LPA receptors in ovarian cancer cells as potential therapeutic targets for blocking metastatic spread Free

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It is known from the work by our laboratory and others that lysophophatidic acid (LPA) levels increase in the blood and ascites of patients with early and advanced stages of ovarian cancer, when compared to healthy controls or patients with benign diseases. In a recent work we demonstrate that ovarian cancer cells secrete LPA, when they come in contact with laminin, and subsequently stimulate cell migration in an autocrine fashion via the LPA3 receptor (Sengupta et.al FASEBJ, 2003). In this work, we demonstrated the role of LPA in regulating the invasive properties of ovarian cancer cells. Primary ovarian cancer cells responded to LPA and it is cancer stage specific. While borderline tumor cells and stage I tumor cells did not respond to LPA, stage III tumor cells had a high degree of invasion in response to LPA. Our results also indicated that LPA stimulated TIMP deactivation in cells leading to an increased invasion. LPA1 and LPA3 inhibitor VPC 12249 completely inhibited the invasive property of cells in vitro. Thus we hypothesized the involvement of both LPA1 and LPA3 receptors in invasion. Using pharmacological inhibitors and genetic manipulations we demonstrate that LPA –dependent invasion was probably LPA1 specific and PI3 Kinase dependent. Experiments also reveal that this invasion is p38 and cPLA2 dependent and pERK independent. Thus inhibition of LPA specific receptors can be of potential therapeutic importance. We have also successfully generated a mouse model of ovarian cancer, and we demonstrated that in vivo LPA stimulated metastasis of ovarian cancer cells, particularly in the mesentery, bowels, liver, body wall and the diaphragm. Inhibitor trials in vivo are currently under investigation.