Abstract
BackgroundExosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear.MethodsWe investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms.ResultsGC-Ex prolonged neutrophil survival and induced expression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastric cancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κB pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophil activation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediated neutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues. Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally, gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell lines in neutrophil activation.ConclusionWe demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides new insights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role of exosomes in reshaping tumor microenvironment.
Highlights
Exosomes are extracellular vesicles that mediate cellular communication in health and diseases
We have reported that IL-6 derived from tumor-resident mesenchymal stem cells induces neutrophil activation, resulting in enhanced angiogenesis and tumor metastasis [21]
The conditioned medium from gastric cancer cells induces autophagy and pro-tumor activation of neutrophils To investigate the role of gastric cancer cells in neutrophil phenotype and function, we treated neutrophils isolated from human peripheral blood with gastric cancer cell-derived conditioned medium (GC-CM) for 12 hours
Summary
Exosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils have been shown to promote carcinogenesis, growth and metastasis, angiogenesis, and immunosuppression. The previous studies have shown that tumor cells produce oxysterol [16], C-X-C motif chemokine ligand 5 (CXCL5) [17], hyaluronan fragments (HA) [18], granulocyte-macrophage colony stimulating factor (GM-CSF) [19], and macrophage migration inhibitory factor (MIF) [20]. These factors induce pro-tumor activation of neutrophils, leading to increased tumor growth and metastasis. Mechanisms for the modulation of neutrophil phenotype and function in tumor milieu remain not fully characterized
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