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.

Keywords: NETosis; neutrophil extracellular trap (NET); tumor associated neutrophils (TANs); tumor microenvironment (TEM); tumors.

Figure 1

Cancer cell, TAN, and NET co-operation in tumor progression and metastasis. Cancer cells recruit neutrophils to tumor microenvironment through several signals (green arrows). In tumor microenvironment Tumor Associated Neutrophils (TANs) are activated to release Neutrophil Extracellular Traps (NETs) (blue arrows), able to promote tumor growth, tumor progression, metastasis, and tumor associated thrombosis.

Figure 2

NETosis. NETs as targets for therapy. Neutrophil stimulation (green arrows) results in NETosis and extrusion of Neutrophil Extracellular Traps (NETs) (blue arrows). During these processes, targets for therapies have been postulated, and interfering drugs (red arrows) have been already used in clinical practice or are under investigation in vivo.