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[email protected] Current Drug Targets, 2012, 13, 1649-1653
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Targeting Pathways Contributing to Epithelial-Mesenchymal Transition (EMT) in Epithelial Ovarian Cancer Ruby Yun-Ju Huang1,2,*, Vin Yee Chung2 and Jean Paul Thiery2,3,4 1
Department of Obstetrics & Gynaecology, National University Hospital, Singapore; 2Cancer Science Institute of Singapore, National University of Singapore; 3Department of Biochemistry, National University of Singapore; 4Institute of Molecular and Cell Biology, A*STAR, Singapore Abstract: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Discovery of novel therapeutic opportunities 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 migration 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 different modes of cell reorganization have been described to operate in one cnidarian species to establish a second epithelial 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 plasticity i.e. allows epithelial cells to alter their contact sites with neighbouring cells possibly leading to neighbour exchange, branching morphogenesis or delamination through the modulation of cell adhesion and polarity molecular regulators. Epithelial plasticity operates to form the second epithelial-like layer in diploblasts by promoting either invagination, 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 stomach). As already observed in diploblasts, several mechanisms operate to establish these three layers called ectoderm, mesoderm and endoderm. Genetic studies in Drosophila embryos revealed that specific mutants affect the process of gastrulation particularly impacting the formation of mesoderm. Two transcription factors Twist and Snail were identified to contribute decisively to the invagination of a limited number of cells in the blastula followed by their delamination 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:
[email protected] /12 $58.00+.00
Twist induces actomyosin contraction in the apical domain to promote invagination but it also inhibits cell proliferation, and together with Snail abrogates Drosophila cadherinmediated intercellular adhesion ultimately leading to EMT. A similar scenario is also observed in Sea urchin gastrulation. Interestingly in this model system, a very sophisticated gene regulatory network has been established by systematically 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 transcription 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. Another transcription factor Zeb2 not present in Drosophila is potentially involved in neural crest EMT since its inactivation 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) operate 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 coordinated activation of TGFbetaR, ErbB3 and Notch pathways whereas EMT of the epicardium involves the Wilms Tumor transcription factor Wt1 which drives several pathways including the Wnt canonical and non-canonical pathways. A recent review provides a detailed description of these pathways [2]. A striking feature of EMT pathways utilized during embryogenesis is their complexity and interconnection with induction and differentiation programs. However some landmark drivers and effectors are well conserved through © 2012 Bentham Science Publishers
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Huang et al.
Type I collagen
Gab2
Up-regulation Down-regulation Inhibition
PI3K
ET-1/ET(A)R
p70(S6K) E2
BMP4/ALK
CA-125/MUC-16
SNAI1
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SNAI2 Vimentin
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Fig. (1). Multiple signaling pathways leading to epithelial-mesenchymal transition in ovarian cancer.
evolution. About 20 years ago we hypothesized that a developmental EMT-like program could have been co-opted by carcinoma cell to engage in the invasive and metastatic cascades [3]. Initial argument in favor of such as a hypothesis is the presence of single carcinoma cells in blood vessels and in the bone marrow. In addition there are rare tumors with a mixed sarcoma-carcinoma like phenotype. Other physical evidence was provided by a pioneer study in colon carcinoma where single cells with an EMT phenotype were formed at the invasive front. More recently a large number of studies have reported that carcinoma cells can undergo at least a partial EMT phenotype both in experimental model systems [4] and in human tumors [5, 6]. It is also becoming clear that a number of circulating tumor cells have acquired a mixed EM phenotype [7]. Thus it is now critical to explore in depth mechanisms driving EMT in tumor cell subpopulations in order to develop new therapeutic intervention based on the EMT concept [8]. EMT IN EPITHELIAL OVARIAN CANCER Over the past decade, roles of EMT in solid tumors have been extensively demonstrated since the first suggestion of its implication in carcinoma progression [3]. Accumulative evidence has shown that EMT is utilized by cancer cells to enhance aggressiveness by acquiring chemoresistance and stem-cell-like properties, and escaping from host immunity [6]. Among the panel of solid tumors that EMT has been implicated to play crucial roles, epithelial ovarian cancer (EOC) is the least understood and studied. EOC represents a heterogeneous disease entity with unique biology [9]. Unlike other carcinoma which usually display pure epithelial lineage, many EOC tumors co-express epithelial and mesenchymal determinants to begin with [10, 11]. Therefore, the interpretation of whether conventional EMT does occur in
