title: Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis.
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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guglietta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chiavelli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Zagato
authors.affiliation: Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Krieg
authors.affiliation: Division of Epidemiology and Biostatistic, European Institute of Oncology, I-20141 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.affiliation: Gastrointestinal and Neuroendocrine Tumor Unit, European Institute of Oncology, I-20141 Milan, Italy.
authors.forename: Paola Simona
authors.initials: PS
authors.lastname: Ravenda
authors.affiliation: Division of Epidemiology and Biostatistic, European Institute of Oncology, I-20141 Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bazolli
authors.affiliation: Childrens' Hospital, Harvard Medical School, Boston, Massachussetts 02115, USA.
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penna
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via adamello, 16, I-20139 Milan, Italy.|Department of Oncology and Haemato-Oncology, University of Milan, Milan 20139, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Rescigno
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D003167:Complement Activation / Q000187:drug effects; D003170:Complement Pathway, Alternative / Q000187:drug effects; D018450:Disease Progression; D065206:Extracellular Traps / Q000187:drug effects / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D007414:Intestinal Neoplasms / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D011951:Receptors, Complement / Q000378:metabolism*
chemical_list: D006495:Heparin, Low-Molecular-Weight; D011951:Receptors, Complement; C085567:complement C3a receptor