WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited
Luke Boulter, … , Owen J. Sansom, Stuart J. Forbes
Luke Boulter, … , Owen J. Sansom, Stuart J. Forbes
Published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1269-1285. https://doi.org/10.1172/JCI76452.
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Research Article

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Abstract

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.

Authors

Luke Boulter, Rachel V. Guest, Timothy J. Kendall, David H. Wilson, Davina Wojtacha, Andrew J. Robson, Rachel A. Ridgway, Kay Samuel, Nico Van Rooijen, Simon T. Barry, Stephen J. Wigmore, Owen J. Sansom, Stuart J. Forbes

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Figure 1

Canonical WNT signaling is activated in human CC.

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Canonical WNT signaling is activated in human CC. (A) mRNA expression of...
(A) mRNA expression of WNT pathway genes and WNT target genes in CC versus patient-matched non-cancerous tissue (n = 11). Represented as a 3-fold change; P < 0.05. (B) WNT7B and WNT10A mRNA expression in human CC versus non-diseased liver (n = 37 vs. n = 30). (C) Immunohistochemistry of WNT7B (green) in CD68-positive macrophages (red). (D) Quantification of CD68+WNT7B+ TAMs (n = 42). (E) Immunohistochemistry for CTNNB1 (red) and BCL9 (green) in human CC and non-tumor, patient-matched liver. (F) Quantification of biliary nuclear staining for BCL9 (n = 42 per group). (G) Immunohistochemistry in non-tumor versus CC for CCND2, LEF1, BIRC5, C-MYC, and SOX9. Yellow lines, non-cancerous bile ducts; red lines, malignant biliary ducts; black arrows, nuclear positivity for C-MYC. (H) Quantification of biliary nuclear staining for CCND2, LEF1, BIRC5, C-MYC, and SOX9 in non-tumor and CC tissue (n = 42 per group). Data are presented as mean ± SEM. Mann-Whitney U test; **P < 0.01, ***P < 0.001. Photomicrograph scale bars: 50 μm (in C, right panel, 20 μm).