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

Abstract

UNLABELLED:

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.

• Authors: 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
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 1 Pg. 174-85 (Jan 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 25158955 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• LPAR5 protein, mouse
• Receptors, Lysophosphatidic Acid
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase

Topics

• Animals
• Carcinogenesis (genetics)
• Humans
• Lung Neoplasms (genetics, pathology, secondary)
• Melanoma, Experimental (genetics, pathology)
• Mice
• Mice, Knockout
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis
• Phosphoric Diester Hydrolases (genetics)
• Receptors, Lysophosphatidic Acid (genetics)
• Signal Transduction (genetics)
• Tumor Microenvironment