Cell type‐selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment

The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show...

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Published in:	Molecular oncology Vol. 13; no. 2; pp. 185 - 201
Main Authors:	Reinartz, Silke, Lieber, Sonja, Pesek, Jelena, Brandt, Dominique T., Asafova, Alina, Finkernagel, Florian, Watzer, Bernard, Nockher, Wolfgang Andreas, Nist, Andrea, Stiewe, Thorsten, Jansen, Julia M., Wagner, Uwe, Konzer, Anne, Graumann, Johannes, Grosse, Robert, Worzfeld, Thomas, Müller‐Brüsselbach, Sabine, Müller, Rolf
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-02-2019 John Wiley and Sons Inc Wiley
Subjects:	Ascites Ascites - metabolism Ascites cells autotaxin Binding sites CD163 antigen Cell culture Cell Line, Tumor Cytokines Development and progression Disease-Free Survival Female Gene expression Gene Expression Regulation, Neoplastic Humans Kinases Leukocyte migration lipid signaling Lymphocytes T Lysophosphatidic acid lysophospholipid Lysophospholipids - biosynthesis macrophage Macrophages Macrophages - metabolism Macrophages - pathology Mass spectrometry Mass spectroscopy Medical prognosis Medical research Metabolome Metabolomics Metastases Neoplasms, Cystic, Mucinous, and Serous - pathology Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Peritoneal fluid Peritoneum phospholipase Phospholipase A2 Receptors, Lysophosphatidic Acid - metabolism Ribonucleic acid RNA Secretome Signal Transduction T cells Treatment Outcome Tumor cells Tumor Microenvironment - genetics Up-Regulation - genetics Germany phospholipase macrophage lysophospholipid autotaxin ovarian cancer lipid signaling
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Summary:	The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl‐LPA species are strongly elevated in ascites versus plasma and are associated with short relapse‐free survival. Data derived from transcriptome and secretome analyses of primary ascite‐derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor‐associated macrophages play an essential role as main producers of PLA2G7 and autotaxin. The latter conclusion is consistent with mass spectrometry‐based metabolomic analyses of conditioned medium from ascites cells, which showed that tumor‐associated macrophages, but not tumor cells, are able to produce 20:4 acyl‐LPA in lipid‐free medium. Furthermore, our transcriptomic data revealed that LPA receptor (LPAR) genes are expressed in a clearly cell type‐selective manner: While tumor cells express predominantly LPAR1‐3, macrophages and T cells also express LPAR5 and LPAR6 at high levels, pointing to cell type‐selective LPA signaling pathways. RNA profiling identified cytokines linked to cell motility and migration as the most conspicuous class of LPA‐induced genes in macrophages, suggesting that LPA exerts protumorigenic properties at least in part via the tumor secretome. Lysophosphatidic acid (LPA) in the ovarian cancer microenvironment is produced via phospholipase PLA2 and autotaxin secreted by tumor‐associated macrophages (TAM). After binding to LPAR receptors on tumor cells, LPA induces the production of growth factors and cytokines and triggers matrix invasion, associated with an early disease recurrence in patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Silke Reinartz, Sonja Lieber, Jelena Pesek and Dominique T. Brandt contributed equally to this article.
ISSN:	1574-7891 1878-0261
DOI:	10.1002/1878-0261.12396