1. ¹Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
2. ²Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, OH, USA
3. ³Department of Obstetrics and Gynecology, Chonbuk National University Medical School, Chonju, Chonbuk, Korea
4. ⁴Department of Drug Discovery and Development, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
5. ⁵Harvard Institute of Proteomics, Harvard Medical School, Cambridge, MA, USA
6. ⁶Monash Institute of Medical Research, Clayton Victoria, Australia
7. ⁷Department of Obstetrics and Gynecology, Indiana University, Indianapolis, IN, USA

Correspondence: Dr Y Xu, Department of Obstetrics and Gynecology, Indiana University, 975 W Walnut St IB355A, Indianapolis, IN 46202, USA. E-mail: xu2@iupui.edu

Received 2 June 2006; Revised 14 August 2006; Accepted 19 September 2006; Published online 27 November 2006.

Abstract

Ovarian cancer is a highly metastatic disease. Lysophosphatidic acid (LPA) levels are elevated in ascites from ovarian cancer patients, but its potential role in ovarian cancer metastasis has just begun to be revealed. In this work, we show that LPA stimulates invasion of primary ovarian cancer cells, but not ovarian epithelial or borderline ovarian tumor cells, although these benign cells indeed respond to LPA in cell migration. We have found that LPA downregulates tissue inhibitor of metalloproteinases (TIMPs). TIMP2 and TIMP3 play functional role in LPA-induced invasion as negative regulators. G_i protein, phosphatidylinositol-3 kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), cytosolic phospholipase A₂ and urokinase type plasminogen activator (uPA) are required for LPA-induced cells invasion. TIMP3 may affect two independent downstream targets, vascular endothelial growth factor receptor and p38 MAPK. In vivo, LPA stimulates tumor metastasis in an orthotopic ovarian tumor model, which can be inhibited by a PI3K inhibitor, LY294002. In summary, LPA is likely a key component for promoting ovarian metastasis in vivo. LPA downregulates TIMP3, which may have targets other than metalloproteinases. Our in vivo metastasis mouse model is useful for studying the efficacy of therapeutic regimes of ovarian cancer.