J Cancer 2020; 11(15):4384-4396. doi:10.7150/jca.44215

Research Paper

IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis

Luyu Yang1,2,#, Lu Liu3,#, Rui Zhang1,#, Jun Hong1, Yaping Wang1, Jian Wang1, Jieliang Zuo1, Jubo Zhang3, Jinhong Chen1,✉, Hankun Hao1,✉

1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
2. Caner Metastasis Institute, Fudan University, Shanghai, China
3. Department of Infection Disease, Huashan Hospital, Fudan University, Shanghai, China
# Co-first authors

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Yang L, Liu L, Zhang R, Hong J, Wang Y, Wang J, Zuo J, Zhang J, Chen J, Hao H. IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis. J Cancer 2020; 11(15):4384-4396. doi:10.7150/jca.44215. Available from http://www.jcancer.org/v11p4384.htm

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Host and tumorous inflammation actively affect liver metastasis of colorectal cancer (CRC). Neutrophils have been recognized as one active participant in metastasis procedure, with controversial roles however. Activated neutrophils release extracellular traps (NETs) which are involved in infection and multiple pathological conditions. NETs on cancer metastasis is getting recognized but less elucidated in mechanism. How NETs interact with cancer cells is still largely unknown. In this study, we found that neutrophils from CRC patients, especially those with liver metastatic, underwent remarkably enhanced NETs. Clinically, sera and pathological NETs marker closely correlated with onset of liver metastasis. Through in vivo and in vitro studies, we proved that increased NETs positively contribute to onset of CRC liver metastasis. Digesting NETs with DNase 1 diminished the increased liver metastasis associated with NETs. In detail, NETs trapped CRC cells in liver and exerted no cytotoxicity on tumor cells, but boosted tumorous proliferation and invasion capacity. We further found this enhanced malignancy of trapped CRC cells was due to the elevated tumorous interleukin (IL)-8 expression triggered by NETs. Blocking IL-8 activity effectively abrogated the enhanced proliferation and invasion triggered by NETs. Moreover, overproduced IL-8 in turn activate neutrophils towards NETs formation, thus forming a positive loop optimizing CRC liver metastasis. Collectively, our study propose a novel positive feedback between elevated tumorous IL-8 and NETs to promote CRC liver metastasis, and identify potential strategy against liver metastasis.

Keywords: colorectal cancer (CRC), liver metastasis, Neutrophil extracellular traps (NETs), IL-8