Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation
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Yong-Chao Li1,*, Jiu-Ming Zou1,*, Chao Luo1, Yu Shu1, Jing Luo1, Jian Qin1, Yu Wang1, Dong Li1, Shan-Shan Wang1, Gang Chi1, Fang Guo1, Gui-Mei Zhang1, Zuo-Hua Feng1
1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, The People’s Republic of China
*These authors contributed equally to this work
Gui-Mei Zhang, email: [email protected]
Chao Luo, email: [email protected]
Keywords: circulating tumor cells (CTCs), disseminated carcinoma cells, metastatic colonization, inflammation, neutrophils
Received: October 19, 2016 Accepted: February 28, 2017 Published: March 10, 2017
Circulating tumor cells (CTCs) have been studied well in the prognosis for malignant diseases as liquid biopsy, but their contribution to tumor metastasis is not clearly defined. Here we report that CTCs could promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation and neutrophil recruitment to pre-metastatic organs. Depletion of neutrophils in vivo could effectively abrogate the promoting effect of CTCs on tumor cell metastasis. In the presence of CTCs, the pro-tumor function of neutrophils was augmented, whereas the antitumor function of neutrophils was suppressed. Mechanically, CTC-derived ligands for TLR2 and TLR4 (TLR2/4) induced the systemic inflammation, thus increasing the production of proinflammatory cytokines such as G-CSF and IL-6 that could induce the conversion of neutrophil function from tumor-suppressing to tumor-promoting. Moreover, CTCs induced the production of endogenous TLR2/4 ligands such as S100A8, S100A9, and SAA3, which may amplify the stimulating effect that induces the expression of proinflammatory cytokines. The promoting effect of CTCs on tumor cell metastasis could be abrogated by suppressing inflammatory response with IL-37, an anti-inflammatory cytokine, or blocking CTC-derived ligands for TLR2/4. Identification of the metastatic axis of CTCs/systemic inflammation/neutrophils may provide potential targets for preventing tumor cell metastasis.
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