PMID- 30518816
OWN - NLM
STAT- In-Data-Review
LR  - 20190307
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 120
IP  - 2
DP  - 2019 Jan
TI  - Mitochondrial DNA in the tumour microenvironment activates neutrophils and is
      associated with worse outcomes in patients with advanced epithelial ovarian
      cancer.
PG  - 207-217
LID - 10.1038/s41416-018-0339-8 [doi]
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.
FAU - Singel, Kelly L
AU  - Singel KL
AD  - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA.
FAU - Grzankowski, Kassondra S
AU  - Grzankowski KS
AD  - Department of Surgery, Division of Gynecologic Oncology, Roswell Park
      Comprehensive Cancer Center, Buffalo, NY, USA.
AD  - Arizona Center for Cancer Care, Phoenix, AZ, USA.
FAU - Khan, A N M Nazmul H
AU  - Khan ANMNH
AD  - Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY,
      USA.
FAU - Grimm, Melissa J
AU  - Grimm MJ
AD  - Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY,
      USA.
FAU - D'Auria, Anthony C
AU  - D'Auria AC
AD  - Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY,
      USA.
FAU - Morrell, Kayla
AU  - Morrell K
AD  - Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer
      Center, Buffalo, NY, USA.
FAU - Eng, Kevin H
AU  - Eng KH
AD  - Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer
      Center, Buffalo, NY, USA.
FAU - Hylander, Bonnie
AU  - Hylander B
AD  - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA.
FAU - Mayor, Paul C
AU  - Mayor PC
AD  - Department of Surgery, Division of Gynecologic Oncology, Roswell Park
      Comprehensive Cancer Center, Buffalo, NY, USA.
FAU - Emmons, Tiffany R
AU  - Emmons TR
AD  - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA.
FAU - Lenart, Nikolett
AU  - Lenart N
AD  - Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine,
      Hungarian Academy of Sciences, Budapest, Hungary.
FAU - Fekete, Rebeka
AU  - Fekete R
AD  - Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine,
      Hungarian Academy of Sciences, Budapest, Hungary.
FAU - Kornyei, Zsuzsanna
AU  - Kornyei Z
AD  - Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine,
      Hungarian Academy of Sciences, Budapest, Hungary.
FAU - Muthukrishnan, Uma
AU  - Muthukrishnan U
AD  - Department of Pharmacology and Clinical Neuroscience, Umea University, Umea,
      Sweden.
FAU - Gilthorpe, Jonathan D
AU  - Gilthorpe JD
AD  - Department of Pharmacology and Clinical Neuroscience, Umea University, Umea,
      Sweden.
FAU - Urban, Constantin F
AU  - Urban CF
AD  - Department of Clinical Microbiology, Umea University, Umea, Sweden.
FAU - Itagaki, Kiyoshi
AU  - Itagaki K
AD  - Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical
      School, Boston, MA, USA.
FAU - Hauser, Carl J
AU  - Hauser CJ
AD  - Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical
      School, Boston, MA, USA.
FAU - Leifer, Cynthia
AU  - Leifer C
AD  - Department of Microbiology and Immunology, Cornell University College of
      Veterinary Medicine, Ithaca, NY, USA.
FAU - Moysich, Kirsten B
AU  - Moysich KB
AD  - Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer
      Center, Buffalo, NY, USA.
FAU - Odunsi, Kunle
AU  - Odunsi K
AD  - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA.
AD  - Department of Surgery, Division of Gynecologic Oncology, Roswell Park
      Comprehensive Cancer Center, Buffalo, NY, USA.
AD  - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA.
FAU - Denes, Adam
AU  - Denes A
AD  - Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine,
      Hungarian Academy of Sciences, Budapest, Hungary.
FAU - Segal, Brahm H
AU  - Segal BH
AD  - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA. brahm.segal@roswellpark.org.
AD  - Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY,
      USA. brahm.segal@roswellpark.org.
AD  - Department of Medicine, Jacobs School of Medicine and Biomedical Sciences,
      University at Buffalo, Buffalo, NY, USA. brahm.segal@roswellpark.org.
LA  - eng
GR  - P30CA016056/Roswell Park Cancer Institute (RPCI)
GR  - P30 CA016056/CA/NCI NIH HHS/United States
GR  - R01CA188900/Roswell Park Cancer Institute (RPCI)
GR  - K01LM012100/Roswell Park Cancer Institute (RPCI)
GR  - R01 CA188900/CA/NCI NIH HHS/United States
GR  - P50CA159981/Roswell Park Cancer Institute (RPCI)
GR  - T32CA085183/Roswell Park Cancer Institute (RPCI)
GR  - 5T32CA108456/Roswell Park Cancer Institute (RPCI)
PT  - Journal Article
DEP - 20181206
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
EDAT- 2018/12/07 06:00
MHDA- 2018/12/07 06:00
CRDT- 2018/12/07 06:00
PHST- 2018/07/24 00:00 [received]
PHST- 2018/10/25 00:00 [accepted]
PHST- 2018/10/09 00:00 [revised]
PHST- 2018/12/07 06:00 [pubmed]
PHST- 2018/12/07 06:00 [medline]
PHST- 2018/12/07 06:00 [entrez]
AID - 10.1038/s41416-018-0339-8 [doi]
AID - 10.1038/s41416-018-0339-8 [pii]
PST - ppublish
SO  - Br J Cancer. 2019 Jan;120(2):207-217. doi: 10.1038/s41416-018-0339-8. Epub 2018
      Dec 6.