Fig. 5.

Remodelling of the tumour microenvironment by bioactive lipids. Eicosanoids and lysophosphatidic acid species can be secreted into the surrounding microenvironment and stimulate cell proliferation through both autocrine and paracrine mechanisms. Arachidonic acid (AA) serves as the main precursor for eicosanoid synthesis, and these include pro-inflammatory prostaglandins, leukotrienes and eicosatetraenoic acids. PGE2 can stimulate cell proliferation through autocrine and paracrine signalling, and this is largely mediated through the activation of EP1–EP4 receptors. Moreover, prostaglandins contribute to immunosuppression by attenuating the activation of natural killer, dendritic and cytotoxic T cells. Lysophosphatidic acids are also relevant signalling molecules, and can be produced intracellularly from glycerol-3-phosphate or phosphatidic acid, or extracellularly through the enzyme autotaxin, which uses existing phospholipids, such as phosphatidylglycerols and phosphatidylethanolamines as substrates. Similar to eicosanoids, lysophosphatidic acids exert their tumorigenic effects by binding to the LPAR family of G-protein-coupled receptors. Abbreviations: RTK, receptor tyrosine kinase; LOX, lipoxygenase; COX, cyclo-oxygenase; PGG2, prostaglandin G2; PGH2, prostaglandin H2; PGE2, prostaglandin E2; PGI2, prostaglandin I2; TXA2, thromboxane A2; HETE, hydroxytetraenoic acid; EP, prostaglandin E2 receptor; NK, natural killer cell; G3P, glyceraldehyde 3-phosphate; GPAT, glycerol-3-phosphate acyltransferase; PA, phosphatidic acid; PLA2, phospholipase A2; LPA, lysophosphatidic acid; LPAR, lysophosphatidic acid receptor; ATX, autotaxin.