%0 Journal Article
%T Lysophosphatidic Acid Disrupts Junctional Integrity and Epithelial Cohesion in Ovarian Cancer Cells
%A Yueying Liu
%A Rebecca Burkhalter
%A Jaime Symowicz
%A Kim Chaffin
%A Shawn Ellerbroek
%A M. Sharon Stack
%J Journal of Oncology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/501492
%X Ovarian cancer metastasizes via exfoliation of free-floating cells and multicellular aggregates from the primary tumor to the peritoneal cavity. A key event in EOC metastasis is disruption of cell-cell contacts via modulation of intercellular junctional components including cadherins. Ascites is rich in lysophosphatidic acid (LPA), a bioactive lipid that may promote early events in ovarian cancer dissemination. The objective of this paper was to assess the effect of LPA on E-cadherin junctional integrity. We report a loss of junctional E-cadherin in OVCAR3, OVCA429, and OVCA433 cells exposed to LPA. LPA-induced loss of E-cadherin was concentration and time dependent. LPA increased MMP-9 expression and promoted MMP-9-catalyzed E-cadherin ectodomain shedding. Blocking LPA receptor signaling inhibited MMP-9 expression and restored junctional E-cadherin staining. LPA-treated cells demonstrated a significant decrease in epithelial cohesion. Together these data support a model wherein LPA induces MMP-9 expression and MMP-9-catalyzed E-cadherin ectodomain shedding, resulting in loss of E-cadherin junctional integrity and epithelial cohesion, facilitating metastatic dissemination of ovarian cancer cells. 1. Introduction Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. In 2010, approximately 21,880 women were newly diagnosed with EOC and 13,850 women died from complications due to disseminated intraperitoneal metastasis [1]. Clinically, tumors often involve the ovary and omentum, with diffuse, multifocal intraperitoneal metastases and malignant ascites. As 75% of women with EOC are initially diagnosed with previously disseminated intra-abdominal disease, a more detailed understanding of factors that promote successful metastasis can ultimately improve patient survival. In women with advanced EOC, obstruction of peritoneal lymphatics together with enhanced vascular permeability results in accumulation of malignant ascites, and the presence of ascites is an adverse prognostic factor [1¨C4]. Ascites is comprised of >200 proteins, tumor and inflammatory cells, and cytokines. A major bioactive component of EOC ascites is the lipid lysophosphatidic acid (LPA). Elevated LPA levels (up to >80£¿¦ÌM) are detectable in 98% of patients with EOC, including 90% of patients with stage I disease [5¨C10]. Multiple studies have shown that LPA contributes to tumor development, progression, and metastasis through binding to a subfamily of G protein-coupled receptors termed LPA receptors (LPAR), thereby effecting expression
%U http://www.hindawi.com/journals/jo/2012/501492/