and Carpino et al.7, 8 have proposed another new classification RAD001 of cholangiocarcinomas based on cell lineage. Under their classification scheme, which is compatible with the pathological classification of ICC proposed by Nakanuma et al.,5 it is suggested that there are multiple cells of origin in cholangiocarcinoma, including hepatic stem/progenitor cells postulated to be located within the

canals of Hering (hepatic stem/progenitor cell lineage) or peribiliary glands (biliary tree stem/progenitor cell lineage), as well as immature or more mature cholangiocyte derivatives, that underlie biological, epidemiological, and clinical heterogeneity in small versus large duct ICCs and extrahepatic bile duct cancer. Hepatic stem/progenitor cell “biomarkers,” such as neural cell adhesion molecule (NCAM), have been demonstrated to be selectively expressed in combined HCC-CCA9 and in the bile ductular (cholangiolocellular) type.5, 10 Small bile duct type ICCs have also been suggested to originate from

interlobular bile ducts.11 Conversely, large duct or perihilar ICCs have been suggested to arise from biliary tree stem/progenitor cells or from more mature descendents.7, 8 A multistep carcinogenesis process indicative of a hyperplasia- selleck screening library dysplasia-carcinoma sequence is also currently recognized.12-15 In this context, malignant progression of precancerous precursor lesions, notably biliary intraepithelial neoplasia (BilIN) without12, 13 or with14 intestinal metaplasia, as well as intraductal selleck chemicals papillary neoplasm of the

bile ducts exhibiting various phenotypes (e.g., intestinal type, gastric type, and oncocytic type),5 are consistent with different and distinct cell lineage pathways in the cytohistogenesis of ICC variants (i.e., conventional ICC versus less common subtypes, such as intestinal-type ICC or biliary cystic mucinous neoplasm with ovarian stroma5, 14). Although it has been generally considered that ICCs are derived from either cholangiocytes or, possibly, hepatic and/or biliary stem/progenitor cells, Fan et al.16 and Sekiya and Suzuki17 have now independently demonstrated, with unique mouse models and eloquent hepatocyte fate tracing methods, a compelling alternative to the cellular origin of ICC, namely, through transdifferentiation and neoplastic conversion of normal hepatocytes into malignant cholangiocytes by a mechanism mediated, in part, by overexpression of activated Notch. In the model described by Fan et al., ICCs induced in liver after hydrodynamic tail vein injection of the intracellular domain of Notch1 receptor plasmid, combined with concomitant injection of an Akt-overexpressing plasmid, were of the cystadenocarcinoma type, which formed in noncirrhotic liver.