Introduction/Background*NETosis has recently been described as a new form of neutrophils’ immune response, by which they release extracellular networks (NETs) of DNA, histones and proteins. In the tumor environment, NETs participate in immunothrombosis, tumor progression, metastasis, and evasion of the immune system. Recent studies show that NETosis is involved in the initial metastasis of high-grade serous ovarian cancer (HGSOC), although its contribution in advanced stages or as a diagnostic biomarker is unknown, which is the objective of this study.
Methodology We analyzed paired plasma and ascites fluid samples from women with HGSOC (n=28) and controls (n=16). As NETosis markers, we quantified cell-free circulating DNA (cfDNA, Quant-iT PicoGreen dsDNA kit), nucleosomes (Cell Death Detection ELISAPLUS kit), calprotectin (Human Calprotectin ELISA kit) and myeloperoxidase (MPO) (Human MPO ELISA kit) and we evaluated their differences with the SPSS program (v.21).
Result(s)*Patients with HGSOC presented a higher concentration of cfDNA in plasma (median 1785,9 ng/mL; Q1-Q3, 1618,5-2181,6) compared to the controls (1526,7; 1452,0-1610,9) (p<0,001). In addition, we observed an increase in the 4 NETosis markers evaluated in patients’ ascites: cfDNA [(2128,9; 1477,8-2814,5) vs. (1148,1; 990,8-1235,3), p<0.001], nucleosomes [(2,58 AU; 1,27-3,16) vs. (0,09; 0,003-0,55), p<0,001], calprotectin [(2606,8 ng/mL; 1028,3-5021,7) vs. (353,5; 195,5-722,3), p<0,001] and MPO [(73,3 ng/mL; 48,8-141,4) vs. (25,3; 22.6-29,4); p<0,001] (figure 1).
The levels of the 4 markers were positively correlated with each other in both biofluids (p<0.032) and with the levels of neutrophils in plasma (p<0.001). We also observed that cfDNA in plasma was able to distinguish patients from controls (AUC=0.842). Furthermore, the levels of cfDNA, calprotectin and MPO in plasma showed statistically significant differences in related to neoadjuvant treatment. (Figure 2).
Conclusion*The observed correlation between the values of the different markers and neutrophils’ levels suggests their validity as biomarkers of NETosis. For the first time, we describe an increase in NETosis markers in ascites of advanced HGSOC, which could show the contribution of NETosis in the progression of HGSOC in the pelvic microenvironment. Furthermore, cfDNA in plasma could represent a minimally invasive diagnostic biomarker for HGSOC that could reduce the pre-surgical rate of false positives.
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