Cholangiocarcinoma is a cancer of the bile duct that has a poor prognosis, largely due to it being refractory to available therapies. In this episode, Stuart Forbes and Luke Bolter reveal that the canonical WNT signaling pathway drives cholangiocarcinoma growth by regulating epithelial cell proliferation. Inflammatory macrophages, which infiltrate the cancer, are a major source of the WNT-inducing signal and thereby facilitate cholangiocarcinoma growth. The results of this study support further investigation into the use of WNT inhibitors to treat 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.
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