Abstract
Human neutrophils, the most abundant circulating leukocytes, are fundamental components of the host response against different pathogens. Until a few years ago, neutrophils received limited attention in cancer immunology. Recently, it was discovered that both circulating, and tumor-associated, neutrophils possess functional plasticity when exposed to various inflammatory stimuli and in the tumor microenvironment. Neutrophils and their mediators can exert several pro-tumor activities in cancer and promote metastasis through different mechanisms. Angiogenesis plays a pivotal role in inflammation and tumor growth. Activated human neutrophils release several angiogenic factors [vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (ANGPT1), CXCL8, hepatocyte growth factor (HGF), and metalloproteinase 9 (MMP-9)] and form neutrophil extracellular traps (NETs). NETs promote tumor growth and metastasis formation through several mechanisms: they can awake dormant cancer cells, capture circulating tumor cells, coat and shield cancer cells, thus preventing CD8+- and natural killer (NK) cell-mediated cytotoxicity. ANGPTs released by endothelial and periendothelial mural cells induce platelet-activating factor (PAF) synthesis and neutrophil adhesion to endothelial cells. NETs can directly exert several proangiogenic activities in human endothelial cells and NETs induced by ANGPTs and PAF increase several aspects of angiogenesis in vitro and in vivo. A better understanding of the pathophysiological functions of NETs in cancer and angiogenesis could be of importance in the early diagnosis, prevention and treatment of tumors.
Highlights
Human neutrophils are conventionally considered fundamental players of the host response against a wide spectrum of different pathogens [1,2]
When we investigated the effects of sPLA2 on the release of lymphangiogenic factors from human neutrophils, we found that these cells do not express
There is some evidence that neutrophils and neutrophil extracellular traps (NETs) exert reparative effects in the context of tumor inflammation [198,213]
Summary
Human neutrophils are conventionally considered fundamental players of the host response against a wide spectrum of different pathogens [1,2]. Peripheral blood neutrophils have the propensity to migrate into inflamed tissues in response to a plethora of chemotactic stimuli produced within the inflammatory site [3]. These cells kill pathogens through phagocytosis, the release of their potent antimicrobial arsenal, which includes cytoplasmic enzymes, oxidants (e.g., reactive oxygen species: ROS), and lipid mediators [4,5], and the formation of neutrophil extracellular traps (NETs) [6–8]. Neutrophils are generated in the bone marrow and enter the bloodstream as terminally differentiated cells with a short lifespan. Human neutrophils display several activating cell surface receptors that activate different intracellular signaling mechanisms to mediate effector functions [2]. We provide a general overview of the pathogenic roles of neutrophils in cancer with emphasis on NETs and angiogenesis
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