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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 March 2, 2015; First published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1269-1285. https://doi.org/10.1172/JCI76452.
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Category: Research Article

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

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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 6

Macrophage inhibition reduces CC growth in vivo.

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Macrophage inhibition reduces CC growth in vivo.
(A) Schematic represent...
(A) Schematic representing macrophage depletion in TAA using Lipclod. (B) mRNA expression of Wnt7b, Wnt10a, and Porcn following macrophage depletion in TAA CC using vehicle versus Lipclod (n = 5 vs. n = 7). (C) Immunohistochemistry on vehicle- versus Lipclod-treated TAA tissue for WNT7B (red) and KRT19 (green). (D) mRNA expression of WNT pathway target genes following Lipclod depletion of macrophages (n = 6 per group); green denotes downregulation. Represented as a 3-fold change; P < 0.05 (E) H&E of rat liver from TAA rats treated with vehicle versus Lipclod. (F) Quantification of area and number of rat TAA-induced CC tumors following treatment with vehicle or Lipclod (n = 14 vs. n = 5). Data are represented as mean ± SEM. Mann-Whitney U test; *P < 0.05, **P < 0.01. Scale bars in C: 50 μm; insets, 10 μm. Scale bars in E: 1 mm.
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