WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

被引:237
作者
Boulter, Luke [1 ,2 ]
Guest, Rachel V. [1 ]
Kendall, Timothy J. [2 ,3 ]
Wilson, David H. [2 ]
Wojtacha, Davina [1 ]
Robson, Andrew J. [1 ]
Ridgway, Rachel A. [4 ]
Samuel, Kay [1 ]
Van Rooijen, Nico [5 ]
Barry, Simon T. [6 ]
Wigmore, Stephen J. [3 ]
Sansom, Owen J. [4 ]
Forbes, Stuart J. [1 ,3 ]
机构
[1] Scottish Ctr Regenerat Med, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland
[2] Western Gen Hosp Campus, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland
[3] Queens Med Res Inst, MRC Ctr Inflammat Res, Edinburgh, Midlothian, Scotland
[4] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
[5] Vrije Univ Amsterdam, Dept Mol Biol, Amsterdam, Netherlands
[6] AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England
基金
欧洲研究理事会; 英国医学研究理事会; 英国惠康基金;
关键词
CANCER STEM-CELLS; BETA-CATENIN; RAT CHOLANGIOCARCINOMA; LIVER; BILIARY; TARGET; EXPRESSION; PORCUPINE; KINASE; MYC;
D O I
10.1172/JCI76452
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.
引用
收藏
页码:1269 / 1285
页数:17
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