Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 3, Pages 1269-1285Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76452
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Funding
- Medical Research Council [G1000868/97900]
- Cancer Research UK [C26848/A14889]
- Alan Morement Memorial Fund
- UK Regenerative Medicine Platform [MR/M007588/1]
- MRC
- European Research Council
- Wellcome Trust
- MRC [MR/M007588/1, G1000868, MR/K026666/1] Funding Source: UKRI
- Cancer Research UK [14889] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [21139] Funding Source: researchfish
- Medical Research Council [MR/K026666/1, MR/M007588/1, G1000868] Funding Source: researchfish
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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.
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