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Review
. 2023 Mar 13;41(3):505-526.
doi: 10.1016/j.ccell.2023.02.001. Epub 2023 Feb 23.

NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps

Affiliations
Review

NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps

Jose M Adrover et al. Cancer Cell. .

Abstract

Neutrophils are major effectors and regulators of the immune system. They play critical roles not only in the eradication of pathogens but also in cancer initiation and progression. Conversely, the presence of cancer affects neutrophil activity, maturation, and lifespan. By promoting or repressing key neutrophil functions, cancer cells co-opt neutrophil biology to their advantage. This co-opting includes hijacking one of neutrophils' most striking pathogen defense mechanisms: the formation of neutrophil extracellular traps (NETs). NETs are web-like filamentous extracellular structures of DNA, histones, and cytotoxic granule-derived proteins. Here, we discuss the bidirectional interplay by which cancer stimulates NET formation, and NETs in turn support disease progression. We review how vascular dysfunction and thrombosis caused by neutrophils and NETs underlie an elevated risk of death from cardiovascular events in cancer patients. Finally, we propose therapeutic strategies that may be effective in targeting NETs in the clinical setting.

Keywords: NETs; cancer; metastasis; neutrophil extracellular traps; neutrophils; tumor.

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Conflict of interest statement

Declaration of interests M.E. is a member of the research advisory board for brensocatib for Insmed, Inc.; a member of the scientific advisory board for Vividion Therapeutics, Inc.; a consultant for Protalix, Inc.; and holds shares in Agios. She is also a member of the Cancer Cell advisory board. The rest of the authors declare no competing interests.

Figures

Figure 1:
Figure 1:. NET formation.
Overview schematic of key steps in the process of NET formation (left), and a confocal microscopy image of a NET (right, arrow), showing the overlap of DNA (DAPI), myeloid peroxidase (MPO), and citrullinated histone 3 (citH3), which are commonly used to define a NET. Note the presence of a neutrophil in the process of forming a NET showing citrullinated histone 3, DNA, and MPO overlap prior to membrane rupture (arrowhead).
Figure 2:
Figure 2:. The neutrophil lifecycle.
Overview of neutrophils’ lifecycle, from their production in the bone marrow compartment, to their release into circulation, to their subsequent circadian aging, and to their final clearance into the tissues, where they are educated to perform specific functions before being disposed of through efferocytosis by tissue-resident macrophages. Top right: signals governing neutrophil mobilization from the bone marrow. Bottom right: mechanisms through which the tumor can affect the neutrophil lifecycle. HSPC (hematopoietic stem and progenitor cell); GMP (granulocyte-monocyte progenitor).
Figure 3:
Figure 3:. Overview of key NET components.
Main components of NETs (left), their functions in the context of cancer (center), and their main target cells or compartments (right).
Figure 4:
Figure 4:. NETs in cancer progression.
Overview of the steps of cancer progression in which NETs have been found to play a role, from malignant transformation and cancer initiation to cancer progression, invasion, intravasation, survival in circulation, entrapment, extravasation and, finally, to the establishment of a successful metastasis.
Figure 5:
Figure 5:. NETs and vascular inflammation.
A) NETs can damage the endothelium and induce platelet activation to form intravascular thrombi (top). Cancer is also a vascular disease (bottom). Intravascular exposition of tissue factor (TF) and extracellular matrix (ECM) components due to pericyte loss and poor vascular integrity in the tumors induces platelet activation and NET formation. NETs, in return, induce vascular remodeling and together with platelets, once activated, promote vascular dysfunction in other organs. B) Various lifestyle risk factors (e.g., smoking, poor diet, and possibly stress), or metabolic risk factors (e.g., obesity, diabetes, hyperglycemia, hypercholesterolemia or metabolic syndrome), likely cross-talk with cancer to amplify the effects of cancer on vascular health.

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