Mesenchymal stem cells in inflammatory microenvironment potently promote metastatic growth of cholangiocarcinoma via activating Akt/NF-?B signaling by paracrine CCL5.

ABSTRACT: Our previous work has demonstrated that mesenchymal stem cells (MSCs) could induce metastatic growth of the inflammation-related cholangiocarcinoma (CCA). However, the functional mechanism of MSCs on CCA progression in the early inflammatory microenvironment remained undetermined. Here, we showed that TNF-? and IFN-?-induced inflammatory microenvironment stimulated the expression of TNF-?, CCL5, IL-6, IDO, and activated the NF-?B signaling with p65 nuclear translocation in MSCs cells. CCA cell lines QBC939 and Mz-chA-1 exposed to the conditioned medium of MSCs after being stimulated by TNF-? and IFN-? (TI-CM) exhibited enhanced mobility. Moreover, MSCs pre-stimulated by both inflammatory cytokines (TI-MSCs) increased tumor metastasis in vivo. The conditioned medium of TI-MSCs stimulated the transcription of snail, slug, ZEB1 and ZEB2. Next, the expression of CCL5 of TI-MSCs was verified by ELISA, which indicated that MSCs contributed to CCA migration and metastasis in a paracrine fashion. CCA cells treated with TI-CM up-regulated CCA chemokine receptors, especially CCR5; CCL5 neutralizing antibody or CCR5 inhibitor Maraviroc inhibited the effects of MSCs on CCA cells migration. We also found that Akt/NF-?B signaling was activated by CCL5/CCR5 axis, which increased the expression of MMP2, MMP9. Together, these findings suggest that MSCs in tumor inflammatory microenvironment are elicited of CCL5, which activate AKT/NF-?B signaling and lead to metastatic growth of CCA cells.

SUBMITTER: Zhong W 

PROVIDER: S-EPMC5650292 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature