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Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer
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2019 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 120, no 2, p. 207-217Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Advanced cancer causes necrosis and releases damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs activate neutrophils, including generation of neutrophil extracellular traps (NETs), which are injurious, thrombogenic, and implicated in metastasis. We hypothesised that extracellular mitochondrial DNA (mtDNA) in ascites from patients with epithelial ovarian cancer (EOC) would correlate with worse outcomes.

METHODS: Banked ascites supernatants from patients with newly diagnosed advanced EOC were analysed for mtDNA, neutrophil elastase, and activation of healthy donor neutrophils and platelets. TCGA was mined for expression of SELP and ELANE.

RESULTS: The highest quartile of ascites mtDNA correlated with reduced progression-free survival (PFS) and a higher likelihood of disease progression within 12-months following primary surgery (n = 68, log-rank, p = 0.0178). NETs were detected in resected tumours. Ascites supernatants chemoattracted neutrophils, induced NETs, and activated platelets. Ascites exposure rendered neutrophils suppressive, based on abrogation of ex vivo stimulated T cell proliferation. Increased SELP mRNA expression correlated with worse overall survival (n = 302, Cox model, p = 0.02).

CONCLUSION: In this single-centre retrospective analysis, ascites mtDNA correlated with worse PFS in advanced EOC. Mitochondrial and other DAMPs in ascites may activate neutrophil and platelet responses that facilitate metastasis and obstruct anti-tumour immunity. These pathways are potential prognostic markers and therapeutic targets.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 120, no 2, p. 207-217
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Infectious Diseases; cellforskning; Immunology
Identifiers
URN: urn:nbn:se:umu:diva-156192DOI: 10.1038/s41416-018-0339-8ISI: 000456328200009PubMedID: 30518816OAI: oai:DiVA.org:umu-156192DiVA, id: diva2:1286560
Funder
NIH (National Institute of Health), R01CA188900NIH (National Institute of Health), T32CA108456NIH (National Institute of Health), T32CA085183NIH (National Institute of Health), K01LM012100Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2019-02-26Bibliographically approved

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Muthukrishnan, UmaGilthorpe, Jonathan D.Urban, Constantin F.

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Muthukrishnan, UmaGilthorpe, Jonathan D.Urban, Constantin F.
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Department of Pharmacology and Clinical NeuroscienceDepartment of Clinical Microbiology
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British Journal of Cancer
Cell and Molecular BiologyCancer and Oncology

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