Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies

Abstract

Extracellular DNA may serve as marker in liquid biopsies to determine individual diagnosis and prognosis in cancer patients. Cell death or active release from various cell types, including immune cells can result in the release of DNA into the extracellular milieu. Neutrophils are important components of the innate immune system, controlling pathogens through phagocytosis and/or the release of neutrophil extracellular traps (NETs). NETs also promote tumor progression and metastasis, by modulating angiogenesis, anti-tumor immunity, blood clotting and inflammation and providing a supportive niche for metastasizing cancer cells. Besides neutrophils, other immune cells such as eosinophils, dendritic cells, monocytes/macrophages, mast cells, basophils and lymphocytes can also form extracellular traps (ETs) during cancer progression, indicating possible multiple origins of extracellular DNA in cancer. In this review, we summarize the pathomechanisms of ET formation generated by different cell types, and analyze these processes in the context of cancer. We also critically discuss potential ET-inhibiting agents, which may open new therapeutic strategies for cancer prevention and treatment.

Comparative Analysis of Molecular Functions and Biological Role of Proteins from Cell-Free DNA-Protein Complexes Circulating in Plasma of Healthy Females and Breast Cancer Patients

“…Indeed, the development of oncological diseases was shown to be accompanied by an increase in the concentration of cfDNA in the blood [ 15 ], but the causes, mechanisms, and consequences of this phenomenon are still unknown. In addition, the alterations found in the cfDNA present in the bloodstream of cancer patients are consistent with those observed in the DNA of their corresponding tumor cells [ 2 , 3 , 16 ], and proteins with DNA-binding motifs were shown to protect this DNA from hydrolysis by endogenous nucleases [ 17 ], forming NPCs [ 5 , 6 , 7 , 8 , 9 ]. Thus, a comparative analysis of proteins in the NPCs circulating in the blood of healthy donors and cancer patients might allow for the expansion of the fundamental knowledge of the mechanisms that lead to the appearance of extracellular nucleic acids in the external environment, ensure their circulation in the blood and, as a consequence, reveal the mechanisms of tumor dissemination at the molecular level.…”

“…To date, it is known that blood cfDNA is circulating predominantly in the form of nucleoprotein complexes (NPCs), including complexes with histones [ 5 , 6 ], amyloid P [ 7 ], and blood and cell proteins [ 8 , 9 ], as well as in apoptotic particles [ 10 , 11 , 12 ]. The structure, properties, and biological activity of NPCs, the features of their circulation and protein composition are currently not well understood.…”

Moonlighting chromatin: when DNA escapes nuclear control

“…Also, in mammals, extracellular DNA traps can originate not only from neutrophils [ 18 ] but also from other immune cells (eosinophils, dendritic cells, monocytes, macrophages, mast cells, basophils, T cells, and B cells); DNA traps can also arise from non-immune cells (endothelial cells, platelets, and cardiomyocytes) [ 19 ]. The evolutionary conservation of DNA traps suggests that the evolution of DNA has involved both hereditary and gene regulation as well as the potential weaponization against invading pathogens [ 20 ].…”

Coagulation and complement: Key innate defense participants in a seamless web

“…Activated neutrophils can also release neutrophil extracellular traps (NETs) ( Figure 3 ), a process referred to as NETosis. NETs are web-like structures that are secreted during a specialized type of cell death where the cell remains intact and retains certain biological function ( 81 , 82 ). NETs can also be released by activated eosinophils, basophils and monocytes.…”