The emerging role of lysophosphatidic acid in cancer

Key Points Lysophosphatidic acid (LPA) is a serum phospholipid with growth-factor-like activities for many cell types. It acts through specific G-protein-coupled receptors on the cell surface. LPA stimulates cell proliferation, migration and survival. In addition, LPA induces cellular shape changes, increases endothelial permeability and inhibits gap-junctional communication between adjacent cells. LPA promotes wound healing in vivo and suppresses intestinal damage following irradiation. LPA receptors couple to multiple signalling pathways that are now being clarified. These pathways include those initiated by the small GTPases RAS, RHO and RAC, with RAS controlling cell-cycle progression and RHO/RAC signalling having a dominant role in (tumour) cell migration and invasion. Significant levels (>1 μM) of bioactive LPA are detected in various body fluids, including serum (but not plasma), saliva, follicular fluid and malignant effusions. The mechanisms by which bioactive LPA is produced were unknown until recently. Recent evidence shows that LPA is produced extracellularly from lysophosphatidylcholine by 'autotaxin' (ATX/lysoPLD). ATX/lysoPLD is a ubiquitous exo-phosphodiesterase that was originally identified as an autocrine motility factor for melanoma cells and is implicated in tumour progression. Through local production of bioactive LPA, ATX/lysoPLD might support an invasive microenvironment for tumour cells and therefore contribute to the metastatic cascade. Both LPA receptors and ATX/lysoPLD are aberrantly expressed in several cancers. The use of inhibitory drugs directed against LPA receptors and/or ATX/lysoPLD could be effective in suppressing tumour metastasis. The bioactive phospholipid lysophosphatidic acid (LPA) stimulates cell proliferation, migration and survival by acting on its cognate G-protein-coupled receptors. Aberrant LPA production, receptor expression and signalling probably contribute to cancer initiation, progression and metastasis. The recent identification of ecto-enzymes that mediate the production and degradation of LPA, as well as the development of receptor-selective analogues, indicate mechanisms by which LPA production or action could be modulated for cancer therapy.