In a range of human
cancers,
tumorigenesis is promoted by activation of the
endothelin A receptor (ET(A)R)/
endothelin-1 (ET-1) axis. ET-1 and ET(A)R are overexpressed in primary and metastatic ovarian
carcinomas, and high levels of ET-1 are detectable in patient
ascites, suggesting that ET-1 may promote
tumor dissemination. Moreover, in these
tumors, engagement of ET(A) receptor by ET-1 triggers
tumor growth, survival, angiogenesis, and invasiveness. Thus, ET-1 enhances the secretion of
matrix metalloproteinases, disrupts intercellular communications, and stimulates cell migration and invasion. Therefore, we investigated the role of the ET-1/ET(A)R autocrine axis in promoting epithelial to mesenchymal transition (EMT) in ovarian
tumor cells, a key event in
cancer metastasis, in which epithelial cells depolarize, disassemble cell-cell contacts, and adopt an invasive phenotype. Here, we examine the potential role of ET-1 in regulating cell morphology and behavior and epithelial and mesenchymal
proteins employing an in vitro 3-D culture system. We found that in 3-D serum-free
collagen I gel cultures, HEY and OVCA 433 ovarian
carcinoma cells undergo fibroblast-like morphologic changes between 3 and 5 days of ET-1 treatment. In these cells, ET-1 induces loss of adherens and
tight-junction protein expression,
E-cadherin,
beta-catenin, and zonula occludens-1, and gain of
N-cadherin and
vimentin expression. These results confirm the ability of ET-1 to promote EMT, a metastable process involving sustained loss of epithelial markers and gain of mesenchymal markers. Collectively, these findings provide evidence of a critical role for the ET-1/ET(A)R axis during distinct steps of ovarian
carcinoma progression, thus underlining this axis as a potential target in the treatment of
ovarian cancer.