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2017 Fiscal Year Final Research Report

Indentification of cancer initiating cells using a mouse model of cholangitis-associated cholangiocarcinoma

Research Project

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Project/Area Number 15K09039
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

Uchino Koji  東京大学, 医学部附属病院, 助教 (00748725)

Co-Investigator(Kenkyū-buntansha) 中川 勇人  東京大学, 医学部附属病院, その他 (00555609)
Project Period (FY) 2015-04-01 – 2018-03-31
Keywords胆管癌 / IL-33 / オルガノイド / 胆管周囲付属腺
Outline of Final Research Achievements

Based on the frequent mutations of Ras and TGFb pathways in ECC, we generated mice with tamoxifen-inducible duct cell-specific Kras activation and TGFbR2 deletion by crossing LSL-KrasG12D, Tgfbr2flox/flox, and K19CreER mice (KT-K19CreER). However, KT-K19CreER mice did not develop biliary tumors. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreER mice were crossed with CDH1flox/flox mice (KTC-K19CreER). KTC-K19CreER mice developed invasive periductal infiltrating ECC within 4 weeks. Time-course analysis revealed that recombined biliary epithelial cells (BECs) lining the bile duct lumen died due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs). Dying BECs released IL-33 and stimulated a regeneration by PBGs via type 2 innate lymphoid cells, eventually leading to ECC. Cell lineage tracing suggested PBGs as the cellular origin of ECC. This mouse model provides new insight into biliary injury-based ECC development.

Free Research Field

消化器病学

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Published: 2019-03-29  

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