Casting a NET on cancer: the multiple roles for neutrophil extracellular traps in cancer

The role of the innate immune system has become widely appreciated in cancer and cancer-associated disorders. Neutrophils, the most abundant circulating leukocytes, have prognostic value in determining cancer progression and survival. One of the ways by which neutrophils negatively impact outcome is by formation of neutrophil extracellular traps (NETs) which result in release of nuclear chromatin and bioactive proteins into the extracellular space. Here, we review the evidence for NETs contributions to cancer progression, metastasis, and cancer-associated thrombosis (CAT).

NETs are increased across several cancer types and predict progression and adverse outcome. Several preclinical and clinical observations implicate NETs in promoting tumor growth, angiogenesis and metastasis via distinct pathways. Furthermore, NETs are shown to contribute to resistance to immunotherapy. NETs also emerge as key players in the prothrombotic phenotype associated with cancer that can result in potentially life-threatening arterial and venous thrombosis. Recent mechanistic insights expose several potential targets to inhibit NET formation and disrupt the interaction between NETs and tumor cells.

Clinical and translational insights highlight the central role of NETs in cancer progression and metastasis, disease resistance and CAT. Targeting NETs and NET-associated pathways may represent a novel approach to treat cancer.