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39: The invasive phenotype of the placenta accrete extravillous trophoblasts (EVTs) is characterized by epithelial-mesenchymal-transition (EMT) and loss of E-cadherin (E-CAD)

      Objective

      EMT is a process characterized by molecular and phenotypic alterations resulting in increased invasiveness and metastasis of cancer cells. Loss of E-CAD, a transmembrane protein involved in cell-cell adhesion, is a marker of EMT. Proteolysis of E-CAD into C- and N-terminus fragments by ADAM10 and presenilin-1, respectively, generates soluble forms (sE-CAD) which act as transcription factors. Here, we interrogated the expression patterns of E-CAD in the serum and EVTs of women with invasive placentation.

      Study Design

      A cross-sectional study was conducted to determine the serum sE-CAD levels in nonpregnant women (n=15), healthy pregnant women (GA: 27±2 weeks; n=21) and patients with histologically-confirmed invasive placentation (n=21, GA: 29±1 weeks; accreta, n=3; increta, n=13; percreta, n=5), prior to blood transfusion or steroids. Expression level of sE-CAD was assessed by Western blot and ELISA. Myometrial-villous sections of hysterectomy specimens were immunostained for E-CAD (C- and N-terminus domains), cytokeratin-7 (epithelial marker), vimentin (mesenchymal marker), ADAM10 and presenilin-1. Normal placental bed biopsies (n=4) served as control (CRL).

      Results

      1) In healthy CRLs, systemic sE-CAD levels were unaffected by pregnancy status or GA (P=.377); 2) Women with advanced trophoblast invasion (increta & percreta) display specific serum immunoreactive bands and lower levels of sE-CAD independent of GA (P=.018); 3) EVTs of accreta but not CRLs immunostained for both cytokeratin and vimentin, consistent with EMT; 4) E-CAD intracellular C-terminus immunoreactivity predominated over that of the extracellular N-terminus, consistent with preferential presenilin-1 processing; 5) Histological scoring showed that EVTs near the myometrial-villous junction had less E-CAD expression compared to EVTs deeper in the myometrium (P=.001).

      Conclusion

      We provide evidence that in placenta accreta EVTs display prototype EMT features. Processing of the C-terminus of E-CAD seems to be an important feature of the molecular mechanisms controlling the invasive phenotype of EVTs.