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Clinical significance of epithelial‐mesenchymal transition

Konrad Steinestel, Stefan Eder, Andres Jan Schrader and 1 more

Clinical and Translational Medicine · 2014 · Review · CC BY

doi:10.1186/2001-1326-3-17

Abstract

The concept of epithelial‐mesenchymal transition (EMT), a process where cells change their epithelial towards a mesenchymal phenotype, has gained overwhelming attention especially in the cancer research community. Thousands of scientific reports investigated changes in gene, mRNA and protein expression compatible with EMT and their possible correlation with tumor invasion, metastatic spread or patient prognosis; however, up to now, a proof of clinical significance of the concept is still missing. This review, with a main focus on the role of EMT in tumors, will summarize the basic molecular events underlying EMT including the signaling pathways capable of its induction as well as changes in EMT‐associated protein expression and will very briefly touch the role of microRNAs in EMT. We then outline protein markers that are used most frequently for the assessment of EMT in research and diagnostic evaluation of tumor specimens and depict the link between EMT, a cancer stem cell (CSC) phenotype and resistance to conventional antineoplastic therapies. Furthermore, we evaluate a possible correlation between EMT marker expression and patient prognosis as well as current therapeutic concepts targeting the EMT process to slow down or prevent metastatic spread of malignant tumors.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Epithelial-mesenchymal transition (EMT) is a central element of embryonic development, wound healing and tumor cell migration, and has thus obtained much attention by the research community since Greenburg and Hay firstly described a mesenchymal-like transformation of epithelial cells when suspended in collagen gels. Basically, the term describes a process in which cells lose epithelial and gain mesenchymal characteristics; this is accompanied by a loss of cell-cell cohesiveness, leading to enhanced migratory capacity. Multiple genes as well as proteins that seem to play a central role in EMT have so far been identified and are either up- or downregulated during the process, thus serving as possible markers in the assessment of EMT. Since it seems to be a key element in wound healing and tumor cell migration, there is also great interest in EMT as a pharmaceutical target; recent publications even proposed vaccination against drivers of EMT as an immunotherapeutic approach against tumor progression.

However, since many studies on EMT are based on in vitro results and not all findings could be confirmed in vivo, the clinical significance of the concept remains unclear. This review lays the main focus on EMT in tumor cells and aims at recapitulating what is known about the molecular basis of EMT. Furthermore, we will summarize current markers of EMT that are in clinical and/or diagnostic use and, finally, evaluate EMT from a translational point of view and in the context of clinical feasibility.

