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2016 ; 17
(1
): 108
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A transcriptome-based global map of signaling pathways in the ovarian cancer
microenvironment associated with clinical outcome
#MMPMID27215396
Reinartz S
; Finkernagel F
; Adhikary T
; Rohnalter V
; Schumann T
; Schober Y
; Nockher WA
; Nist A
; Stiewe T
; Jansen JM
; Wagner U
; Müller-Brüsselbach S
; Müller R
Genome Biol
2016[May]; 17
(1
): 108
PMID27215396
show ga
BACKGROUND: Soluble protein and lipid mediators play essential roles in the tumor
environment, but their cellular origins, targets, and clinical relevance are only
partially known. We have addressed this question for the most abundant cell types
in human ovarian carcinoma ascites, namely tumor cells and tumor-associated
macrophages. RESULTS: Transcriptome-derived datasets were adjusted for errors
caused by contaminating cell types by an algorithm using expression data derived
from pure cell types as references. These data were utilized to construct a
network of autocrine and paracrine signaling pathways comprising 358 common and
58 patient-specific signaling mediators and their receptors. RNA sequencing based
predictions were confirmed for several proteins and lipid mediators. Published
expression microarray results for 1018 patients were used to establish clinical
correlations for a number of components with distinct cellular origins and target
cells. Clear associations with early relapse were found for STAT3-inducing
cytokines, specific components of WNT and fibroblast growth factor signaling,
ephrin and semaphorin axon guidance molecules, and TGF?/BMP-triggered pathways.
An association with early relapse was also observed for secretory
macrophage-derived phospholipase PLA2G7, its product arachidonic acid (AA) and
signaling pathways controlled by the AA metabolites PGE2, PGI2, and LTB4. By
contrast, the genes encoding norrin and its receptor frizzled 4, both selectively
expressed by cancer cells and previously not linked to tumor suppression, show a
striking association with a favorable clinical course. CONCLUSIONS: We have
established a signaling network operating in the ovarian cancer microenvironment
with previously unidentified pathways and have defined clinically relevant
components within this network.