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WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited.

TitleWNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited.
Publication TypeJournal Article
Year of Publication2015
AuthorsBoulter L, Guest RV, Kendall TJ, Wilson DH, Wojtacha D, Robson AJ, Ridgway RA, Samuel K, van Rooijen N, Barry ST, Wigmore SJ, Sansom OJ, Forbes SJ
JournalJ Clin Invest
Date Published2015 Feb 17
ISSN1558-8238
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.

DOI10.1172/JCI76452
Alternate JournalJ. Clin. Invest.
PubMed ID25689248
Publication institute
CRM