Increased levels of NETosis biomarkers in high-grade serous ovarian cancer patients' biofluids: Potential role in disease diagnosis and management

Front Immunol. 2023 Feb 3:14:1111344. doi: 10.3389/fimmu.2023.1111344. eCollection 2023.

Abstract

Introduction: High-grade serous ovarian cancer (HGSOC) is the second most frequent gynecological malignancy but the most lethal, partially due to the spread of the disease through the peritoneal cavity. Recent evidence has shown that, apart from their role in immune defense through phagocytosis and degranulation, neutrophils are able to participate in cancer progression through the release of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are composed of DNA, histones, calprotectin, myeloperoxidase (MPO) and elastase and the NETosis process has been proposed as a pre-requisite for the establishment of omental metastases in early stages of HGSOC. Nevertheless, its role in advanced stages remains to be elucidated. Therefore, our principal aim is to characterize a NETosis biomarker profile in biofluids from patients with advanced HGSOC and control women.

Methods: Specifically, five biomarkers of NETosis (cell-free DNA (cfDNA), nucleosomes, citrullinated histone 3 (citH3), calprotectin and MPO) were quantified in plasma and peritoneal fluid (PF) samples from patients (n=45) and control women (n=40).

Results: Our results showed that HGSOC patients presented a higher concentration of cfDNA, citH3 and calprotectin in plasma and of all five NETosis biomarkers in PF than control women. Moreover, these biomarkers showed a strong ability to differentiate the two clinical groups. Interestingly, neoadjuvant treatment (NT) seemed to reduce NETosis biomarkers mainly systemically (plasma) compared to the tumor environment (PF).

Discussion: In conclusion, NETosis biomarkers are present in the tumor environment of patients with advanced HGSOC, which might contribute to the progression of the disease. Besides, plasma cfDNA and calprotectin could represent minimally invasive surrogate biomarkers for HGSOC. Finally, NT modifies NETosis biomarkers levels mainly at the systemic level.

Keywords: NETosis; biomarkers; calprotectin; cfDNA; high-grade serous ovarian cancer; peritoneal fluid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cell-Free Nucleic Acids*
  • Extracellular Traps*
  • Female
  • Histones
  • Humans
  • Neutrophils
  • Ovarian Neoplasms*

Substances

  • Histones
  • Biomarkers
  • Cell-Free Nucleic Acids

Grants and funding

This research was funded by the “Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional” (ISCIII-FEDER), Spain (PI17/01945, PI17/00495, PI20/00075 and PI22/01872), the “Generalitat Valenciana”, Spain (GV/2020/200), the “Sociedad de Obstetricia y Ginecología de la Comunidad Valenciana” (SOGCV), Spain (Prize SOGCV 2019), the “Fundación para la Investigación del Hospital General Universitario de Valencia” (FIHGUV), Spain (Prize FIHGUV 2019, Prize FIHGUV 2020 and Prize FIHGUV 2021) and the “Sociedad Española de Trombosis y Hemostasia” (SETH), Spain (Prize SETH). EG-C is supported by a grant from Generalitat Valenciana ACIF/2020/216, respectively; BM by a grant from SETH (Prize SETH 2021), RH by a grant from ISCIII (FI21/00171) and ST-P by a grant from the “Junta Asociada Provincial de Valencia de la Asociación Española Contra el Cáncer (AECC)”.