Aberrant Expression of Pancreatic Stem Cell Markers in the Biliary Tree Relates to Intrahepatic Cholangiocarcinogenesis in Hepatolithiasis.
Saya Igarashi, Maylee Hsu, Motoko Sasaki, Kenichi Harada, Yasuni Nakanuma. Kanazawa University Graduate School of Medicine, Japan
Background: During development, the biliary system and ventral pancreas arise from a contiguous region of the endoderm, and transcription factors, such as pancreatic duodenal homeobox factor 1 (PDX1) and hairy and enhancer of split 1 (Hes1), a downstream target of the Notch signaling pathway, help guide pancreaticobiliary differentiation. Recently, biliary intraepithelial neoplasia (BilIN) has been proposed as a preneoplastic lesion leading to intrahepatic cholangiocarcinoma (ICC) through a dysplasia-carcinoma sequence, and morphologically resembles pancreatic intraepithelial neoplasia (PanIN), a preneoplastic lesion of pancreatic carcinoma. During PanIN development, reactivation of embryonic pancreatic transcription factors and dysregulation of notch signaling has been suggested to play a role in pancreatic carcinogenesis. We hypothesize that the same molecules that are expressed in PanIN and pancreatic cancer, including PDX1, Hes1, Notch, and other stem cell like markers (CD44, cMET and CXCR4), are also involved in the development of BilIN and the carcinogenesis of ICC.
Design: From 90 cases with hepatolithiasis and 40 cases of ICC without hepatolithiasis, normal bile ducts (31), reactive bile ducts (63), BilIN-1 (68), BilIN-2 (47), BilIN-3 (43), and ICC (80) were immunohistochemically examined for PDX1, CXCR4, CD44, cMet, Hes1 and Notch2 expression. RNA samples were extracted from BilIN lesions by laser capture microdissection, and mRNA levels were quantitatively evaluated by real time PCR.
Results: 45% of ICC cases with and without hepatolithiasis were positive for PDX1. Furthermore, PDX1 was more frequently expressed in BilIN-2 (74.0%) and BilIN-3 (79.1%) than in normal bile ducts (22.2%), reactive bile ducts (41.3%), and BilIN-1 (47.1%). Real time PCR revealed that PDX1 expression was significantly greater in BilIN-2/3 lesions compared to normal/reactive/BilIN-1 lesions. The expression of CXCR4 and cMET tended to increase with higher grades of BilIN, while CD44 tended to decrease. Hes1 and Notch2 was predominantly expressed in normal ducts and BilIN lesions, however there was less and weaker expression in ICC.
Conclusions: Expression of the stem cell like markers and pancreatic specific marker (PDX1) correlated with grades of BilIN lesions, suggesting that ICCs with hepatolithasis express several stem cell like properties in the early steps of carcinogenesis, and that dysregulation of embryonic transcription factors is involved in intrahepatic cholangiocarcinogenesis in hepatolithiasis.
Category: Liver & Pancreas
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 202, Wednesday Morning