Positive Feedback Between Vascular Endothelial Growth factor-A and Autotaxin in Ovarian Cancer Cells

Mol Cancer Res. 2008 Mar;6(3):352-63. doi: 10.1158/1541-7786.MCR-07-0143.

Abstract

Tumor cell migration, invasion, and angiogenesis are important determinants of tumor aggressiveness, and these traits have been associated with the motility stimulating protein autotaxin (ATX). This protein is a member of the ectonucleotide pyrophosphatase and phosphodiesterase family of enzymes, but unlike other members of this group, ATX possesses lysophospholipase D activity. This enzymatic activity hydrolyzes lysophosphatidylcholine to generate the potent tumor growth factor and motogen lysophosphatidic acid (LPA). In the current study, we show a link between ATX expression, LPA, and vascular endothelial growth factor (VEGF) signaling in ovarian cancer cell lines. Exogenous addition of VEGF-A to cultured cells induces ATX expression and secretion, resulting in increased extracellular LPA production. This elevated LPA, acting through LPA(4), modulates VEGF responsiveness by inducing VEGF receptor (VEGFR)-2 expression. Down-regulation of ATX secretion in SKOV3 cells using antisense morpholino oligomers significantly attenuates cell motility responses to VEGF, ATX, LPA, and lysophosphatidylcholine. These effects are accompanied by decreased LPA(4) and VEGFR2 expression as well as by increased release of soluble VEGFR1. Because LPA was previously shown to increase VEGF expression in ovarian cancer, our data suggest a positive feedback loop involving VEGF, ATX, and its product LPA that could affect tumor progression in ovarian cancer cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antibodies / pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Cyclic AMP / physiology
  • DNA Primers
  • Female
  • Gene Deletion
  • Humans
  • Lysophospholipids / physiology
  • Multienzyme Complexes / genetics*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Phosphodiesterase I / genetics*
  • Phosphoric Diester Hydrolases
  • Polymerase Chain Reaction
  • Pyrophosphatases / genetics*
  • RNA, Messenger / genetics
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor Receptor-1 / immunology
  • Vascular Endothelial Growth Factor Receptor-2 / immunology

Substances

  • Antibodies
  • DNA Primers
  • Lysophospholipids
  • Multienzyme Complexes
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Cyclic AMP
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Pyrophosphatases
  • lysophosphatidic acid