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

Author

Listed:
  • 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
    University of Milan)

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.

Suggested Citation

  • Silvia Guglietta & Andrea Chiavelli & Elena Zagato & Carsten Krieg & Sara Gandini & Paola Simona Ravenda & Barbara Bazolli & Bao Lu & Giuseppe Penna & Maria Rescigno, 2016. "Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11037
    DOI: 10.1038/ncomms11037
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    Cited by:

    1. Weiwei Dai & Ruotong Tian & Liubing Yu & Shasha Bian & Yuling Chen & Bowen Yin & Yuxuan Luan & Siqi Chen & Zhuoyang Fan & Rucheng Yan & Xin Pan & Yingyong Hou & Rong Li & Juxiang Chen & Minfeng Shu, 2024. "Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Zhiyuan Zheng & Ya-nan Li & Shanfen Jia & Mengting Zhu & Lijuan Cao & Min Tao & Jingting Jiang & Shenghua Zhan & Yongjing Chen & Ping-Jin Gao & Weiguo Hu & Ying Wang & Changshun Shao & Yufang Shi, 2021. "Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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