Neutrophil Extracellular Traps in Breast Cancer: Roles in Metastasis and Beyond

Abstract

Despite advances in the treatment of breast cancer, the disease continues to exhibit high global morbidity and mortality. The importance of neutrophils in cancer development has been increasingly recognized. Neutrophil extracellular traps (NETs) are web-like structures released into the extracellular space by activated neutrophils, serving as a potential antimicrobial mechanism for capturing and eliminating microorganisms. The roles played by NETs in cancer development have been a subject of intense research in the last decade. In breast cancer, current evidence suggests that NETs are involved in various stages of cancer development, particularly during metastasis. In this review, we try to provide an updated overview of the roles played by NETs in breast cancer metastasis. These include: 1) facilitating systemic dissemination of cancer cells; 2) promoting cancer-associated inflammation; 3) facilitating cancer-associated thrombosis; 4) facilitating pre-metastatic niche formation; and 5) awakening dormant cancer cells. The translational implications of NETs in breast cancer treatment are also discussed. Understanding the relationship between NETs and breast cancer metastasis is expected to provide important insights for developing new therapeutic strategies for breast cancer patients.

Keywords: Breast cancer; Neutrophil extracellular trap (NET); Therapeutic target; Tumor immunity; Tumor microenvironment.

Figure 1

Pathways of NET formation. (a) Different stimuli such as PMA, antibodies (such as autoantibodies), or cholesterol crystals can induce suicidal NETosis, which occurs a few hours after stimulation. Following the activation of NOX, ROS are generated and PAD4 is activated, followed by chromatin decondensation. Subsequently, NE and MPO are translocated from granules to the nucleus, promoting further chromatin unfolding and subsequent disruption of the nuclear membrane. In addition, NE activates GSDMD, forming pores on granules and plasma membranes, resulting in membrane rupture and cell death. (b) Vital NETosis can be induced by Staphylococcus aureus within minutes through complement receptors and TLR2 ligands. Alternatively, vital NETosis can be induced via TLR4 activation by Escherichia coli. PLTs indirectly activated through TLR4 also contribute to this process. In this pathway, NOX activity is not required. PAD4 is activated, inducing chromatin decondensation. Nuclei containing DNA are extruded without disrupting the plasma membrane, and decondensed chromatin is transported via vesicles for the expulsion of nuclear DNA. The intact cell membrane of neutrophils allows for the survival of non-nucleated neutrophils while retaining physiological functions such as phagocytosis. DAMPs that amplify ongoing immune reactions are also involved in inducing vital NETosis. PMA, phorbol 12-myristate 13-acetate; NOX, NADPH oxidase; ROS, reactive oxygen species; PAD4, peptidylarginine deiminase 4; NE, neutrophil elastase; MPO, myeloperoxidase; GSDMD, Gasdermin D; TLR2, Toll-like receptor 2; PLTs, platelets; TLR4, Toll-like receptor 4; DAMPs, damage-associated molecular patterns.

Figure 2

Roles of NETs in breast cancer metastasis. In breast cancer, NETs play different functions in various aspects of cancer metastasis. See the main text for detailed description of each of the functions played by NETs in breast cancer metastasis.

Figure 3

Strategies for targeting the NETs. Currently evaluated or potentially available strategies for targeting the NETs to intervene breast cancer metastasis include: 1) inhibition of TLRs; 2) inhibition of CXCR1/2; 3) scavenging of ROS; 4) inhibition of PAD4; 5) blocking of GSDMD; 6) DNase therapy; 7) inhibition of HIF-1α; and 8) inhibition of MPO/NE. TLR, Toll-like receptor; CXCR, CXC chemokine receptor; ROS, reactive oxygen species; PAD4, peptidylarginine deiminase 4; GSDMD, Gasdermin D.