Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer.
Aged
Alarmins
/ genetics
Ascites
/ genetics
Blood Platelets
/ metabolism
Carcinoma, Ovarian Epithelial
/ genetics
DNA, Mitochondrial
/ genetics
Extracellular Traps
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Leukocyte Elastase
/ genetics
Middle Aged
Neoplasm Metastasis
Neoplasm Staging
Neutrophils
/ metabolism
Progression-Free Survival
Tumor Microenvironment
/ genetics
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
24
07
2018
accepted:
25
10
2018
revised:
09
10
2018
pubmed:
7
12
2018
medline:
21
9
2019
entrez:
7
12
2018
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 30518816
doi: 10.1038/s41416-018-0339-8
pii: 10.1038/s41416-018-0339-8
pmc: PMC6342981
doi:
Substances chimiques
Alarmins
0
DNA, Mitochondrial
0
Leukocyte Elastase
EC 3.4.21.37
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
207-217Subventions
Organisme : NCI NIH HHS
ID : P50 CA159981
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016056
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA108456
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188900
Pays : United States
Organisme : NLM NIH HHS
ID : K01 LM012100
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA085183
Pays : United States
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