title: Autotaxin and LPA1 and LPA5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis.
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.
  
  
  CONCLUSIONS
  These findings suggest that tumor and stromal LPA receptors, in particular LPA1 and LPA5, play different roles in invasion and the seeding of metastasis.
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Sue-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Yoshibumi
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Norman
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Szabo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Souvik
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Louisa
authors.initials: L
authors.lastname: Balazs
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Manik C
authors.initials: MC
authors.lastname: Ghosh
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.affiliation: Immunology and Oncology, Lexicon Pharmaceuticals, The Woodlands, Texas.
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee. gtigyi@uthsc.edu.
authors.forename: Gabor J
authors.initials: GJ
authors.lastname: Tigyi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D059016:Tumor Microenvironment; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C548235:LPAR5 protein, mouse