EOC is less straightforward and EMT is often considered not fully executed in EOC [11]. Nevertheless, in recent years, there is an increase in findings implicating EMT in promoting EOC aggressiveness. It has been suggested that there could be several rounds of EMT happening during the progression of EOC [8, 12]. Pathways or expression profiling signatures enriched in EMT genes have been identified to distinguish subgroups of EOC with worse clinical survival outcomes [13, 14]. Here, we summarize how EMT is executed in EOC to contribute to its aggressiveness in various functional aspects. Migration and Invasion EMT drivers such as SNAI1 and SNAI2 have been shown to elevate invasiveness in ovarian cancer cells [15]. Ectopically expressedSNAI1 or SNAI2 induced EMT in SKOV3 cells and enhanced motility, invasiveness and tumorigenecity. In this model, SNAI1 and SNAI2 seem to exert slightly different transcriptional suppression on cell-cell adhesion genes. SNAI1 suppresses expression of adherens and tight junction components, while SNAI2further suppresses expression of desmosome; concertedly, bringing down the intercellular adhesion between cells [15]. EMT mediated via SNAI1 or SNAI2 in EOC could be downstream of several signaling pathways such as endothelin A receptor (ET(A)R)/endothelin-1 (ET-1) axis [16, 17], bone morphogenetic protein-4 (BMP4) [18], phosphatidylinositol 3-kinase (PI3K)- p70 S6 kinase (p70(S6K)) axis [19]. The ET1/ET(A)R autocrine pathway drives EMTand induces an invasive phenotype in EOC cells through SNAI1 downregulation of E-cadherin and up-regulation of N-cadherin and Vimentin in Hey and OVCA433 cells [17]. In response to exogenous BMP4, the up-regulation of SNAI1 and SNAI2were in commitment with changes in the level of acti-
Targeting Pathways Contributing to Epithelial-Mesenchymal Transition (EMT)
vated Rho GTPases in EOC cells [18]. Similarly, constitutive activation of BMP4 receptor ALK resulted in spindle-shaped morphology of cultured OVCA429 cells eliciting an EMTlike response which correlated with increased SNAI1 and SNAI2with reduced E-cadherin mRNA expression [20]. p70(S6K) induced EMT by repressing E-cadherin and inducing mesenchymal markers N-cadherin and vimentin through the up-regulation of SNAI1 but not SNAI2. This induction of SNAI1 was achieved at multiple levels by increasingtranscription, inhibiting degradation, and enhancing nuclear localization of SNAI1 [19]. Up-regulation of PI3K pathway was also found to be responsible for E-cadherin downregulation induced by Type I collagen in SKOV3 cells [21] and EMT mediated by scaffolding adaptor protein Gab2 [22]. From these data, it is clear that many EMT effects in EOC are mediated via the up-regulation of SNAI1 and SNAI2 following autocrine or paracrine growth factor signaling. Apart from being the downstream effect or of the growth factor signaling, SNAI1up-regulation has also been linked to the increased invasiveness in EOC cells induced by 17beta-Estradiol (E2) [23]. The effect of E2 in EMT has been further confirmed by depletion of endogenous SNAI1 using small interfering RNA (siRNA) which attenuated E2mediated decrease in E-cadherin, migration and invasion in EOC cells [24]. Reports on other mechanisms driving EMT in EOC are sporadic. Down-regulation of the high-molecular-weight glycoprotein CA-125/MUC-16 in OVCAR3 cells caused an EMTed phenotype with concomitant enhanced epidermal growth factor receptor (EGFR) activation with increased Akt and ERK1/2 phosphorylation [25]. Overexpression of another mucin glycoprotein MUC-4, on the other hand, resulted in EMT changes via up-regulating TWIST1, TWIST2 and SNAIL [26]. Stanniocalcin-2 (STC2), a human glycoprotein of HIF-1 target, promoted EMT in SKOV3 cells under hypoxia condition [27]. Chemoresistance and Cancer Stemness EMT has been associated with resistance to conventional chemotherapy [6]. However, it is not entirely clear if clones of cancer cells with EMTed phenotype are more chemoresistant or exposure to chemotherapy itself induces some surviving cancer cells to undergo EMT afterwards. Several studies have shown that EOC cells undergoing chronic and sustained exposure to chemotherapeutic agents such as cisplatin or paclitaxel would generate cells which exhibit an EMT phenotype [28-31]. Interestingly, in A2780 cells and its in vitro chemoresistant sublines A2780 CIS and A2780 TAX, the chemoresistant lines not only exhibited EMTed phenotype and molecular features [32, 33] but were also up-regulated in ET-1/ET(A)R signaling axis [32]. This cisplatin resistance was thought to be contributed by both SNAI1 and SNAI2 in this model [33]. Despite evidences gathered from in vitro data suggesting a link between EMT and acquiring chemoresistance, it is still elusive how EMT contributes to chemoresistance when correlating with in vivo clinical data from EOC patients. In a study aimed to identify overlapping pathways associated with platinum-based chemotherapy resistance mechanisms in EOC using pathway analysis on nine published gene sets associated with platinum resistance in EOC, TGF signaling, one of the key signaling pathways
