Journal
MOLECULAR CANCER
Volume 17, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12943-018-0898-6
Keywords
Exosome; Neutrophil; Gastric cancer; Pro-tumor; Activation; Autophagy
Categories
Funding
- National Natural Science Foundation of China [81672416, 81572075, 81670502]
- Natural Science Foundation of the Jiangsu Province [BK20141303]
- Jiangsu Province's Major Project in Research and Development [BE2015667, BE2017694]
- Key Research and Development Project of Zhenjiang [SH2015034]
- Major Natural Science Reasearch Project for Universities in Jiangsu Province [18KJA320001]
- Jiangsu Province's 333 project
- Funds for Young Academic Leader of Jiangsu University
- Startup Funds for Senior Talents of Jiangsu University [13JDG086]
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Background: Exosomes 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. Methods: We investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms. Results: GC-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-kappa B pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-kappa B 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. Conclusion: We demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-kappa B 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.
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