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Review
. 2012 Feb 1;4(2):a011908.
doi: 10.1101/cshperspect.a011908.

Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases

Paola Nisticò  1 , Mina J Bissell, Derek C Radisky
Affiliations
Review

Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases

Paola Nisticò et al. Cold Spring Harb Perspect Biol. .

Abstract

Epithelial-mesenchymal transition (EMT) is a physiological process in which epithelial cells acquire the motile and invasive characteristics of mesenchymal cells. Although EMT in embryonic development is a coordinated, organized process involving interaction between many different cells and tissue types, aspects of the EMT program can be inappropriately activated in response to microenvironmental alterations and aberrant stimuli, and this can contribute to disease conditions including tissue fibrosis and cancer progression. Here we will outline how EMT functions in normal development, how it could be activated in pathologic conditions-especially by matrix metalloproteinases-and how it may be targeted for therapeutic benefit.

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Figures

Figure 1.
Figure 1.
Developmental versus pathological EMT. (A) Developmental EMT is a process that involves the entire epithelial tissue. (a) Specification of cells that will undergo EMT occurs through coordination of cell–cell, cell-ECM, and soluble signals. (b) Degradation or disruption of the basement membrane is followed by cell ingression and morphogenesis of the retained epithelial cells to close the gap. (c) The fully detached cell undergoes phenotypic mesenchymal shift. (B) Activation of the EMT program in pathological conditions can occur in a disorganized and more cell-autonomous fashion.
Figure 2.
Figure 2.
Characteristics of epithelial and mesenchymal cells. (A) Epithelial cells are interconnected through tight junctions (gray), E-cadherin-based junctions (red), which are connected to the actin cytoskeleton, gap junctions (red/blue), and hemidesmosomes (cyan), which are connected to the cytokeratin-based intermediate filament cytoskeleton. Epithelial cells also have specialized cell-ECM interactions for adhesion to the laminin-rich basement membrane. (B) Mesenchymal cells show a shift to a vimentin-based intermediate filament cytoskeleton and altered composition of cell-ECM interactions optimized for adhesion to the collagen-rich interstitial matrix. Mesenchymal cells also produce abundant TGFb, growth factors (GF), and matrix metalloproteinases (MMPs), as well as components of the extracellular matrix.
Figure 3.
Figure 3.
Primary and secondary branching morphogenesis of the mammary gland. (Left) Whole mount of mouse mammary gland. (Inset, right) Primary (1°) branching occurs through bifurcation of the endbuds, whereas secondary (2°) branching involves many aspects of the EMT program, including breakdown of epithelial tissue structure, degradation of basement membrane, and acquisition of invasive characteristics, processes dependent on MMP-3, which is produced in response to morphogenic signals by the surrounding stromal cells.
Figure 4.
Figure 4.
EMT facilitates tumor progression. (A) EMT stimulates proinvasive and antiapoptotic processes that facilitate metastasis. (B) EMT can produce reactive stromal cells, which drive tumor initiation and progression through disruption of the surrounding ECM and production of soluble tumorigenic factors. (C) EMT mediators contribute to the cancer stem cell phenotype, which confers resistance to radiation or chemotherapeutic agents and increased ability of tumor regrowth.
Figure 5.
Figure 5.
EMT facilitates evasion of immunosurveillance. (A) Tumor cells isolated from MMTV-Her2/neu mice have an epithelial morphology and express the cell-surface rat Her2/neu antigen. (B) When reimplanted into nontransgenic mice, these tumor cells are initially targeted by the immune system, but eventually regrow. (C) Isolated tumor cells from the xenografted mice show a mesenchymal morphology and do not display the Her2/neu antigen. (D) Reinjection of these cells into MMTV-Her2/neu mice leads to rapid tumor regrowth. (E) Isolation of secondary tumors reveals an epithelial morphology and reexpression of Her2/neu. (Adapted from Reiman et al. 2010.)
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