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.

Recent advances in understanding neutrophils

“…A similar neutrophil phenotypic duplicity has been identified in the blood of tumor-bearing mice and cancer patients based on separation by density gradient 55, 75 . In these samples, elevated levels of both immature and mature neutrophil populations were found in the low-density fraction, collectively termed low-density neutrophils (LDNs), in addition to the previously named tumor-entrained neutrophils (TENs) in the high-density layer, termed high-density neutrophils (HDNs).…”

Complement in cancer: untangling an intricate relationship

“…Mechanistically, circulating lipopolysaccharide, likely leaking from the intestine, appears to induce complement activation and upregulate the expression levels of C3aR on neutrophils. C3aR-mediated signalling then triggers NET release, coagulation pathways and polarization of neutrophils towards a pro-tumorigenic phenotype 78 .…”

Neutrophils and cancer: guilt by association

“…However, whether either of these neutrophil populations had a preformed identity or whether they were moulded by the local tissue microenvironment was not resolved. Similarly, in the study by Guglietta et al 3 , a low-density (N2) neutro phil subtype could be found in the local tumour environment, but these cells could also be found in the peripheral blood, implying the existence of multiple phenotypes prior to recruitment. Although it has been previously suggested that neutrophils might play a part in clot formation 7 , the latest study provides evidence that these clots act to further shape neutrophil function.…”

“…This approach involves the administration of monoclonal antibodies to neutralize VEGF, resulting in reduced vascularization of the tumour. Interestingly, only small tumours seemed to benefit from systemic coagulation, whereas larger tumours appear more dependent on vascularization and blood flow, suggesting fundamental differences between tumour types 3,10 .…”

“…The work by Guglietta et al 3 highlights our lack of knowledge in a number of areas, particularly the role of neutrophils in cancer. Evidence has suggested that neutrophils can have roles in both the clearance and growth of tumours, depending on the specific type of cancer and microenvironment studied 5 .…”