Metastatic potential of NET in neoplastic disease

Abstract

In response to various stimuli, neutrophils and eosinophils can release neutrophil extracellular traps (NET) consisting of proteolytic enzymes, DNA and other components of the cell nucleus. The NETosis process has been characterized as a mechanism of programmed cell death, which leads to chromatin decondensation and disintegration of organelles, followed by lysis of the cell membrane. In recent years the significant role of neutrophils in the pathogenesis of cancer has been highlighted. The presence of two subpopulations of TAN with different phenotypes and functions - acting antitumor "N1" and the pro-cancerous "N2" - has been discovered. By the release of cytokines and chemokines neutrophils may affect angiogenesis and contribute to escape of tumor cells from immune surveillance. Interactions between cells and the microenvironment are of vital importance both for the preservation of homeostasis in normal tissue and tumor growth. They affect the initiation of disease progression and prognosis. The impact of NETosis on the process of metastasis is evaluated in the context of the functions of the individual components of the NET (MMP-9, CG, NE). Furthermore, presumably the pro- or anti-tumor effect of NETosis depends on many factors including the status of the immune system or tumor microenvironment. Probably the cancer cells can be captured by the NET microenvironment in the same manner as microorganisms. However, the high concentration of proteins released during NETosis can induce their proliferation and inhibit apoptosis, thus promoting tumor growth. A better understanding of NETosis function in tumor progression may lead to the emergence of new prognostic factors and targets for therapy in many types of cancer.

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

“…NETs have been identified in the blood and tumors of both animal models and patients where they may serve as pro- or anti-tumoral factors, depending on the status of the immune system or tumor microenvironment ( 20 , 31 ). In particular, the correlation between NET formation, tumorigenesis, tumor progression, and metastasis has been investigated and there have been reports of the direct activity of NETs on tumor cell proliferation, through their proteases or activating signals ( 3 , 19 , 20 , 46 ).…”

“…NETs have been identified in the blood and tumors of both animal models and patients where they may serve as pro- or anti-tumoral factors, depending on the status of the immune system or tumor microenvironment ( 20 , 31 ). In particular, the correlation between NET formation, tumorigenesis, tumor progression, and metastasis has been investigated and there have been reports of the direct activity of NETs on tumor cell proliferation, through their proteases or activating signals ( 3 , 19 , 20 , 46 ). Furthermore, the ability of cancer cells to promote NETosis in vivo and in vitro ( 41 ) and the presence of Tumor Associated Neutrophils (TANs) in the tumor microenvironment, as well as their association with NET formation, have been demonstrated ( 41 , 47 – 49 ).…”

“…They are also involved in other pathological processes, such as coagulation disorders, thrombosis ( 10 ), diabetes ( 11 , 12 ), atherosclerosis ( 13 ), vasculitis ( 14 ), wound healing ( 12 ), and periodontitis ( 15 , 16 ). Recently, several studies have investigated the role of NETs in tumors and reported their involvement in cancer immunoediting ( 3 ), progression ( 3 , 17 – 19 ), metastatic spread ( 20 ), and cancer associated thrombosis ( 20 ). NETs can exert an anti-tumor or pro-tumor activity.…”

“…NETs can exert an anti-tumor or pro-tumor activity. NET components like myeloperoxidase (MPO) ( 21 ), proteinases ( 20 , 22 ), and histones ( 23 ) can kill a tumor, inhibit tumor growth, and metastasis ( 21 ). NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation, and metastasis ( 20 , 22 ).…”

Direct and indirect methods of evaluating the NETosis process

“…Bacteria are quickly killed by proteolytic enzymes and antibacterial proteins [1]. In 2004, Brinkmann et al were the first to present a not previously described process responsible for the destruction of micro-organisms -by means of NETs composed of DNA, granule components (including proteolytic enzymes) and the contents of the cell nucleus, which are released into the extracellular space [2,3,4]. This network is formed in response to the activity of Gram-positive and Gram-negative bacteria [2,5,6,7].…”