Abstract
<div>Abstract<p>Autotaxin (ENPP2/ATX) and lysophosphatidic acid (LPA) receptors represent two key players in regulating cancer progression. The present study sought to understand the mechanistic role of LPA G protein–coupled receptors (GPCR), not only in the tumor cells but also in stromal cells of the tumor microenvironment. B16F10 melanoma cells predominantly express LPA<sub>5</sub> and LPA<sub>2</sub> receptors but lack LPA<sub>1</sub>. LPA dose dependently inhibited invasion of cells across a Matrigel layer. RNAi-mediated knockdown of LPA<sub>5</sub> relieved the inhibitory effect of LPA on invasion without affecting basal invasion. This suggests that LPA<sub>5</sub> exerts an anti-invasive action in melanoma cells in response to LPA. In addition, both siRNA-mediated knockdown and pharmacologic inhibition of LPA<sub>2</sub> reduced the basal rate invasion. Unexpectedly, when probing the role of this GPCR in host tissues, it was found that the incidence of melanoma-derived lung metastasis was greatly reduced in LPA<sub>5</sub> knockout (KO) mice compared with wild-type (WT) mice. LPA<sub>1</sub>-KO but not LPA<sub>2</sub>-KO mice also showed diminished melanoma-derived lung metastasis, suggesting that host LPA<sub>1</sub> and LPA<sub>5</sub> receptors play critical roles in the seeding of metastasis. The decrease in tumor cell residence in the lungs of LPA<sub>1</sub>-KO and LPA<sub>5</sub>-KO animals was apparent 24 hours after injection. However, KO of LPA<sub>1</sub>, LPA<sub>2</sub>, or LPA<sub>5</sub> did not affect the subcutaneous growth of melanoma tumors.</p><p><b>Implications:</b> These findings suggest that tumor and stromal LPA receptors, in particular LPA<sub>1</sub> and LPA<sub>5</sub>, play different roles in invasion and the seeding of metastasis. <i>Mol Cancer Res; 13(1); 174–85. ©2014 AACR</i>.</p></div>
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