Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 19, Pages E3806-E3815Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1619416114
Keywords
extrahepatic cholangiocarcinoma; IL-33; organoid; ILC2; amphiregulin
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Funding
- Japanese Society for the Promotion of Science [15K09039]
- Astellas Foundation for Research on Metabolic Disorders
- Nakayama Cancer Research Institute
- Okinaka Memorial Institute for Medical Research
- Princess Takamatsu Cancer Research Fund
- Foundation for Promotion of Cancer Research in Japan
- Grants-in-Aid for Scientific Research [15K09039, 15K09038, 15H04807] Funding Source: KAKEN
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The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras-and TGF beta/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGF beta receptor type 2 (TGF beta R2) deletion were first generated by crossing LSL-Kras(G12D), Tgfbr2(flox/flox), and K19(CreERT) mice (KT-K19(CreERT)). However, KT-K19CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreERT mice were crossed with CDH1flox/flox mice (KTCK19CreERT). Surprisingly, KTC-K19CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high (l)evels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGF beta R2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.
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