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

Autor: Bao Lu, Maria Rescigno, Elena Zagato, Silvia Guglietta, Carsten Krieg, Giuseppe Penna, Sara Gandini, Andrea Chiavelli, Paola Simona Ravenda, Barbara Bazolli
Rok vydání: 2015
Předmět:
0301 basic medicine
Lipopolysaccharide
Carcinogenesis
Neutrophils
Complement Pathway
Alternative
General Physics and Astronomy
medicine.disease_cause
Extracellular Traps
chemistry.chemical_compound
Intestine
Small
Receptor
Complement Activation
Gastrointestinal Neoplasms
Aged
80 and over
Mice
Knockout
Multidisciplinary
biology
Chemistry
Middle Aged
Receptors
Complement
Phenotype
Adenomatous Polyposis Coli
Disease Progression
medicine.symptom
Adult
Science
Models
Biological
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Downregulation and upregulation
Intestinal Neoplasms
medicine
Animals
Humans
Blood Coagulation
Aged
Hemostasis
General Chemistry
Neutrophil extracellular traps
Heparin
Low-Molecular-Weight
Neutrophilia
Complement system
Hematopoiesis
Mice
Inbred C57BL
030104 developmental biology
Immunology
biology.protein
Guilt
C3a receptor
Zdroj: Nature Communications
Nature Communications, Vol 7, Iss 1, Pp 1-14 (2016)
ISSN: 2041-1723
Popis: 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.
It is unclear whether cancer-related hypercoagulation and neutrophilia contribute to tumorigenesis. In this study, the authors find that activation of the complement cascade causes hypercoagulation that leads to polarization of neutrophils in a mouse model of intestinal cancer, and show that blocking complement activation can reduce tumour formation.
Databáze: OpenAIRE
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