title: A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome.
abstract: 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.
  
  
  
  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 TGFβ/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.
  
  
  
  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.
authors.affiliation: Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Reinartz
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Finkernagel
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Adhikary
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Rohnalter
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Schumann
authors.affiliation: Metabolomics Core Facility and Institute of Laboratory Medicine and Pathobiochemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schober
authors.affiliation: Metabolomics Core Facility and Institute of Laboratory Medicine and Pathobiochemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: W Andreas
authors.initials: WA
authors.lastname: Nockher
authors.affiliation: Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nist
authors.affiliation: Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.affiliation: Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Jansen
authors.affiliation: Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wagner
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043, Germany. rmueller@imt.uni-marburg.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta
keywords: Arachidonic acid; IL-10; Malignancy-associated ascites; Ovarian carcinoma; Signaling network; TGFβ; Tumor microenvironment; Tumor-associated macrophages