TY - JOUR
T1 - Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer
AU - Singel, Kelly L.
AU - Grzankowski, Kassondra S.
AU - Khan, A. N.M.Nazmul H.
AU - Grimm, Melissa J.
AU - D’Auria, Anthony C.
AU - Morrell, Kayla
AU - Eng, Kevin H.
AU - Hylander, Bonnie
AU - Mayor, Paul C.
AU - Emmons, Tiffany R.
AU - Lénárt, Nikolett
AU - Fekete, Rebeka
AU - Környei, Zsuzsanna
AU - Muthukrishnan, Uma
AU - Gilthorpe, Jonathan D.
AU - Urban, Constantin F.
AU - Itagaki, Kiyoshi
AU - Hauser, Carl J.
AU - Leifer, Cynthia
AU - Moysich, Kirsten B.
AU - Odunsi, Kunle
AU - Dénes, Ádám
AU - Segal, Brahm H.
N1 - Publisher Copyright: © 2018, The Author(s).
PY - 2019/1/22
Y1 - 2019/1/22
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85058029797
U2 - 10.1038/s41416-018-0339-8
DO - 10.1038/s41416-018-0339-8
M3 - Article
C2 - 30518816
SN - 0007-0920
VL - 120
SP - 207
EP - 217
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 2
ER -