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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 2

Transgenic induction of TAA in mouse has an activated WNT pathway.

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Transgenic induction of TAA in mouse has an activated WNT pathway.
(A) S...
(A) Schematic showing strategy for generating CC using Krt19-CreERT R26R-eYFP p53fl/fl mice. (B) Wnt7b and Wnt10a mRNA expression in Krt19-CreERT R26R-eYFP p53fl/WT or Krt19-CreERT R26R-eYFP p53WT/WT versus Krt19-CreERT R26R-eYFP p53fl/fl mice (n = 6 vs. n = 4). (C) Immunohistochemistry for CTNNB1 (red), WNT7B (pink), and YFP (green) in Krt19-CreERT R26R-eYFP p53fl/fl mice. Dotted line, the tumor—non-tumor interface. (D) Immunohistochemistry for CTNNB1. Boxes, regions that are magnified in the images below; black arrows, strong nuclear staining. (E) mRNA expression of Axin2, Lef1, Ccnd2, Sox9, and c-Myc in Krt19-CreERT R26R-eYFP p53fl/+ or Krt19-CreERT R26R-eYFP p53+/+ versus Krt19-CreERT R26R-eYFP p53fl/fl mice (n = 6 vs. n = 4). (F) Immunohistochemistry in Krt19-CreERT R26R-eYFP p53fl/fl tumors for active (dephosphorylated) CTNNB1, LEF1, CCND2, or SOX9 (red), and YFP (green) or C-MYC (brown). Data are presented as mean ± SEM. Mann-Whitney U test; *P < 0.05, **P < 0.01. Photomicrograph scale bars: 50 μm; insets, 10 μm.
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