The invasive phenotype of placenta accreta extravillous trophoblasts associates with loss of E-cadherin

•EMT is a program that converts immotile epithelial to migratory mesenchymal cells.•E-cadherin (E-CAD) is a mediator of EMT with an unknown role in placenta accreta.•Serum E-CAD levels did not differentiate normal from aberrant trophoblast invasion.•Extravillous trophoblast (EVT) of invasive placentas had variable E-CAD staining.•Local processing of E-CAD seems to be an important feature of accreta EVT invasion.

IntroductionEpithelial-to-mesenchymal transition (EMT) is a process of molecular and phenotypic epithelial cell alteration promoting invasiveness. Loss of E-cadherin (E-CAD), a transmembrane protein involved in cell adhesion, is a marker of EMT. Proteolysis into N- and C-terminus fragments by ADAM10 and presenilin-1 (PSEN-1) generates soluble (sE-CAD) and transcriptionally active forms. We studied the protein expression patterns of E-CAD in the serum and placenta of women with histologically-confirmed over-invasive placentation.MethodsThe patterns of expression and levels of sE-CAD were analyzed by Western blot, immunoassay, and immunoprecipitation. Tissue immunostaining for E-CAD, cytokeratin-7 (epithelial marker), vimentin (mesenchymal marker), ADAM10, PSEN-1 and β-catenin expression were investigated in parallel.ResultsN-terminus cleaved 80 kDa sE-CAD fragments were present in serum of pregnant women with gestational age regulation of the circulatory levels. Women with advanced trophoblast invasion did not display circulatory levels of sE-CAD different from those of women with normal placentation. Histologically, extravillous trophoblasts (EVT) closer to the placental-myometrial interface demonstrated less E-CAD staining than those found deeper in the myometrium. These cells expressed both vimentin and cytokeratin, an additional feature of EMT. EVT of placentas with advanced invasion displayed intracellular E-CAD C-terminus immunoreactivity predominating over that of the extracellular N-terminus, a pattern consistent with preferential PSEN-1 processing.DiscussionLocal processing of E-CAD may be an important molecular mechanism controlling the invasive phenotype of accreta EVT.