The emerging role of neutrophil extracellular traps in cancer: from lab to ward

Abstract

Neutrophil extracellular traps (NETs) are web-like structures derived from neutrophils, which typically consist of DNA, released from the nucleus or mitochondria, and decorated with histones and granule proteins. They are well known as an important structure in innate immunity to eliminate pathogenic bacteria, similar to neutrophils. Initially, NETs are reported to take part in the progression of inflammatory diseases; now, they have also been implicated in the progression of sterile inflammation such as autoimmune disease, diabetes, and cancer. In this review, we will describe the recent studies which have investigated the role of NETs in the development of cancer, especially metastasis. We also prescribe the strategies for targeting NETs in the multiple cancer types, which suggest that NETs are a promising treatment for cancer patients.

Keywords: cancer; metastasis (cancer metastasis); neutrophil extracellular traps; therapeutics; tumor microenvironment.

Figure 1

Progression of NET formation. When neutrophils are stimulated by stimulus, they can produce NETs in two main ways according to the different destinies. (A) The lytic NET formation. When stimuli including LPS, PMA, and IL-8 bind to the receptors of neutrophils, NADPH-oxidase is active, which can increase the level of ROS. Then, the increased ROS promotes chromosome decondensation by activating PAD4. The DNA derived from the chromosome is decorated with granule proteins and forms NETs, which are released from the dead neutrophil. (B) The non-lytic NET formation. The stimulus including damage-associated molecular patterns (DAMPs), bacteria, and injury can promote NET formation in neutrophils by forming vesicles. Different from the destiny of neutrophils in the lytic NET formation, these neutrophils still preserve intact membranes and the phagocytic function. Notably, the DNA in NETs derived from the chromosome of the nucleus is ROS-independent; however, the formation of NETs comprising mitochondrial DNA is ROS-dependent.

Figure 2

The crucial role of NETs in cancer biology. NETs, a net-like structure produced by neutrophils, play an important role in TME, which can influence cancer biology by cross-talking with tumor cells. NET-DNA, which is the main component of NETs, can interact with CCDC25 on the cytomembrane of tumor cells and then activate the ILK-β-Parvin pathway to promote cell motility. NETs are decorated with HMGB1, and RAGE is the major receptor for HMGB1 in mediating sterile inflammation. The NE, MMP9, and CEACAM1 released by NETs trigger the TLR-4 and TLR-9 receptors on cancer cells, accelerating the growth, metastasis, and recurrence of the tumor by altering the metabolism and “waking up” dormant tumor cells. Other components in the TME also have a mutual effect with NETs. The amyloid β derived from CAF and other factors produced by tumor cells, including IL-8, G-CSF, CTSC, and EVs, will increase the level of NETs. NETs can also promote the differentiation of Treg cells and affect the immune-modulating function of T cells.