Neutrophil extracellular trap formation correlates with improved overall survival in ovarian cancer

Abstract

It is still a question of debate whether neutrophils, often found in the tumor microenvironment, mediate tumor-promoting or rather tumor-inhibiting activities. The present study focusses on the involvement of neutrophils in high grade serous ovarian cancer (HGSOC). Multi-omics data comprising proteomics, eicosadomics, metabolomics, Luminex-based cytokinomics, and FACS data were generated from ascites samples. Integrated data analysis demonstrates a significant increase of neutrophil extracellular trap-(NET) associated molecules in non-miliary ascites samples. A co-association network analysis performed with the ascites data further revealed a striking co-correlation between NETosis-associated metabolites with several eicosanoids. Investigating primary neutrophils from healthy domors, NET formation was induced using ionomycin or phorbol ester. Data congruence with ascites analyses indicated the predominance of NOX-independent NETosis. NETosis is associated with S100A8/A9 release. An increase of the S100A8/CRP abundance ratio was found to correlate with improved survival of HGSOC patients. The analysis of additional five independent proteome studies with regard to S100A8/CRP ratios confirmed this observation. In conclusion, here we present evidence that increased NET formation relates to improved outcomes in cancer patients. Graphical abstractNETs releasing neutrophils through detaching of small tumor nods dictate the building of bigger in size and fewer in number of tumors in the non-miliary spreading tumor. Increased angiogenesis associated with increased blood circulation may contribute to less suppressive effects on NETs formation in the non-miliary tumor type. Tumor origin, i.e. fallopian tube for the miliary or ovary for the non-miliary tumors, may influence the angiogenesis and therewith - through facilitating of neutrophils activation - (co)determine the type of tumor spread. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/862292v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@895250org.highwire.dtl.DTLVardef@17b2a78org.highwire.dtl.DTLVardef@1213959org.highwire.dtl.DTLVardef@3c35ed_HPS_FORMAT_FIGEXP M_FIG C_FIG