A novel laminin-induced lysophosphatidic acid autocrine loop in the migration of ovarian

We have reported previously that levels of lysophosphatidic acid (LPA) are elevated in the blood and ascites from patients with ovarian cancer. LPA stimulates proliferation of ovarian cancer cells and has been proposed as an autocrine growth factor. Here, we show that a novel autocrine loop of LPA promotes the imigration of ovarian cancer cells, which is a critical step of tumor metastasis. We report that laminin, but not other extracellular matrix proteins, induces LPA production in ovarian cancer cells. A neutralizing antibody against beta(1) integrin and a calcium-independent phospholipase A(2)-specific inhibitor, HELSS, block both LPA production and the haptotactic activity of laminin. Exogenously added LPA restores the migratory ability of HEY ovarian cancer cells to laminin. These data suggest that laminin-induced cell migration is mediated by LPA. We further show that a specific receptor for LPA, LPA(3), is required for mediating the chemotactic activity of LPA. In addition, we show that cytosolic PLA(2) is required for cell migration and its activation is phosphatidylinositol-3 kinase-dependent. These findings have revealed a new mechanism of crosstalk between a beta(1) integrin receptor and a G protein-coupled receptor.