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      A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome

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          Abstract

          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 TGFβ/BMP-triggered pathways. An association with early relapse was also observed for secretory macrophage-derived phospholipase PLA 2G 7, its product arachidonic acid (AA) and signaling pathways controlled by the AA metabolites PGE 2, PGI 2, and LTB 4. 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.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13059-016-0956-6) contains supplementary material, which is available to authorized users.

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          Most cited references29

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          Altered macrophage differentiation and immune dysfunction in tumor development.

          Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.
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            Roles of TGFbeta in metastasis.

            The TGFbeta signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFbeta can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFbeta signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFbeta therapies are currently being developed and tested in pre-clinical studies. However, targeting TGFbeta carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFbeta has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFbeta inhibitors for clinical use will require a deeper understanding of TGFbeta signaling, its consequences, and the contexts in which it acts.
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              Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors.

              Tumor-associated macrophages (TAM) are known to possess the immunosuppressive M2 macrophage phenotype. They contribute to tumor growth, invasion, and metastasis by producing various mediators. Macrophages, especially M2 polarized macrophages, preferentially express CD163 and CD204, but few studies have investigated macrophage phenotypes in human ovarian tumors. The purpose of the present study was therefore to present results on macrophage differentiation in human ovarian serous and mucinous epithelial tumors. The method focused on immunostaining of paraffin-embedded tumor samples. Almost all macrophages infiltrating tumor tissues expressed CD163 and CD204, indicating the phenotypic shift toward M2 macrophage. The numbers of CD68-positive macrophages as well as of CD163- and CD204-positive macrophages in borderline and malignant tumors were significantly higher than in benign tumors. They correlated well with histological gradient of malignancy. Macrophage colony-stimulating factor (also known as colony-stimulating factor; CSF-1), which is one of the cytokines considered to induce TAM to polarize toward an M2 phenotype, was then evaluated. CSF-1 expression in malignant tumor cells was significantly higher than that in benign tumor cells and correlated with histological malignancy. These results suggest that CSF-1 derived from tumor tissues induces macrophages to shift toward the M2 phenotype, which is considered to promote tumor growth.
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                Author and article information

                Contributors
                rmueller@imt.uni-marburg.de
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central (London )
                1474-7596
                1474-760X
                23 May 2016
                23 May 2016
                2016
                : 17
                : 108
                Affiliations
                [ ]Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany
                [ ]Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Hans-Meerwein-Str. 3, Marburg, 35043 Germany
                [ ]Metabolomics Core Facility and Institute of Laboratory Medicine and Pathobiochemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany
                [ ]Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany
                Article
                956
                10.1186/s13059-016-0956-6
                4877997
                27215396
                4cae8fc7-862c-46b0-8efd-636d1f9cf90a
                © Reinartz et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 December 2015
                : 15 April 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008672, Wilhelm Sander-Stiftung;
                Award ID: 2011.082.2
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Genetics
                ovarian carcinoma,tumor-associated macrophages,tumor microenvironment,malignancy-associated ascites,signaling network,arachidonic acid,il-10,tgfβ

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