Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models

Lu, Zhen; Zuo, Bingfeng; Jing, Renwei; Gao, Xianjun; Rao, Quan; Liu, Zhili; Han, Qi; Guo, Hongqian; Yin, HaiFang

doi:10.1016/j.jhep.2017.05.019

Cited by 300 publications

(268 citation statements)

References 26 publications

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“…The immunosuppressive properties of exosomes derived from macrophages and DCs reduced inflammation in animal models of several inflammatory disorders [15, 34]. In autochthonous hepatocellular carcinoma mouse models, DEXs treated in the tumor microenvironment reduced the number of Tregs and the serum concentrations of IL-10 and TGF-β [35]. Using the exosome inhibitor (UW4869), the regulating action of BMDCs on the differentiation of Tregs and Th17 cells is inhibited, suggesting that DEXs can mediate the differentiation of Treg and Th17 cells and accelerating research to determine whether DEXs in the post-I/R hepatocyte microenvironment activate naïve T cells and modulate the balance between Tregs and Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Zheng¹,

Li²,

Wei³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The present study aimed to evaluate the effects as well as the underlying mechanisms of bone marrow-derived dendritic cells (BMDCs) and exosomes produced by BMDCs (DEXs) on hepatic ischemia-reperfusion (I/R) injury (IRI). Methods: Primary hepatocytes were isolated and used to mimic the liver IR microenvironment. BMDCs were induced and characterized both biochemically with a flow cytometer (FCM) and biophysically with a microscope. Then, we exposed BMDCs to the supernatants from primary hepatocytes and evaluated the maturation of BMDCs by FCM. BMDCs were systemically injected into mice before liver IR via the tail vein, and the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), inflammatory cytokines, and histological changes were respectively examined by ELISA, RT-qPCR and microscopy. Furthermore, we isolated DEXs by ultracentrifugation, characterized DEXs by transmission electron microscopy (TEM) and nanosight tracking analysis (NTA) and western blotting (WB), and then we co-cultured BMDCs/DEXs and naïve T cells and performed FCM, ELISA and confocal imaging. Moreover, we injected DEXs into mice prior to liver IR via the tail vein and examined its therapeutic effects by microscopy and ELISA. Finally, inhibitors of HSP70 (cmHSP70.1), PI3K (BKM120) and mTOR (Rapamycin) were used to investigate the role of HSP70 and the PI3K/mTOR axis in the effects of DEXs on naïve T cells by WB and FCM. Results: Bone marrow cells were efficiently induced into dendritic cells (DCs) with typical DC characteristics. The supernatants from primary hepatocytes exposed to H/R upregulated DC maturation markers. After DC administration, liver IR injury was improved with histopathological scores and serum transaminases. Additionally, we found that the anti-inflammatory cytokines TGF-β, Foxp3 and interleukin (IL)-10 were upregulated and that IL-17 was downregulated. Furthermore, confocal imaging revealed that the uptake of H/R-DEXs by naïve T cells was greater than that of DEXs derived from the control or negative group of BMDCs, and this increase was correlated with a significantly greater degree of differentiation of Tregs and Th17 cells. Moreover, H/R-DEXs administration improved liver function in mice after IR. Finally, the inhibition of HSP70, PI3K and mTOR completely abolished the effect of DEXs on naïve T cells. Conclusion: These results demonstrated that BMDCs and DEXs could alleviate hepatic I/R injury via modulating the balance between Tregs and Th17 cells. DEXs transported HSP70 into naïve T cells and stimulated the PI3K/mTOR axis to modulate the balance between Tregs and Th17 cells and protect the liver from IR injury.

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Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Zheng¹,

Li²,

Wei³

et al. 2018

Cell Physiol Biochem

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“…B), indicating that P47 is able to differentiate fibrotic liver from tumor. To investigate the ability of P47 to discriminate abnormal liver and HCC in a clinically relevant setting, we systemically administered AF680‐labeled P47 into an autochthonous HCC mouse model established by diethylnitrosamine (DENA) induction as reported . As expected, specific uptake of AF680‐labeled P47 was detected in tumor tissues bearing binuclear cells irrespective of the number (Fig.…”

Section: Resultsmentioning

confidence: 99%

Fluorescent peptide highlights micronodules in murine hepatocellular carcinoma models and humans in vitro

et al. 2018

Self Cite

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“…36,37) Romagnoli et al 38) revealed how dendritic cell-derived exosomes may contribute to the conversion of poorly immunogenic tumor cells into highly immunogenic targets, and consequently, the control of tumor progression. In the same context, Lu et al 39) demonstrated how dendritic cell-derived exosomes elicit tumor regression in hepatocellular carcinoma mouse models via the activation of functional T cells, particularly CD8 + cytotoxic T lymphocyte (CTL). In the present study, treatment with free DXR enhanced the secretion of exosomes, presumably immune cell-derived exosomes, in non splenectomized mice (Figs.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin Expands <i>in Vivo</i> Secretion of Circulating Exosome in Mice

Emam

Ando

Lila

et al. 2018

Biological & Pharmaceutical Bulletin

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Modulation of tumor immunity is a known factor in the antitumor activity of many chemotherapeutic agents. Exosomes are extracellular nanometric vesicles that are released by almost all types of cells, which includes cancer cells. These vesicles play a crucial role in tumor immunity. Many in vitro studies have reproduced the aggressive secretion of exosomes following treatment with conventional anticancer drugs. Nevertheless, how chemotherapeutic agents including nanomedicines such as Doxil ® affect the in vivo secretion of exosomes is yet to be elucidated. In this study, the effect of intravenous injection of either free doxorubicin (DXR) or liposomal DXR formulation (Doxil ® ) on exosome secretion was evaluated in BALB/c mice. Exosomes were isolated from serum by using an ExoQuick kit. Free DXR treatment markedly increased serum exosome levels in a post-injection time-dependent manner, while Doxil ® treatment did not. Exosomal size distribution and marker protein expressions (CD9, CD63, and TSG101) were studied. The physical/biological characteristics of treatment-induced exosomes were comparable to those of control mice. Interestingly, splenectomy significantly suppressed the copious exosomal secretions induced by free DXR. Collectively, our results indicate that conventional anticancer agents induce the secretion of circulating exosomes, presumably via stimulating immune cells of the spleen. As far as we know, this study represents the first report indicating that conventional chemotherapeutics may induce exosome secretion which might, in turn, contribute partly to the antitumor effect of chemotherapeutic agents.

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Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models

Cited by 300 publications

References 26 publications

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Fluorescent peptide highlights micronodules in murine hepatocellular carcinoma models and humans in vitro

Doxorubicin Expands <i>in Vivo</i> Secretion of Circulating Exosome in Mice

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