Lysophosphatidic Acid Disrupts Junctional Integrity and Epithelial Cohesion in Ovarian Cancer Cells

Abstract EN

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.