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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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 9

Loss of WNT signaling reduces proliferation and induces apoptosis in CC in vivo.

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Loss of WNT signaling reduces proliferation and induces apoptosis in CC ...
(A) Immunohistochemistry for KRT19 (green) and CTNNB1 (red) in TAA CC treated with vehicle, C59, or ICG-001. White arrows, nuclear positivity for CTNNB1. (B) Quantification of nuclear CTNNB1 staining in TAA CC following treatment with vehicle C-59 or ICG-001 (n = 10 per group). (C) Immunohistochemistry for BIRC5 in TAA CC following treatment with vehicle, C-59, or ICG-001 (black arrows, nuclear positivity for BIRC5 in epithelium; red, non-epithelial BIRC5 positivity; yellow, epithelium negative for BIRC5). (D) Quantification of epithelial BIRC5 positivity following treatment with vehicle, C-59, or ICG-001 (n = 10 per group). (E) Immunohistochemistry for TUNEL (green) and Ki-67 (red) in TAA CC treated with vehicle, C-59, or ICG-001. White boxes, regions magnified in lower panels; white arrows, epithelial positivity for Ki-67; yellow arrows, epithelial positivity for TUNEL. (F) Quantification of Ki-67 and TUNEL staining in CC epithelial nuclei following treatment with vehicle, C-59, or ICG-001 (n = 10 per group). Data are presented as mean ± SEM. Kruskal-Wallis test; *P < 0.05, ***P < 0.001. Scale bars: 50 μm; inset, 10 μm.