Targeting epithelial-mesenchymal transition.

Abstract

The epithelial–mesenchymal transition (EMT) is a process in which epithelial cells dedifferentiate to become mesenchymal cells [1–3]. The process requires them to lose their cell polarity, to relinquish their cell–cell adhesion, and to gain migratory and invasive properties. The mesenchymal cells are multipotent stromal cells (mesenchymal stem cells) that can differentiate into various cell types. EMT is essential for the developing embryo to enable mesoderm and neural tube formation. EMT is also necessary for wound healing and other physiological processes. On the other hand, EMT can also be an initiator for metastasis, cancer progression, organ fibrosis, and other pathological conditions. These are disorderly processes. The induction of EMT is complex (Fig. 1) [4]. A fundamental event appears to be the loss of E-cadherin. Transcription factors that can repress E-cadherin directly or indirectly are important to this process. SNAI1/Snail 1, SNAI2/Snail 2 (also known as Slug), ZEB1, ZEB2, E47, and Kruppel-like factor-8 (KLF8) can repress E-cadherin transcription by binding to its promoter. Indirect repressors, such as Twist, Goosecoid, TCF4 (sometimes referred to as immunoglobulin transcription factor 2), homeobox protein SIX1, and FOXC2 (fork-head box protein C2) are able to repress E-cadherin indirectly [5]. Other junction proteins, such as claudins and desmosomes, are also suppressed, facilitating EMT. Various transcription factors such as grainyhead-like protein 2 homologue (GRHL2) and ETS-related transcription factors ELF3 and ELF5 are downregulated during EMT [6, 7]. The induction of EMT is dependent on numerous signaling pathways including TGF-beta, FGF, EGF, HGF, Wnt/beta-catenin, Notch, and hypoxia-induced mechanisms. Ras-MAPK signaling activates Snail and Slug during EMT induction. Slug is involved in disrupting desmosomes, inducing cell spreading, and separating the cell–cell borders [8]. However, EMT involves a second phase that cannot be triggered by Slug. This phase includes the induction of cell motility, repression of the cytokeratin expression, and activation of vimentin expression [9]. Phosphatidylinositol 3′ kinase (PI3K)/AKT-axis activation is emerging as pivotal to EMT. Similarly, hedgehog, nuclear factorkappaB (NF-κB), and activating transcription factor-2 have been implicated [10]. Of course, the EMT processes are specific, so that while Wnt signaling pathways regulate EMT in embryonic development, cardiac valve formation, and cancer, other pathways are important towound healing and fibrosis [11]. EMT is central to two recent J Mol Med contributions. Kimura et al. report on the attenuation of EMT in retinal pigment epithelial cells and subretinal fibrosis by a retinoic-acid receptor-gamma (RAR-γ) agonist [12]. The retinal pigment epithelium belongs the neural retina and is indispensable for vision. In humans, proliferation and transformation (EMT switching) of retinal pigment epithelial cells after injury causes retinal disorders and loss of vision [13]. On the other hand, EMT could develop into a therapeutic target [14]. Subretinal fibrosis contributes to the loss of vision associated with age-related macular degeneration (AMD), a devastating and common disease in older people. The authors began with retinal epithelial cells in culture. When subjected to TGF-β2, the cells expressed mesenchymal markers including α-smooth muscle actin and fibronectin. The cells also released interleukin-6. Paxillin was phosphorylated; MAPK constituents such as ERK, p38, and JNK were activated, as were Smad2 and AKT. A RAR-γ agonist, R667, attenuated the EMT responses. Furthermore, the cells treated * Friedrich C. Luft luft@charite.de