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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Blood Coagulation* / drug effects
  • Carcinogenesis / drug effects
  • Carcinogenesis / immunology*
  • Carcinogenesis / pathology*
  • Complement Activation / drug effects
  • Complement Pathway, Alternative / drug effects
  • Disease Progression
  • Extracellular Traps / drug effects
  • Extracellular Traps / metabolism*
  • Hematopoiesis / drug effects
  • Hemostasis / drug effects
  • Heparin, Low-Molecular-Weight / pharmacology
  • Humans
  • Intestinal Neoplasms / pathology
  • Intestine, Small / drug effects
  • Intestine, Small / pathology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Models, Biological
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Phenotype
  • Receptors, Complement / metabolism*


  • Heparin, Low-Molecular-Weight
  • Receptors, Complement
  • complement C3a receptor