Transdifferentiation of epithelial cells into cells with mesenchymal properties and appearance

Transdifferentiation of epithelial cells into cells with mesenchymal properties and appearance i. signaling pathways in the control of gene reprogramming during EMT. Through ��epithelial-mesenchymal transition�� (EMT) epithelial cells transdifferentiate into mesenchymal cells either partially or fully. Also endothelial cells use similar mechanisms to convert into mesenchymal cells and this process is often named EndMT. Combining EMT with the reciprocal reversion of mesenchymal cells to an epithelial phenotype i.e. ��mesenchymal-epithelial transition�� (MET) allows cell populations to transition through several rounds of EMT in development e.g. in dorsal somite TW-37 cells that arise through MET from early mesoderm and then differentiate into dermal mesenchyme and myoblasts [1]. EMT has TW-37 been classified as three types depending on the physiological context. Type 1 EMT occurs in development while type 2 EMT is seen in wound healing inflammation and fibrosis. In cancer type 3 EMT enables BMP2A carcinoma cell invasion and dissemination has been linked to cancer stem cell properties of some carcinomas and contributes to the tumor stroma through conversion of epithelial and endothelial cells [2]. However underlying these three types of EMT is a common transdifferentiation program with inherent variability depending on cell type and context. Key events in EMT are (1) dissolution of epithelial cell-cell junctions with loss of apical-basal polarity and acquisition of front-rear polarity (2) reorganization of the cytoskeletal architecture with changes in cell shape and increased cell motility (3) reprogramming of gene expression resulting in repression of epithelial gene expression and activation of genes that help define the mesenchymal phenotype. ��Master�� transcription factors such as Snail1 or Snail2/Slug ZEB1 or ZEB2 and Twist drive this reprogramming which often results in a switch in cadherin expression a switch in integrin repertoire and in many cases expression of metalloproteases that degrade extracellular matrix (ECM) proteins thus enabling invasive behavior [3 4 Many EMT inducers few pathways Various secreted factors can induce or are required for EMT. Fibroblast growth factors (FGFs) and hepatocyte growth factor (HGF) which act through receptor tyrosine kinases (RTKs) were among the first reported EMT inducers conferring cell dispersion. Other ligands that activate RTKs or receptor-associated tyrosine kinases also induce EMT and integrin signaling through tyrosine kinases can contribute to activation of the EMT program [1 4 Other EMT inducers execute more direct changes in gene expression during EMT. TGF-�� family proteins that act through Smad transcription factors Wnts acting through ��-catenin and TCF/LEF transcription factors and Hedgehog proteins that activate Gli proteins also induce or are required for EMT in diverse contexts. Aiming to provide a unifying framework for the induction and regulation of EMT it is logical to postulate that EMT requires the cooperation of signaling pathways that coordinately direct changes in cell-cell and cell-matrix interactions cyto-architectural remodeling TW-37 and gene reprogramming. This cooperation may depend on distinct ligands activating complementary pathways while some ligands activate several TW-37 of these and thus depend less on additional autocrine TW-37 or paracrine factors. Among the EMT inducers TGF-�� receives substantial attention largely because of its potency in inducing EMT in cell culture and its roles in cancer-associated EMT while TGF-�� family proteins direct EMT during development. Consequently TGF-��-induced EMT has been better characterized than EMT in response to other inducers and often serves as paradigm for analyses of this process. In TGF-��-induced EMT Smads induce gene reprogramming by directly activating the expression of EMT transcription factors and then TW-37 cooperating with these in the control of target genes [4 5 The functional dependence of Smads on interactions with DNA binding transcription factors additionally enables cooperation with other pathways at the level of gene expression [6]. TGF-�� additionally induces non-Smad signaling leading to activation of Rho.