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Nat Commun. 2016 Mar 21;7:11037. doi: 10.1038/ncomms11037.

Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis.

Author information

1
Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.
2
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
3
Division of Epidemiology and Biostatistic, European Institute of Oncology, I-20141 Milan, Italy.
4
Gastrointestinal and Neuroendocrine Tumor Unit, European Institute of Oncology, I-20141 Milan, Italy.
5
Childrens' Hospital, Harvard Medical School, Boston, Massachussetts 02115, USA.
6
Department of Oncology and Haemato-Oncology, University of Milan, Milan 20139, Italy.

Abstract

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.

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PMID:
26996437
PMCID:
PMC4802169
DOI:
10.1038/ncomms11037
[Indexed for MEDLINE]
Free PMC Article

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