCP could not detect the 2 cases of CBD polyp and 2 cases of distal bile duct thickening. CONCLUSIONS: In patients with normal LFT showing only EHD dilatation on abdominal US, EHD lesions can be detected in high frequency. Therefore, further examination about dilatated EHD should be conducted and for this purpose, EUS is be recommended as a useful tool.