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that drives EMT, as well as TGF signaling related miRNAs in EMT networks were associated with treatment resistance [34]. Similarly, gene expression data from small collections of primary EOC tumours seemed to suggest that TGF signalingan EMT-like pathway are activated in resistant tumours relative to sensitive tumours [33, 35], suggesting that the involvement of EMT may not be limited to in vitro findings [33]. Recently, multidrug resistant ovarian cancer clone was found to demonstrate an EMTed phenotype and express cancer stem cell markers CD44 and CD117 [31]. The link between EMT and cancer stem cell has expanded our understanding on how EMT contributes to tumor aggressiveness and chemoresistance [36]. In EOC, SNAI1 and SNAI2 driven EMT gives rise to a stem-like phenotype [29, 37]. In recurrent ovarian cancers, EMT has been suggested to contribute to a “migratory cancer stem cell-like” phenotype [38]. In addition, ovarian cancer initiating cells isolated using a dye PKH-26 labeling method also revealed a mesenchymal phenotype [39]. Collectively, these data point to a new dimension how EMT contributes to the aggressiveness in EOC by affecting the chemo-sensitivity profiles and stem-cell populations. EMT AS A THERAPEUTIC TARGET FOR EOC EOC has been one of the major fatal malignancies for women worldwide [40]. Ranked as the sixth most common cancer in women, the prognosis for the disease is generally poor due to its insidious onset and the lack of early preneoplastic diagnosis [41]. Most EOC patients are presented at advanced stages and despite aggressive treatments, the overall survival merely hits 30% [42]. Therefore, there is an imperative need for better diagnostic strategies, as well as more efficient, patient-specific treatments. EOC represents a heterogeneous entity classified by morphology into distinct histopathological subtypes [9]. In addition to the histopathological diversities, EOC shows high levels of complex genomic alterations and molecular profiles. In spite of the histopathological and molecular heterogeneity of EOC, the treatment for high risk EOC patients remains as standard surgical debulking followed by taxane/platinum-based chemotherapy [9] over the last three decades. Recently, some potential targeted therapies against VEGF (angiogenesis), EGFR (survival), or c-Kit (stem cell) pathways have been suggested [43]. The existing therapeutic options for EOC are inadequate and have not given patients sufficient survival benefits. Unlike other solid tumors, the molecular mechanism of EOC does not seem to depend much on driver gene mutations but rather more complicated genomic and epigenetic alterations [44]. Therefore, therapeutic guidance based on the driver mutation status might not be feasible for EOC. Thus, the search for novel therapeutic approaches is of great importance. Targeting signaling pathways contributing to EMT is a promising therapeutic approach for cancers [8]. The ET1/ET(A)R axis and its role in EMT in EOC has been relatively well characterized [45]. Using a small molecule ET(A)R antagonist, zibotentan (ZD4054), concomitant suppression of tumor growth and EMT effectors has been achieved pre-clinically [17, 45]. However, the Phase II clinical trial combining zibotentan with platinum-based chemotherapy in platinum-sensitive advanced EOC was terminated
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due to no benefit in progression-free survival [46]. Recently, high throughput and high content screening platforms have been utilized to identify small molecules targeting ALK, MEK, SRC, and PI3K pathways to reverse the EMT phenotype effects in cancer cells [47]. Based on this concept, these targets could be utilized to investigate their EMT reversal effects in EOC. First, targeting PI3K pathway perhaps will be a more promising approach in EOC. Currently, there are several clinical trials involving PI3K-AKT-mTOR inhibitors for both first-line or recurrent settings in EOC [48]. However, due to the main functions of PI3K-AKT-mTOR pathway in regulating apoptosis, metabolism, cell proliferation, angiogenesis, and cell growth in EOC [48], the effect of these inhibitors in EMT reversal might be difficult to assessin patients. Second, MEK inhibition might be able to suppress EMT in some EOC tumors. Selumetinib, a smallmolecule MEK inhibitor, demonstrated the ability to control patients with recurrent low-grade serous EOCfrom a recent phase II study. These compounds might exert more optimal effect in EMT reversal when used in combination because multiple signaling pathways might co-exist to drive EMT [47]. For instance, Dasatinib, a SRC inhibitor, has been found to lack activity towards recurrent EOC as a single agent [49]. Besides the above mentioned targets, for other potential targets such as small molecular inhibitors to angiogenesis, it is unknown whether there will be additional EMT reversal effects. Recently, a novel histone deacetylase inhibitor AR42 was found to alter miRNA profiles that were negatively correlated with EMT genes in a chemoresistant EOC cell line CP70 [50]. Restoration of miR-200c family, an important microRNA family negatively regulates EMT, has also been proposed to be a novel therapeutic strategy for aggressive, drug-resistant cancers [51]. Therefore, targeting EMT via epigenetic or miRNA control might be another therapeutic approach for EOC. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.
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ACKNOWLEDGEMENT This work was supported by National University Health System (NUHS) Bench-to-Bedside Grant.
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Received: September 17, 2012
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Revised: October 09, 2012
Accepted: October 09, 2012
