Abstract
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.
Highlights
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States
Primary EOC cells express abundant E-cadherin; E-cadherin staining in metastatic lesions is less prevalent [2, 3]
It was previously demonstrated that inhibition of the activity of urinary type plasminogen activator could block lysophosphatidic acid (LPA)-induced Ecadherin junction loss [30], incubation of EOC cells with LPA in the presence of the inhibitor uPA-Stop did not result in maintenance of junctional integrity (Figure 2)
Summary
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. 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 improve patient survival. 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 of proteases and growth factors and modulating migration of a variety of cells [11,12,13,14,15,16,17,18,19]. Primary differentiated EOC display abundant expression of the cell-cell junctional protein E-cadherin; reduced E-cadherin staining is found in late-stage carcinomas and data suggest that loss of E-cadherin expression or function is a factor in EOC progression from well-differentiated lesions to poorly differentiated tumors and metastases [2,3,4]. As matrix metalloproteinases (MMPs) are implicated in Ecadherin ectodomain shedding [23,24,25,26] and LPA is linked to altered MMP expression [12,13,14], the current study was designed to evaluate a potential functional link between LPA, posttranslational regulation of E-cadherin function, and epithelial cohesion in EOC
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