Demers Mélanie, Wong Siu Ling, Martinod Kimberly, Gallant Maureen, Cabral Jessica E, Wang Yanming, Wagner Denisa D
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital , Boston, MA, USA.
Oncoimmunology. 2016 Feb 18;5(5):e1134073. doi: 10.1080/2162402X.2015.1134073. eCollection 2016 May.
Neutrophils play a major role in cancer biology and both pro- and antitumoral functions of tumor-infiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.
中性粒细胞在癌症生物学中发挥着重要作用，肿瘤浸润中性粒细胞的促肿瘤和抗肿瘤功能均已得到描述。我们已经表明，肿瘤通过向血液中释放粒细胞集落刺激因子（G-CSF），使循环中的中性粒细胞启动形成中性粒细胞胞外诱捕网（NETs），并且我们已经在肿瘤微环境中检测到NETs的存在。在此，我们报道，使用在中性粒细胞染色质解聚和NET形成方面存在缺陷的PAD4缺陷小鼠，中性粒细胞向NETosis的启动有利于肿瘤生长。有趣的是，在一个不释放G-CSF且中性粒细胞未启动NETosis的肿瘤模型中，PAD4缺陷并未降低肿瘤生长。然而，向野生型（WT）宿主提供外源性G-CSF可促进肿瘤内NETosis和肿瘤生长。综上所述，我们的结果表明，肿瘤或其环境使中性粒细胞启动NETosis会导致肿瘤内NETs的积累以及肿瘤的生长优势。我们的工作揭示了NETs的促肿瘤作用，这增强了它们作为抗癌新靶点的潜力。
