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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

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Mesenchymal stem cells in inflammatory microenvironment potently promote metastatic growth of cholangiocarcinoma <i>via</i> activating Akt/NF-κB signaling by paracrine CCL5.

Zhong Wei W Tong Yinping Y Li Yang Y Yuan Jiahui J Hu Shaoping S Hu Tianhui T Song Gang G

Oncotarget 20170511 43

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 l ...[more]

PMID: 29088737

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Project description:BackgroundIncreasing evidence has shown that mesenchymal stem cells (MSCs) yield a favorable therapeutic benefit for thermal burn skin wounds. Human amniotic MSCs (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammatory potential which makes them suitable for treating skin wounds. However, the exact effects of hAMSCs on the healing of thermal burn skin wounds and their potential mechanisms are not explored.MethodshAMSCs were isolated from amniotic membrane and characterized by RT-PCR, flow cytometry, immunofluorescence, and tumorigenicity test. We assessed the effects of hAMSCs and hAMSC conditional medium (CM) on wound healing in a deep second-degree burn injury model of mice. We then investigated the biological effects of hAMSCs and hAMSC-CM on the apoptosis and proliferation of heat stress-injured human keratinocytes HaCAT and dermal fibroblasts (DFL) both in vivo and in vitro. Next, we explored the underlying mechanisms by assessing PI3K/AKT and GSK3?/?-catenin signaling pathways in heat injured HaCAT and DFL cells after hAMSCs and hAMSC-CM treatments using PI3K inhibitor LY294002 and ?-catenin inhibitor ICG001. Antibody array assay was used to identify the cytokines secreted by hAMSCs that may activate PI3K/AKT signaling pathway.ResultsOur results showed that hAMSCs expressed various markers of embryonic stem cells and mesenchymal stem cells and have low immunogenicity and no tumorigenicity. hAMSC and hAMSC-CM transplantation significantly promoted thermal burn wound healing by accelerating re-epithelialization with increased expression of CK19 and PCNA in vivo. hAMSCs and hAMSC-CM markedly inhibited heat stress-induced apoptosis in HaCAT and DFL cells in vitro through activation of PI3K/AKT signaling and promoted their proliferation by activating GSK3?/?-catenin signaling. Furthermore, we demonstrated that hAMSC-mediated activation of GSK3?/?-catenin signaling was dependent on PI3K/AKT signaling pathway. Antibody array assay showed that a panel of cytokines including PAI-1, C-GSF, periostin, and TIMP-1 delivered from hAMSCs may contribute to the improvement of the wound healing through activating PI3K/AKT signaling pathway.ConclusionOur results demonstrated that hAMSCs and hAMSC-CM efficiently cure heat stress-induced skin injury by inhibiting apoptosis of skin cells and promoting their proliferation through activating PI3K/AKT signaling pathway, suggesting that hAMSCs and hAMSC-CM may provide an alternative therapeutic approach for the treatment of skin injury.

Dataset Information

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

Publications

Mesenchymal stem cells in inflammatory microenvironment potently promote metastatic growth of cholangiocarcinoma <i>via</i> activating Akt/NF-κB signaling by paracrine CCL5.

Similar Datasets

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