Autotaxin and LPA 1 and LPA 5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 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. Implications: These findings suggest that tumor and stromal LPA receptors, in particular LPA 1 and LPA 5 , play different roles in invasion and the seeding of metastasis.

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

Fingerprint

Lysophosphatidic Acid Receptors
Melanoma
Neoplasm Metastasis
Neoplasms
lysophosphatidic acid
G-Protein-Coupled Receptors
Knockout Mice
Lung

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Autotaxin and LPA 1 and LPA 5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis . / Lee, Sue; Fujiwara, Yuko; Liu, Jianxiong; Yue, Junming; Shimizu, Yoshibumi; Norman, Derek D.; Wang, Yaohong; Tsukahara, Ryoko; Szabo, Erzsebet; Patil, Renukadevi; Banerjee, Souvik; Miller, Duane; Balazs, Louisa; Ghosh, Manik C.; Waters, Christopher; Oravecz, Tamas; Tigyi, Gabor.

In: Molecular Cancer Research, Vol. 13, No. 1, 01.01.2015, p. 174-185.

Research output: Contribution to journalArticle

Lee, Sue ; Fujiwara, Yuko ; Liu, Jianxiong ; Yue, Junming ; Shimizu, Yoshibumi ; Norman, Derek D. ; Wang, Yaohong ; Tsukahara, Ryoko ; Szabo, Erzsebet ; Patil, Renukadevi ; Banerjee, Souvik ; Miller, Duane ; Balazs, Louisa ; Ghosh, Manik C. ; Waters, Christopher ; Oravecz, Tamas ; Tigyi, Gabor. / Autotaxin and LPA 1 and LPA 5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis In: Molecular Cancer Research. 2015 ; Vol. 13, No. 1. pp. 174-185.
@article{2c0173fa0dbc44549829daad30440246,
title = "Autotaxin and LPA 1 and LPA 5 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 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. Implications: These findings suggest that tumor and stromal LPA receptors, in particular LPA 1 and LPA 5 , play different roles in invasion and the seeding of metastasis.",
author = "Sue Lee and Yuko Fujiwara and Jianxiong Liu and Junming Yue and Yoshibumi Shimizu and Norman, {Derek D.} and Yaohong Wang and Ryoko Tsukahara and Erzsebet Szabo and Renukadevi Patil and Souvik Banerjee and Duane Miller and Louisa Balazs and Ghosh, {Manik C.} and Christopher Waters and Tamas Oravecz and Gabor Tigyi",
year = "2015",
month = "1",
day = "1",
doi = "10.1158/1541-7786.MCR-14-0263",
language = "English (US)",
volume = "13",
pages = "174--185",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Autotaxin and LPA 1 and LPA 5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis

AU - Lee, Sue

AU - Fujiwara, Yuko

AU - Liu, Jianxiong

AU - Yue, Junming

AU - Shimizu, Yoshibumi

AU - Norman, Derek D.

AU - Wang, Yaohong

AU - Tsukahara, Ryoko

AU - Szabo, Erzsebet

AU - Patil, Renukadevi

AU - Banerjee, Souvik

AU - Miller, Duane

AU - Balazs, Louisa

AU - Ghosh, Manik C.

AU - Waters, Christopher

AU - Oravecz, Tamas

AU - Tigyi, Gabor

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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. Implications: These findings suggest that tumor and stromal LPA receptors, in particular LPA 1 and LPA 5 , play different roles in invasion and the seeding of metastasis.

AB - 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. Implications: These findings suggest that tumor and stromal LPA receptors, in particular LPA 1 and LPA 5 , play different roles in invasion and the seeding of metastasis.

UR - http://www.scopus.com/inward/record.url?scp=84921722737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921722737&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-14-0263

DO - 10.1158/1541-7786.MCR-14-0263

M3 - Article

VL - 13

SP - 174

EP - 185

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 1

ER -