Mesenchymal stem cells in inflammatory microenvironment potently promote metastatic growth of cholangiocarcinoma via activating Akt/NF-κB signaling by paracrine CCL5.
Mesenchymal stem cells in inflammatory microenvironment potently promote metastatic growth of cholangiocarcinoma via activating Akt/NF-κB signaling by paracrine CCL5.
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炎症微环境中的间充质干细胞通过旁分泌 CCL5 激活 Akt/NF-kappa B 信号传导，有效促进胆管癌的转移生长
DOI：
10.18632/oncotarget.17793
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Song G
中科院分区：
文献类型：
--
作者：
Zhong W;Tong Y;Li Y;Yuan J;Hu S;Hu T;Song G
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-α and IFN-γ-induced inflammatory microenvironment stimulated the expression of TNF-α, CCL5, IL-6, IDO, and activated the NF-κB 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-α and IFN-γ (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-κB 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-κB signaling and lead to metastatic growth of CCA cells.
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