wnt-c59 and Cholangiocarcinoma

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.

Topics: Aniline Compounds; Animals; Anisoles; Antineoplastic Agents; Benzeneacetamides; beta Catenin; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholangiocarcinoma; Clodronic Acid; Heterocyclic Compounds, 2-Ring; Humans; Keratins; Liposomes; Macrophages; Male; Mice, Nude; Pyridines; Pyrimidines; Pyrimidinones; Rats, Sprague-Dawley; Tamoxifen; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Cholangiocarcinoma is a relatively rare cancer of the biliary ducts that is highly refractory to treatment. The factors that drive cholangiocarcinoma are poorly understood, though chronic liver fluke infection is a risk factor for disease. In this issue of the JCI, Boulter and colleagues demonstrate that the WNT/β-catenin signaling pathway is upregulated in patients with sporadic cholangiocarcinoma. The authors determined that macrophages generate WNT ligands in cholangiocarcinomas and depletion or inhibition of this cell population in animal models of cholangiocarcinoma reduced tumor burden and proliferation. Moreover, pharmacological inhibition of WNT secretion or β-catenin activity was efficacious in animal models. Together the results of this study suggest that targeting WNT has potential as a therapeutic strategy for cholangiocarcinoma.

Topics: Animals; Antineoplastic Agents; Benzeneacetamides; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bridged Bicyclo Compounds, Heterocyclic; Cholangiocarcinoma; Humans; Male; Pyridines; Pyrimidinones; Wnt Signaling Pathway