Table 3.

Summary of alterations during the plasma membrane transformation versus epithelial-mesenchymal transition and comparison to animal models.

Category	Alteration	Plasma membrane transformation	Epithelial-mesenchymal transition	Animal implantation models
Apical membrane	Microvilli	Loss of microvilli leads to apical flattening and thus facilitates adhesion	Loss of microvilli causes apical flattening	Loss of microvilli leads to a smooth apical surface in mice (51)
	Actin-rich apical protrusions	Up-regulation of pinopods co-localized with vesicles containing LIF contribute to blastocyst adhesion and implantation	Formation of actin-rich invadopodia co-localized with vesicles containing MMPs aid tumor cell invasion (52)	LIF null mice fail to develop apical pinopods and no implantation is observed (53)
	Integrins	Integrin αVβ3 up-regulation and apical recruitment of integrins contribute to blastocyst adhesion	Increased apical integrin αVβ3 expression and integrin clustering at the leading edge contribute to tumor cell invasion (54)	Increased expression of integrin αVβ3 is observed in mouse luminal surface at the time of implantation and blockade of integrin αVβ3 impairs implantation (55, 56),
	Mucins	MUC-1 and MUC-4 down-regulation and MUC-2 up-regulation facilitates adhesion	MUC-1 and MUC-4 play a crucial role in tumorigenesis, invasion, and metastasis (57)	Substantial reduction of MUC-1 and loss of MUC-4 occur before implantation in rat facilitates adhesion (58, 59),
Lateral membrane	Tight junctions	Tight junctions become morphologically “tighter” and increase in depth 3-fold down the lateral membrane. Claudin-3 and claudin-10 expression is increased	Tight junctions are lost, contributing to cell individualization. Claudin-1, claudin-4 and claudin-10 are differentially expressed (60, 61),	Lateral tight junctions also increase in complexity on the day of implantation in both mouse and rat models. Claudin-3 shift localization to apical surface while Claudin-10 is undetectable in luminal epithelium in mice (48)
	Adherens junctions	Adherens junctions are displaced and E-cadherin down-regulated, contributing to reduced cell-cell adhesion. This is associated with reduced expression of Crumbs, Stardust, αPKC, and Scribble	E-cadherin endocytosis leads to adherens junction dissolution, thus facilitating cell individualization. This may be associated with Crumbs internalization (62)	E-cadherin expression is down-regulated and redistributed from basal and lateral regions to a more apicolateral region (63)
	Terminal web	Actin polymerization, mediated by RhoA, and dissociation with ERM proteins, regulated by PC6, contributes to cytoskeletal alterations and apical flattening	Actin polymerization, mediated by Rho GTPases, and dissociation with ERM proteins may contribute to cytoskeletal alterations and apical flattening (64). However, increased moesin expression may contradict this (65)	Dysregulation of RhoA impair embryo implantation in mice. Inhibit PC6 block embryo implantation in mice (66, 67),
Basal membrane	Focal adhesions	Focal adhesions disruption facilitates cell individualization	Focal adhesions disassembly facilitates cell individualization from invasion (32)	In rat model, focal adhesion proteins disassemble along the basal membrane at the time of implantation (68)
Epithelial-stromal communication	Direct stromal-epithelial signaling	Direct stromal-epithelial cell signaling in the endometrium may regulate the events of the plasma membrane transformation	Direct tumor-stromal communication is involved in the differential regulation of key regulators for tumorigenesis (69)	WNT pathway in the stroma modulates E-cadherin-β-catenin complex in the uterine epithelium, thus regulating apical-basal polarity (70)
	Stromal cell-derived factors	Decidualized stromal cell-derived factors may be involved in the regulation of the plasma membrane transformation	Stromal-cell derived factors contribute to tumorigenesis (71)	Different to humans, the transformation of stroma into secretory decidual cells is triggered by embryo attachment (72)

Similarity and difference compared to PMT were accordingly indicated in green and red in both EMT and animal models. Black indicates incomparable. Abbreviations: LIF, leukemia inhibitory factor; MMPs, matrix metalloproteinases; MUC, mucin; αPKC, atypical protein kinase C; RhoA, Ras homolog family member A; ERM, ezrin, radixin, and moesin; PC6, proprotein convertase 5/6.