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Epithelial cell plasticity is associated with coordinated changes in cell adhesion and migratory behavior. The cell-cell adhesion protein E-cadherin regulates the functional integrity of epithelia by mediating specific intercellular adhesion. E-cadherin is a well-established invasion/tumor suppressor. Dynamic transcriptional regulation is a major mechanism of controlling E-cadherin expression during embryogenesis and malignant progression of various epithelial tumors. A variety of transcription regulators implicated in both embryonic development and tumorigenesis have been described to regulate E-cadherin expression in a reversible way.

The cadherin-catenin system of cell-cell adhesion molecules plays a key role in determining cellular and tissue morphogenesis. The normal function of this molecular complex is indispensable during various stages throughout development, not only for determining the proper adhesive interactions between neighboring cells, but also for transducing the signals elicited by the Wnt pathway, mostly by β-catenin. The dual role of β-catenin in the assembly of cell-cell adherens junctions and its role as a cotranscriptional activator of target genes in the Wnt pathway is often disrupted in cancer cells. In this perspective, we discuss the interplay between the adhesive and signaling roles of the cadherin-catenin system, its regulation by various mechanisms, with special emphasis on its role in the development of cancer.

Transitions between epithelial and mesenchymal cell phenotypes occur as part of normal organ development and wound healing, and are also observed in cancer, fibrosis and other diseases. Although the latter processes involve dysregulated interconversion of epithelial and mesenchymal cell phenotypes, the molecular mechanisms and sequences of cellular changes often closely resemble events that occur as a part of normal development and tissue repair. While primarily epithelial to mesenchymal transition (EMT) has been implicated in cancer and fibrosis, both EMT and mesenchymal to epithelial transition (MET) occur during organogenesis and development.

IGFs (insulin-like growth factors) are peptides known to stimulate a wide range of actions on different tissues. Indeed, IGFs can stimulate anabolism, acute metabolic effects as well as enhancing more chronic effects such as cell proliferation and differentiation together with protecting cells from apoptosis. Recently, it was shown that IGFs induce an epithelial to mesenchymal transition (EMT), a crucial morphogenic event during development and transformation. Here, the cellular and molecular aspects of IGF-induced EMT are reviewed. Major signaling pathways downstream of IGFs are described in order to introduce molecules that are believed to convey the EMT signal. The roles and targets of these molecules are analysed. The importance of IGFs in cellular events which when dysregulated lead to neoplasia is discussed in this review.

The transforming growth factor β (TGFβ) is involved in a whole range of biological functions, from cell growth to cell differentiation and apoptosis. The role of TGFβ in epithelial-mesenchymal-transitions (EMTs) has been shown for both embryonic development and tumorigenesis. All three TGFβ mammalian isoforms-TGFβl, TGFβ2 and TGFββcan regulate EMTs, with distinct outcomes depending on the tissue and on the state of cell differentiation. This diversity in the TGFβ response relies on a complex network of signals starting with different sets of TGFβ receptors and subsequently involving distinct TGFβ-dependent pathways. The purpose of this review is to recapitulate the current knowledge on the various signaling pathways—including the Smads, Ras, p38MAPK, RhoA and PI3K-which, upon activation by TGFβ can together give rise to TGFβ—induced EMT phenotypes.

This contribution is to discuss key elements of the intracellular signaling cascades that bring about the cellular transformation referred to as epithelium-to-mesenchyme transition (EMT). EMT can be defined as the events that allows epithelial cells to dissociate from the tissue from which they originate and to migrate freely. EMT is therefore thought to play a fundamental role during the early steps of invasion and metastasis of carcinoma cells. Among biological agents which have been identified as inducers of EMT are a number of cytokines and extracellular matrix macromolecules. The coordinated changes in cell morphology, associated with the induction of cell motility and the disruption of intercellular junctions, are the consequence of signaling cascades emanating from the activation of the receptors specific for the inducing molecules and leading to changes in gene expression. Two of the transduction cascades that play a crucial role in the generation of EMT, namely the Src kinase family and the Ras signal, are discussed extensively with respect to their contribution of scattering signals.

Cell-cell adhesions are rearranged dynamically during tissue development and tumor metastasis. Recently, Rho-family GTPases, including RhoA, Rac1, and Cdc42, have emerged as key regulators of cadherin-mediated cell-cell adhesion. Following the identification and characterization of regulators and effectors of Rho GTPases, signal transduction pathways from cadherin to Rho GTPases and, in turn, from Rho GTPases to cadherin are beginning to be clarified.

Wnt signaling lies at the heart of metazoan development. The Wnt pathway bifurcates a number of times and regulates cell polarity, migration, adhesion and gene expression. I review the complexity of this network with a focus on the role of SOX proteins in its regulation.

Classical cadherin adhesion molecules are not only essential for the formation of cell-cell junctions but also act as adhesion-activated signaling receptors involved in a diverse range of physiological processes. Cadherins through their association with catenin proteins interact with the actin cytoskeleton and cadherin-mediated signaling pathways, acting in part through Rho GTPases, regulate cadherin anchoring to the actin cytoskeleton. The microtubule (MT) network recendy emerged as having a role in cadherin-mediated cell-cell adhesion. Indeed, MT have been shown to serve as tracks for directed cadherin-containing vesicles movement toward the cell periphery and for the turnover of the junction. In addition, cadherin-based adhesion regulates MT dynamics, which become stabilized. Finally recent data have proposed that association of proteins of the catenin family to MT might be important for linking the MT ends to the F-actin-rich cortex and thus orienting mitotic spindles and the placement of the cytokinetic furrow during cell division.

The epithelial to mesenchymal transition (EMT) is characterized by the loss of epithelial characteristics and the gain of mesenchymal attributes in epithelial cells. It has been associated with physiological and pathological processes requiring epithelial cell migration and invasion. Initially, EMT was observed in embryological and adult development with many well characterized examples including the conversions of epiblast to primary mesenchyme (gastrulation), somite to sderotome, somite to dermis, myotome to migratory myoblast, dorsal neural tube to neural crest, placodal ectoderm to cranial ganglion precursor, intermediate mesoderm to nephric mesenchyme, lateral mesoderm to connective/muscular tissue, endocardium to cardiac cushion mesenchyme and trophectoderm invasion.[],[] In addition, evidence is mounting to support an important role of EMT pathways in the progression of carcinoma to metastasis providing epithelial tumour cells with the ability to migrate, invade the surrounding stroma and disseminate in secondary organs.[]–[]