Send Orders of Reprints at reprints@benthamscience.org Current Drug Targets, 2012, 13, 1649-1653 1649 Targeting Pathways Contributing to Epithelial-Mesenchymal Transition (EMT) in Epithelial Ovarian Cancer Ruby Yun-Ju Huang 1,2,* , Vin Yee Chung 2 and Jean Paul Thiery 2,3,4 1 Department of Obstetrics & Gynaecology, National University Hospital, Singapore; 2 Cancer Science Institute of Sin- gapore, National University of Singapore; 3 Department of Biochemistry, National University of Singapore; 4 Institute of Molecular and Cell Biology, A*STAR, Singapore Abstract: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Discovery of novel therapeutic op- portunities for EOC is important for the improvement of clinical outcome of the patients. Emerging evidence is suggesting that epithelial-mesenchymal transition (EMT) plays a crucial role in the aggressiveness in EOC including increasing mi- gration and invasion ability, contributing to chemoresistance and cancer stem cell populations. Targeting EMT in EOC thus offers an attractive therapeutic option. Keywords: Epithelial-mesenchymal transition, ovarian cancer. INTRODUCTION OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) Epithelial-mesenchymal transition (EMT) is an essential developmental mechanism that allows polarized epithelial cells to convert into motile mesenchymal cells [1]. EMT is a conserved mechanism which appeared early during evolution in very primitive species including those belonging to the phylum of the diploblastic cnidarians. No less than nine dif- ferent modes of cell reorganization have been described to operate in one cnidarian species to establish a second epithe- lial cell layer from a single layered epithelium in order to form a diploblastic embryo. These mechanisms rely on the intrinsic ability of most embryonic epithelia to exhibit plas- ticity i.e. allows epithelial cells to alter their contact sites with neighbouring cells possibly leading to neighbour ex- change, branching morphogenesis or delamination through the modulation of cell adhesion and polarity molecular regu- lators. Epithelial plasticity operates to form the second epithelial-like layer in diploblasts by promoting either in- vagination, involution, or EMT. Similar mechanisms operate in all the triploblastic (three epithelial layers) embryos. The formation of three-layered embryos requires a fundamental process called gastrulation (literally formation of the stom- ach). As already observed in diploblasts, several mechanisms operate to establish these three layers called ectoderm, mesoderm and endoderm. Genetic studies in Drosophila em- bryos revealed that specific mutants affect the process of gastrulation particularly impacting the formation of meso- derm. Two transcription factors Twist and Snail were identi- fied to contribute decisively to the invagination of a limited number of cells in the blastula followed by their delamina- tion and migration into the blastocoelic cavity. In particular *Address correspondence to this author at the Department of Obstetrics & Gynaecology, National University Hospital, IE Kent Ridge Road, Singapore 119228, Singapore; Tel: +6565161148; Fax: +6567794753; E-mail: ruby_yj_huang@nuhs.edu.sg Twist induces actomyosin contraction in the apical domain to promote invagination but it also inhibits cell proliferation, and together with Snail abrogates Drosophila cadherin- mediated intercellular adhesion ultimately leading to EMT. A similar scenario is also observed in Sea urchin gastrula- tion. Interestingly in this model system, a very sophisticated gene regulatory network has been established by systemati- cally injecting morpholino oligonucleotides into blastomeres at the origin of mesoderm in order to interfere with gene transcripts involved in gastrulation. Twist and Snail were found to be central to the EMT program during gastrulation. Studies on the vertebrates have amply confirmed the critical importance of Snail and Twist. However these two transcrip- tion factors are not working in concert in a given embryonic territory. Snail1, a Drosophila ortholog plays a major role in gastrulation and in neural crest formation in the mouse while Twist plays a secondary role in promoting the maintenance of the mesenchymal state in delaminated neural crest. An- other transcription factor Zeb2 not present in Drosophila is potentially involved in neural crest EMT since its inactiva- tion in mouse embryos leads to neural crest delamination defects. EMT has been extensively analysed at slightly later stages of development particularly in the formation of the heart. Four consecutive cycles of EMT and its reversed mechanism Mesenchymal Epithelial Transition (MET) oper- ate at critical stages of heart morphogenesis. One of the EMT cycles involves the delamination of endothelial cell to form the endothelial cushion; this EMT is driven by the coordi- nated activation of TGFbetaR, ErbB3 and Notch pathways whereas EMT of the epicardium involves the Wilms Tumor transcription factor Wt1 which drives several pathways in- cluding the Wnt canonical and non-canonical pathways. A recent review provides a detailed description of these path- ways [2]. A striking feature of EMT pathways utilized dur- ing embryogenesis is their complexity and interconnection with induction and differentiation programs. However some landmark drivers and effectors are well conserved through /12 $58.00+.00 © 2012 Bentham Science Publishers