Autotaxin and LPA1 and LPA5 Receptors Exert Disparate Functions in Tumor Cells versus the Host Tissue Microenvironment in Melanoma Invasion and Metastasis

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(5) and LPA(2) receptors but lack LPA(1). LPA dose dependently inhibited invasion of cells across a Matrigel layer. RNAi-mediated knockdown of LPA(5) relieved the inhibitory effect of LPA on invasion without affecting basal invasion. This suggests that LPA(5) exerts an anti-invasive action in melanoma cells in response to LPA. In addition, both siRNA-mediated knockdown and pharmacologic inhibition of LPA(2) 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(5) knockout (KO) mice compared with wild-type (WT) mice. LPA(1)-KO but not LPA(2)-KO mice also showed diminished melanoma-derived lung metastasis, suggesting that host LPA(1) and LPA(5) receptors play critical roles in the seeding of metastasis. The decrease in tumor cell residence in the lungs of LPA(1)-KO and LPA(5)-KO animals was apparent 24 hours after injection. However, KO of LPA(1), LPA(2), or LPA(5) did not affect the subcutaneous growth of melanoma tumors. (C) 2014 AACR.