The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis

Abstract

Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

“…Shortly after their discovery in 2004, neutrophil extracellular traps (NETs) were pinpointed as another way of platelet extravasation and infiltration into the TME (Cedervall et al, 2018;Masucci et al, 2020). Upon activation and arrest at a leaky tumor vessel, neutrophil granulocytes may undergo NETosis, a suicidal process, which results in the production of ROS and release of decondensed nuclear and mitochondrial DNA into the extracellular space.…”

“…Upon activation and arrest at a leaky tumor vessel, neutrophil granulocytes may undergo NETosis, a suicidal process, which results in the production of ROS and release of decondensed nuclear and mitochondrial DNA into the extracellular space. Histones are modified and released from the denuded chromosomal DNA leaving behind a network of nucleic acid, originally meant to entrap pathogens (Masucci et al, 2020). However, these highly negatively charged nucleic acids form the surface, on which clotting factor XII is activitated, and vWF-bound factor VIII is enriched.…”

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

“…In patients with colorectal or breast cancer, NETs were found more frequent in patients with liver metastases, and in the case of early breast cancer stages, the increased incidence of NETs in patient serum was found a suitable biomarker for the prediction of liver metastases [ 130 ]. The implications of NETs in cancer and cancer-associated pathologies have been extensively reviewed by Masucci et al, Garley et al and Cedervall and Olsson [ 131 , 132 , 133 ]…”

MicroRNAs as New Regulators of Neutrophil Extracellular Trap Formation

“…NET formation is designed to restrain infection but given the nature of its components, NETs can promote severe tissue damages to the host. Indeed, the involvement of NETosis in non-infectious diseases such as cancer [ 15 ], venous thromboembolism [ 16 ], autoimmune diseases [ 17 ], or atherosclerosis [ 18 ] has been clearly demonstrated [ 19 ]. In particular, Engelmann and Massberg established the concept of immunothrombosis that is based on the ability of NETs to induce a procoagulant response that results in thrombus formation [ 20 ].…”