Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression

Abstract

Epithelial-mesenchymal transition (EMT) describes the differentiation (Fig. 1). EMT is therefore envisioned as a differentiation or morphogenetic process in which new tissue types are generated during embryogenesis, and which contributes to the pathogenesis of disease, such as metastatic cancer and tissue fibrosis.(2-5) The inverse process of mesenchymalepithelial transition (MET) describes how transitory mesenchymal cells generate polarized epithelia after migration and homing into new sites of tissue formation (Fig. 1). MET has been described in the context of embryonic development and is also perturbed pathologically in fibrotic disorders.(5) Morphogenetic processes such as EMT or MET are guided by the functional interplay of many signal transduction pathways, usually initiated by secreted polypeptide factors, which aim at regulating a new set of transcriptional and post-translational events, leading to the generation of new cellular phenotypes. Here, we discuss the role of different pathways in the control of EMT during embryogenesis and in disease. EMT is important during embryogenesisDuring the early stages of embryogenesis, the three germ layers, ectoderm, mesoderm and endoderm, form via an ontogenetic process called gastrulation (which stands for gut formation). While gastrulation in lower chordates involves movements of epithelial cell sheets, (6) in higher vertebrates, the same process evolved a dependency on EMT, which leads to the formation of migratory mesenchyme that progresses along the primitive streak and populates new areas of the embryo that will develop into mesoderm and endoderm.(1) Fibroblast growth factor (FGF) signaling via receptor tyrosine kinases (RTK) promotes mesodermal formation and mesenchymal cell migration through the primitive streak.(7) An important target of FGF signaling during gastrulation is the master regulator of EMT, Snail, which directly represses expression of the epithelial integral component of adherens junctions, E-cadherin.(7 -9) Furthermore, Wnt signaling via β-catenin and its nuclear partner LEF-1 is implicated in the EMT process during gastrulation, and stabilization of β-catenin accelerates the emergence of premature EMT in the ectoderm. (10,11) At a later stage of embryogenesis, epithelial cells from the neural tube in the dorsal side of the embryo, the neural crest, undergo EMT, and the mesenchymal cells produced often migrate long distances to new tissue areas, in order to differentiate into several new mesenchymal cell types such as somites, bone and chondrocytes.(6) Neural crest EMT is regulated by dosedependent actions of bone morphogenetic proteins (BMP), which are members of the transforming growth factor (TGF)-β superfamily, and a cohort of transcription factors, including paired-box, high-mobility group (HMG), winged-helix transcription factors and Snail. (12) In addition to neural crest EMT, members of the TGF-β superfamily cause palatal EMT in the mouse in order to create the connective tissue across the palate. (13) This action is mainly attributed...

Characterization of gene expression and activated signaling pathways in solid-pseudopapillary neoplasm of pancreas

“…Interestingly, the expression of epithelial-mesenchymal transition-related genes is linked with activation of the Wnt/b-catenin, Notch, and Hedgehog signaling pathways. 30,[38][39][40][41] We propose that solid-pseudopapillary neoplasm is characterized by activation of Wnt/b-catenin, Hedgehog, androgen receptor signaling pathways and epithelial-mesenchymal transition based on the signature of differentially expressed mRNAs in solid-pseudopapillary neoplasm. Analysis of micro-RNA expression profiles suggests that a large number of solid-pseudopapillary neoplasm-specific upregulated genes belonging to the Wnt/b-catenin, Hedgehog, and androgen receptor signaling pathways are associated with downregulated microRNAs.…”

Transcriptional regulation of cell polarity in EMT and cancer

“…Although still preliminary, the evidence available suggests that components of the PAR polarity complex are not direct targets of EMT transcriptional regulators, but rather they can be modulated in response to different oncogenes, tumour suppressors or EMT regulatory signals (reviewed by Lee and Vasioukhin, 2008). TGF-b is one of the more robust cues inducing EMT in different model systems (reviewed by Zavadil and Bottinger, 2005), leading to the upregulation of several EMT inducers, including SNAI1/SNAI2, ZEB1, Twist and the Id factors through Smad-dependent and Smad-independent pathways (Peinado et al, 2003;Kondo et al, 2004;Thuault et al, 2006;Moustakas and Heldin, 2007). Recent insights into the regulation of cell polarity by TGF-b during EMT have converged on the PAR complex.…”

Potential roles of N-glycosylation in cell adhesion

“…One important feature of EMT is increased cell motility via a decrease in cell-cell adhesion and increase in integrin-mediated cell migration. Different signaling pathways, for example, receptor tyrosine kinase (RTK), Notch, Wnt and TGF-β, are known to provide the necessary stimuli that modulate gene expression and trigger EMT and cell motility [60]. In fact, there is a bidirectional regulatory mechanism between Ecadherin-mediated cell-cell adhesion and GnT-III expression.…”