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

Silvia Guglietta, Andrea Chiavelli, Elena Zagato, Carsten Krieg, Sara Gandini, Paola Simona Ravenda, Barbara Bazolli, Bao Lu, Giuseppe Penna and Maria Rescigno ()
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Silvia Guglietta: European Institute of Oncology
Andrea Chiavelli: European Institute of Oncology
Elena Zagato: European Institute of Oncology
Carsten Krieg: Institute of Experimental Immunology, University of Zurich
Sara Gandini: European Institute of Oncology
Paola Simona Ravenda: Gastrointestinal and Neuroendocrine Tumor Unit, European Institute of Oncology
Barbara Bazolli: European Institute of Oncology
Bao Lu: Childrens’ Hospital, Harvard Medical School
Giuseppe Penna: European Institute of Oncology
Maria Rescigno: European Institute of Oncology

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11037

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