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 5

Macrophage ablation in human CC cell xenografts reduces tumor penetrance.

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Macrophage ablation in human CC cell xenografts reduces tumor penetrance...
(A) Schematic demonstrating the strategy for macrophage depletion in human CC cell xenografts. (B) Quantification of CD68-positive macrophage number in SNU-1079 and CC-LP-1 xenografts following treatment with Lipclod, GW2580, or AZD7507 compared with vehicle alone. Photomicrographs: Immunohistochemistry in xenografts for CD68-positive macrophages (red). (C) Volume and mass of SNU-1079 and CC-LP-1 xenografts following treatment with Lipclod, GW2580, or AZD7507 compared with vehicle alone. (D) Murine Wnt7b expression in SNU-1079 and CC-LP-1 xenografts following treatment with Lipclod, GW2580, or AZD7507 compared with vehicle alone. Data are presented as mean ± SEM. A Kruskal-Wallis test was used to compare GW2580 and AZD7507 and control. Lipclod and control were compared using a Mann-Whitney U test in both cases. **P < 0.01, ***P < 0.001. Photomicrograph scale bars: 50 μm. For SNU-1079: PBS n = 11, liposomes n = 8, Lipclod n = 8, gavage vehicle n = 8, GW2580 n = 4, and AZD7507 n = 6. For CC-LP-1: PBS n = 9, liposomes n = 6, Lipclod n = 15, gavage vehicle n = 6, GW2580 n = 3, and AZD7507 n = 3.