Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress

Oncoimmunology. 2022 Mar 14;11(1):2049487. doi: 10.1080/2162402X.2022.2049487. eCollection 2022.

Abstract

Cancer is associated with systemic pathologies that contribute to mortality, such as thrombosis and distant organ failure. The aim of this study was to investigate the potential role of neutrophil extracellular traps (NETs) in myocardial inflammation and tissue damage in treatment-naïve individuals with cancer. Mice with mammary carcinoma (MMTV-PyMT) had increased plasma levels of NETs measured as H3Cit-DNA complexes, paralleled with elevated coagulation, compared to healthy littermates. MMTV-PyMT mice displayed upregulation of pro-inflammatory markers in the heart, myocardial hypertrophy and elevated cardiac disease biomarkers in the blood, but not echocardiographic heart failure. Moreover, increased endothelial proliferation was observed in hearts from tumor-bearing mice. Removal of NETs by DNase I treatment suppressed the myocardial inflammation, expression of cardiac disease biomarkers and endothelial proliferation. Compared to a healthy control group, treatment-naïve cancer patients with different malignant disorders had increased NET formation, which correlated to plasma levels of the inflammatory marker CRP and the cardiac disease biomarkers NT-proBNP and sTNFR1, in agreement with the mouse data. Altogether, our data indicate that NETs contribute to inflammation and myocardial stress during malignancy. These findings suggest NETs as potential therapeutic targets to prevent cardiac inflammation and dysfunction in cancer patients.

Keywords: NETs; Neutrophil extracellular traps; cancer; cardiac; hypertrophy; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Extracellular Traps* / metabolism
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Myocarditis* / metabolism
  • Myocarditis* / pathology
  • Neoplasms* / pathology
  • Neutrophils

Substances

  • Biomarkers

Grants and funding

This work was supported by grants from The Swedish Cancer Society (Cancerfonden 20 1283) and The Swedish Research Council (Vetenskapsrådet 2016-03036) to AKO, the Swedish Heart-Lung Foundation (Hjärt-Lungfonden 20190639, 20190637) to MH, The Stitching af Jochnick Foundation, the Swedish Society of Medicine, and the Regional Agreement on Clinical Research (ALF) between Stockholm County Council and Karolinska Institutet to CT;Stichting af Jochnick Foundation;Svenska Sällskapet för Medicinsk Forskning;