Reversing EMT

Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cell layers lose polarity and cell-cell contacts and undergo a massive cytoskeleton reorganization involving the rho family and the remodeling of the actin microfilament mesh (Thiery, 2002). Concurrent with a loss of epithelial cell adhesion and cytoskeletal components, cells undergoing EMT acquire expression of mesenchymal components and manifest a migratory phenotype. This is a fundamental process governing morphogenesis in multicellular organisms during embryonic development. This EMT process, first appreciated by developmental biologists in the early 1980s, is now attracting increasing attention from oncologists and nephrologists, because the process is also reactivated in a variety of diseases, including fibrosis and in the progression of carcinoma. From a therapeutic standpoint, it may be important to reverse EMT in these diseases. EMT is characterized by coordinated changes in cell morphology, associated with the induction of cell motility and the disruption of intercellular junctions. In some cases, cells undergoing EMT start synthesizing extracellular matrix molecules such as fibronectin and certain types of collagen. They may also synthesize proteolytic enzymes involved in matrix degradation that contribute to cell motility and invasiveness. It should be stressed that not all EMTs exhibit the whole range of changes listed here. However, EMT is always associated with cell scattering, defined by the loss of intercellular junctions and acquisition of cell motility. The transformation of mesenchyme to epithelium (MET), the reverse of EMT, also occurs during embryonic development. The differentiation of the metanephric blastema provides a striking example of MET. The cardinal feature of kidney development is the formation of epithelial tubules from nonepithelial mesenchymal cells. This conversion of cell type, MET, is controlled by factors secreted from the ureteric bud (Barasch, 1999; Plisov, 2001), and these epithelial inducers have been purified from ureteric bud cell lines (Barasch, 1996). These molecules are endogeneous MET inducers. We have tested some of these [bone morphogenetic protein 7(BMP-7) and lipocalin 2] for their epithelial inducing activities in the context of tumor biology and fibrosis and these results with potential therapeutic applications have been discussed.