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 PLA2 G7 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.