Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma

Abstract

// Weiwei Wang 1, * , Wei Zhong 1, * , Jiahui Yuan 1 , Congcong Yan 1 , Shaoping Hu 1 , Yinping Tong 1 , Yubin Mao 2 , Tianhui Hu 1 , Bing Zhang 2 , Gang Song 1 1 Cancer Research Center, Medical College of Xiamen University, Xiamen 361102, China 2 Department of Basic Medicine, Medical College of Xiamen University, Xiamen 361102, China * These authors have contributed equally to this work Correspondence to: Gang Song, e-mail: gangsongsd@xmu.edu.cn Keywords: cholangiocarcinoma, MSCs, metastasis, chemoresistance, β-catenin Received: April 17, 2015      Accepted: September 05, 2015      Published: October 14, 2015 ABSTRACT Mesenchymal stem cells (MSCs) are multi-potent progenitor cells with ability to differentiate into multiple lineages, including bone, cartilage, fat, and muscles. Recent research indicates that MSCs can be efficiently recruited to tumor sites, modulating tumor growth and metastasis. However, the underlying molecular mechanisms are not fully understood. Here, we first demonstrated that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), when mixed with human cholangiocarcinoma cell lines QBC939 in a xenograft tumor model, significantly increased the cancer cells proliferation and metastatic potency. MSCs and their conditioned media (MSC-CM) could improve the drug resistance of tumor when the compound K (CK) as an anti-cancer drug, a major intestinal bacterial metabolite of panaxoside, was administered to xenograft tumor mice. Furthermore, MSCs greatly increased the colony formation and invasion of cholangiocarcinoma cells QBC939 and Mz-ChA-1. Immunochemistry studies of cholangiocarcinoma tissue chips and transplantation tumor from nude mice showed that the expression of β-catenin was important for cholangiocarcinoma development. We further demonstrated that MSCs and MSCs-CM could promote proliferation and migration of cholangiocarcinoma cells through targeting the Wnt/β-catenin signaling pathway. hUC-MSCs or MSCs-CM stimulated Wnt activity by promoting the nuclear translocation of β-catenin, and up-regulated Wnt target genes MMPs family, cyclin D1 and c -Myc. Together, our studies highlight a critical role for MSCs on cancer metastasis and indicate MSCs promote metastatic growth and chemoresistance of cholangiocarcinoma cells via activation of Wnt/β-catenin signaling.