Autotaxin and LPA1 and LPA5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis

Sue Chin Lee, Yuko Fujiwara, Jianxiong Liu, Junming Yue, Yoshibumi Shimizu, Derek D. Norman, Yaohong Wang, Ryoko Tsukahara, Erzsebet Szabo, Renukadevi Patil, Souvik Banerjee, Duane D. Miller, Louisa Balazs, Manik C. Ghosh, Christopher M. Waters, Tamas Oravecz, Gabor J. Tigyi

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

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 LPA5 and LPA2 receptors but lack LPA1 LPA dose dependently inhibited invasion of cells across a Matrigel layer. RNAi-mediated knockdown of LPA5 relieved the inhibitory effect of LPA on invasion without affecting basal invasion. This suggests that LPA5 exerts an anti-invasive action in melanoma cells in response to LPA. In addition, both siRNA-mediated knockdown and pharmacologic inhibition of LPA2 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 LPA5 knockout (KO) mice compared with wild-type (WT) mice. LPA1-KO but not LPA2-KO mice also showed diminished melanoma-derived lung metastasis, suggesting that host LPA1 and LPA5 receptors play critical roles in the seeding of metastasis. The decrease in tumor cell residence in the lungs of LPA1-KO and LPA5-KO animals was apparent 24 hours after injection. However, KO of LPA1, LPA2, or LPA5 did not affect the subcutaneous growth of melanoma tumors. Implications: These findings suggest that tumor and stromal LPA receptors, in particular LPA1 and LPA5, play different roles in invasion and the seeding of metastasis.

Original languageEnglish
Pages (from-to)174-185
Number of pages12
JournalMolecular Cancer Research
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2015

Bibliographical note

Publisher Copyright:
©2014 AACR.

ASJC Scopus subject areas

  • General Medicine

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