Neutrophil extracellular traps and neutrophil-related mediators in human thyroid cancer
Luca Modestino1,2,3, Leonardo Cristinziano1,2,3, Remo Poto1,2,3
1Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, Naples, Italy.
Background:
Polymorphonuclear neutrophils (PMNs) are the main effector cells in inflammatory responses and play multiple roles in thyroid cancer (TC). PMNs contain and release a plethora of mediators, including granular enzymes [e.g., myeloperoxidase (MPO), pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9)], and neutrophil extracellular traps (NETs). The aim of this study was to evaluate NETs and neutrophil-derived mediators as possible biomarkers in TC patients.
Methods:
20 patients with differentiated thyroid cancer (DTC), 26 patients with dedifferentiated thyroid cancer (De-DTC), 26 patients with multinodular goiter (MNG) and 22 healthy controls (HCs) were recruited. Serum concentrations of free DNA (dsDNA), nucleosomes, citrullinated histone H3 (CitH3) and MPO-DNA complexes were evaluated as NET biomarkers. Neutrophil-related mediators such as MPO, PTX3, MMP-9, CXCL8, and granulocyte-monocyte colony-stimulating factor (GM-CSF) were measured by ELISA.
Results:
Serum levels of all four NET biomarkers were increased in DeDTC patients compared to HCs. CitH3 serum levels were selectively increased in both DeDTC and DTC patients compared to HCs and MNG patients. MPO-DNA complexes and nucleosomes were selectively increased only in DeDTC patients compared to HCs and MNG patients. Moreover, MPO-DNA complexes were selectively increased in DeDTC patients compared to DTC patients also. MPO circulating levels were selectively increased in the DeDTC patient subgroup compared to HCs. Circulating levels of PTX3, MMP-9 and GM-CSF were increased in DTC and DeDTC patients compared to HCs. Nucleosomes positively correlated with dsDNA, CitH3, MPO and CXCL8. MPO-DNA complexes positively correlated with dsDNA, CitH3, CXCL8, MPO and nucleosome levels. Moreover, three out of the four NET biomarkers (i.e., dsDNA, nucleosomes and MPO-DNA complexes) were increased in elderly patients compared to young patients and in patients with metastatic disease at diagnosis compared to non metastatic patients. Nucleosomes were higher in males compared to females.
Conclusion:
MPO-DNA complexes, nucleosomes and, to some extent, CitH3 levels seem to correlate with malignancy and severity of progressive TC. Moreover, serum concentrations of PMN-related mediators (MPO, PTX3, GM-CSF) were increased in TCs compared to MNG and HCs.
Insights
Neutrophil extracellular traps (NETs) and related mediators show potential as biomarkers for thyroid cancer (TC) severity. Elevated levels of NET biomarkers like MPO-DNA complexes and nucleosomes were observed in advanced TC, correlating with malignancy.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Polymorphonuclear neutrophils (PMNs) are key players in inflammation and thyroid cancer (TC).
- PMNs release mediators like myeloperoxidase (MPO), pentraxin-3 (PTX3), matrix metalloproteinase-9 (MMP-9), and neutrophil extracellular traps (NETs).
- NETs and neutrophil-derived mediators are being investigated as potential biomarkers for TC.
Purpose of the Study:
- To assess neutrophil extracellular traps (NETs) and related mediators as potential biomarkers in thyroid cancer (TC) patients.
- To evaluate serum concentrations of NET biomarkers and neutrophil-derived mediators in different thyroid cancer subtypes and control groups.
Main Methods:
- Serum samples from patients with differentiated thyroid cancer (DTC), dedifferentiated thyroid cancer (De-DTC), multinodular goiter (MNG), and healthy controls (HCs) were analyzed.
- NET biomarkers including dsDNA, nucleosomes, citrullinated histone H3 (CitH3), and MPO-DNA complexes were quantified.
- Neutrophil mediators (MPO, PTX3, MMP-9, CXCL8, GM-CSF) were measured using ELISA.
Main Results:
- NET biomarkers were elevated in De-DTC patients compared to HCs. CitH3 levels were increased in both De-DTC and DTC patients versus HCs and MNG.
- MPO-DNA complexes and nucleosomes were significantly higher in De-DTC patients compared to HCs, MNG, and DTC.
- Increased levels of MPO, PTX3, MMP-9, and GM-CSF were observed in DTC and De-DTC patients compared to HCs. NET biomarkers correlated with disease severity, age, and metastatic status.
Conclusions:
- MPO-DNA complexes, nucleosomes, and CitH3 levels may indicate malignancy and progression in thyroid cancer.
- Elevated serum concentrations of PMN-related mediators (MPO, PTX3, GM-CSF) are associated with thyroid cancer compared to benign goiter and healthy controls.
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