LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2)

Gynecol Oncol. 2005 Jun;97(3):870-8. doi: 10.1016/j.ygyno.2005.03.004.

Abstract

Objective: Lysophosphatidic acid (LPA) stimulates ovarian tumor growth partially via induction of VEGF expression through transcriptional activation. Previous studies have shown that LPA induces epithelial ovarian cancer (EOC) in vitro metastasis. In this study, we examined the role of VEGF in LPA-induced EOC invasion and migration and underlying mechanisms.

Methods: The invasiveness of DOV13 cells was determined by in vitro basement membrane Matrigel invasion assay. Ovarian carcinoma cellular migration was quantified by the colloidal gold migration assay. Matrix metalloproteinase (MMP)-2 secretion and activation were detected by gelatin zymography. Urokinase type plasminogen activator (uPA) activity was determined by a coupled colorimetric assay measuring the activity of generated plasmin. Student's t test and one-way ANOVA were used for statistical analysis.

Results: Using a VEGF neutralizing monoclonal antibody (mAb), we show that LPA-induced EOC invasion is dependent upon VEGF. Using the selective VEGF receptor (VEGFR)-2 inhibitor, SU1498, LPA-induced EOC invasion and migration were significantly inhibited in a concentration-dependent manner. In addition, SU1498 inhibits MMP-2 secretion and uPA activity in ovarian cancer DOV13 cells. At 5 and 20 microM, SU1498 almost completely inhibited the activity of MMP-2 and uPA. SU1498 also decreases the LPA-induced increase of uPA activity in DOV13 cells.

Conclusions: Our results show that LPA-induced EOC invasion is at least partially mediated by VEGF. Further, the VEGFR-2-mediated signaling transduction pathway may be involved in LPA-induced EOC invasion and migration by regulating the secretion and activation of MMP-2 and uPA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cinnamates / pharmacology
  • Drug Interactions
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Lysophospholipids / antagonists & inhibitors
  • Lysophospholipids / pharmacology*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / chemically induced
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / physiology*

Substances

  • Antibodies, Monoclonal
  • Cinnamates
  • Lysophospholipids
  • Matrix Metalloproteinase Inhibitors
  • SU 1498
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 2
  • lysophosphatidic acid