Neutrophil Extracellular Traps and Cancer: Trapping Our Attention with Their Involvement in Ovarian Cancer

Abstract

Neutrophils, the most abundant circulating leukocytes, play a well-known role in defense against pathogens through phagocytosis and degranulation. However, a new mechanism involving the release of neutrophil extracellular traps (NETs) composed of DNA, histones, calprotectin, myeloperoxidase, and elastase, among others, has been described. The so-called NETosis process can occur through three different mechanisms: suicidal, vital, and mitochondrial NETosis. Apart from their role in immune defense, neutrophils and NETs have been involved in physiopathological conditions, highlighting immunothrombosis and cancer. Notably, neutrophils can either promote or inhibit tumor growth in the tumor microenvironment depending on cytokine signaling and epigenetic modifications. Several neutrophils' pro-tumor strategies involving NETs have been documented, including pre-metastatic niche formation, increased survival, inhibition of the immune response, and resistance to oncologic therapies. In this review, we focus on ovarian cancer (OC), which remains the second most incidental but the most lethal gynecologic malignancy, partly due to the presence of metastasis, often omental, at diagnosis and the resistance to treatment. We deepen the state-of-the-art on the participation of NETs in OC metastasis establishment and progression and their involvement in resistance to chemo-, immuno-, and radiotherapies. Finally, we review the current literature on NETs in OC as diagnostic and/or prognostic markers, and their contribution to disease progression at early and advanced stages. The panoramic view provided in this article might pave the way for enhanced diagnostic and therapeutic strategies to improve the prognosis of cancer patients and, specifically, OC patients.

Keywords: NETosis; NETs; TLR4; Toll-like receptor 4; cancer; immunothrombosis; metastasis; neutrophil extracellular traps; neutrophils; ovarian cancer.

Figure 1

Pathogen elimination strategies conducted by neutrophils. The immune response is triggered by pathogens such as bacteria, fungi, viruses, and protozoan parasites. Available neutrophil strategies to achieve pathogen clearance include phagocytosis, extracellular degranulation, and neutrophil extracellular traps (NETs) release. Created with BioRender.com, accessed on 9 February 2023.

Figure 2

Types of NETosis. The neutrophil extracellular traps (NETs) formation and release may occur through three different processes: (A) suicidal, (B) vital, and (C) mitochondrial NETosis. Stimulus detection by the neutrophil membrane receptors triggers a signaling cascade. It activates Protein arginine deiminase type IV (PAD4), promotes the translocation of Neutrophil elastase (NE) and myeloperoxidase (MPO) to the nucleus, and could increases in Reactive oxygen species (ROS) levels. In nuclear NETs releases, PAD4 catalyzes histone 3 citrullination (citH3), while NE and MPO decondensed chromatin. PMA, phorbol myristate acetate; DAMPs, damage-associated molecular patterns; TLR2, Toll-like receptor 2; TLR4, Toll-like receptor 4. Created with BioRender.com accessed on 9 February 2023.

Figure 3

Pro-tumor role of NETs in cancer. Cancer cells recruit neutrophils to the tumor microenvironment and tumor-associated neutrophils (TANs) pro-tumor strategies could involve neutrophil extracellular traps (NETs). Those include pre-metastatic niche formation, promotion of tumor-survival processes, inhibition of the immune response, and therapy resistance. Created with BioRender.com accessed on 9 February 2023.

Figure 4

Putative positive feedback loop for ovarian cancer metastasis based on NETosis. Ovarian cancer (OC) cells release cytokines to attract neutrophils to pro-metastatic niches and to induce the release of neutrophil extracellular traps (NETs). In turn, NETosis releases neutrophil elastase (NE) to the tumor environment, acting on Toll-like receptor 4 (TLR4) which increases the release of tumor cytokines, forming a positive pro-metastatic feedback loop. Created with BioRender.com accessed on 9 February 2023.