Guglietta Silvia, Chiavelli Andrea, Zagato Elena, Krieg Carsten, Gandini Sara, Ravenda Paola Simona, Bazolli Barbara, Lu Bao, Penna Giuseppe, Rescigno Maria
Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
Nat Commun. 2016 Mar 21;7:11037. doi: 10.1038/ncomms11037.
Excessive activation of blood coagulation and neutrophil accumulation have been described in several human cancers. However, whether hypercoagulation and neutrophilia are linked and involved in cancer development is currently unknown. Here we show that spontaneous intestinal tumorigenesis correlates with the accumulation of low-density neutrophils with a pro-tumorigenic N2 phenotype and unprompted neutrophil extracellular traps (NET) formation. We find that increased circulating lipopolysaccharide induces upregulation of complement C3a receptor on neutrophils and activation of the complement cascade. This leads to NETosis, induction of coagulation and N2 polarization, which prompts tumorigenesis, showing a novel link between coagulation, neutrophilia and complement activation. Finally, in a cohort of patients with small but not large intestinal cancer, we find a correlation between neutrophilia and hypercoagulation. This study provides a mechanistic explanation for the tumour-promoting effects of hypercoagulation, which could be used as a new biomarker or as a therapeutic target.
在几种人类癌症中，已经发现存在血液凝固过度激活和中性粒细胞聚集的情况。然而，目前尚不清楚高凝状态和中性粒细胞增多是否相关以及是否参与癌症发展。在此，我们表明自发性肠道肿瘤发生与具有促肿瘤N2表型的低密度中性粒细胞的积累以及自发性中性粒细胞胞外陷阱（NET）形成相关。我们发现循环脂多糖增加会诱导中性粒细胞上补体C3a受体上调以及补体级联反应激活。这会导致NETosis、凝血诱导和N2极化，从而促进肿瘤发生，表明凝血、中性粒细胞增多和补体激活之间存在新的联系。最后，在一组患有小肠癌而非大肠癌的患者中，我们发现中性粒细胞增多与高凝状态之间存在相关性。这项研究为高凝状态的促肿瘤作用提供了一种机制解释，这可作为一种新的生物标志物或治疗靶点。
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