The molecular basis of EMT

Basically, EMT stands for a loss of epithelial and a gain of mesenchymal cellular characteristics that enhance migration and invasion by the cell. This process includes loss of cell cohesiveness as well as fundamental reorganization of the cytoskeleton inducing a switch from apical-basal to front-rear polarity, and may furthermore be associated with the acquisition of invasive properties through the secretion of lytic proteases as well as resistance to senescence and apoptosis. EMT is under tight control of multiple regulatory pathways; first and foremost, transforming growth factor β (TGF-β) signaling activity is enhanced in many physiological and pathological conditions in which EMT is observed, such as organogenesis, inflammation and tumor invasion. In canonical TGF-β signaling, binding of TGF-β to its cell surface receptors (type I-III) activates complex formation of Smad family transcription factors, which translocate to the nucleus and cooperate with transcription factors from the Snail and Twist family, so-called “EMT master genes”. Non-Smad signaling molecules downstream TFG-β and supportive of EMT include activated Rho-like GTPases, Phosphatidylinositol-3-kinase (PI3K) and mitogen-associated protein kinase (MAPK; the various signaling pathways mediating TGF-β signaling in EMT are excellently reviewed in). Taken together, these effectors mediate transcriptional repression of genes that are involved in cell polarity and cell-cell adhesion, such as RhoA and E-cadherin (Figure 1A). The latter is mediated by the recruitment of histone deacetylases (HDACs) and other repressors to E-box elements in the E-cadherin promoter, leading to chromatin condensation and transcriptional repression. At the same time, the expression of N-cadherin, another member of the cadherin family that allows for enhanced adhesion between mesenchymal cells, is upregulated; this balanced change in cadherin expression has thus been designated “cadherin switch” and is regarded a hallmark of EMT. Not only the expression, but also specific membraneous targeting of E-cadherin is repressed in EMT via loss of the epithelial-specific intermediate filament keratin; therefore, loss of keratin immunostaining is widely regarded as a marker for ongoing EMT. Further mechanisms that lead to degradation of cell-cell junctions include a repression of claudin and occludin expression, while zonula occludens 1 (ZO-1) is subsequently lost in a post-transcriptional manner. This repression is maintained throughout further progression of EMT. Since protein complexes (such as partitioning defective – PAR) that define the apical compartment of the cell are normally associated with intercellular junctions, degradation of the junctions also weakens the apical-basal polarity cellular phenotype. Moreover, the TGF-β-facilitated signaling along the MAPK axis exerts pro-proliferative and anti-apoptotic effects on the cell, while Ras/MAPK activity alone – without TGF-β induction - has also been linked to enhanced EMT. After losing cohesiveness due to degradation of cell-cell junction complexes, mesenchymal-like tumor cells are able to invade through the basement membrane into underlying tissue by the secretion of lytic enzymes such as matrix metalloproteinases (MMPs) and MAPK-mediated reorganization of the actin cytoskeleton which is enhanced by the expression of Vimentin (Figure 1B). In detail, migration and invasion of moving cells is facilitated by specialized cellular protrusions, such as filopodia, lamellipodia and invadopodia. While filopodia, consisting of actin filaments arranged in a parallel fashion, seem to sense changes to the cellular microenvironment and act as a “guide” through the surrounding matrix, lamellipodia are built upon a branched actin network and allow for actin-myosin interactions as a prerequisite for cellular movement. Both filopodia and lamellipodia have been linked to an EMT-like phenotype in migrating tumor cells. Invadopodia are closely related to lamellipodia in a sense that they also consist of a branched network of actin filaments, but have the ability to degrade the extracellular matrix (ECM) through the secretion of lytic proteases, such as MMP-1, MMP-7 and MMP-9 (Figure 1B). Invadopodia formation has been linked to activity of the EMT transcription factor Twist1 cancer, and own results showed high expression of invadopodia-associated proteins, such as Cortactin and Abelson interactor 1 (Abi1), in a colorectal carcinoma cell line with an EMT-like phenotype shown by loss of E-cadherin. Accordingly, TGF-β signaling activates small GTPases that enhance local reorganization of the actin cytoskeleton as a prerequisite for lamellipodia and filopodia formation, such as Rho, Rac and Cdc42. Vimentin, which is frequently upregulated in cells with an EMT-like phenotype, is then required for the further maturation of invadopodia. Besides clearing the way for migrating tumor cells, MMPs that are released during tumor cell invasion are themselves further fueling the EMT process; the same effect is achieved via liberated TGF-β from the ECM. In a mouse model of gastric cancer, it could be shown that EMT cooperates with MMP activity to gain access to lymph vessels and to spread distant metastases. Accordingly, blood and lymph vessel infiltration by triple-negative breast cancer cells is associated with the expression of EMT transcription factor Zeb1 in surrounding stroma. Alterations in MMP expression are linked to changes in the integrin repertoire with downregulation of some (epithelial) and upregulation of other integrins that facilitate interaction with extracellular matrix components such as collagen. Targeting transmembrane proteins - like E-cadherin - or increasing the levels of intracellular reactive oxygen species via enhanced activation of Rac1b are further mechanisms of MMP-induced EMT.

Upon arrival at the site of metastasis, it seems a prerequisite for metastatic colonization that tumor cells undergo a partial reversal of the EMT, the so-called “mesenchymal-epithelial transition” (MET). During that process, tumor cells regain the expression of epithelial markers, such as E-cadherin, while the expression of EMT-associated transcription factors, such as Twist1, is repressed. Thus, EMT can be seen as a reversible and transient process that enables epithelial tumor cells to gain access to the vasculature, allowing for the formation of distant metastasis.

Besides TGF-β, other signaling pathways have also been implied in the activation of EMT; for example, hypoxia-inducible factor (HIF) contributes to EMT in tissue fibrosis and cancer cell invasion by modulating the activity of pro-EMT transcription factors Notch and β-catenin. HIF1α induces Twist and Snail expression in endothelial as well as ovarian carcinoma cells. Additionally, activation of several receptor tyrosine kinases (RTKs) may result in induction of EMT; in these scenarios, growth factor binding to RTKs as well as activating mutations in oncogenes downstream of the receptors leads to enhanced signaling along the Ras/MAPK or Akt/mTOR axis, resulting in upregulation of Snail expression. Finally, it has been shown that enhanced wnt signaling activity as well as an upregulation of chemokine receptors (such as CXCR-1) also support the process of EMT. Here, wnt signaling leads to an inhibition of glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation of β-catenin; the resulting decrease in proteosomal degradation and cytoplasmic accumulation of β-catenin supports its translocation to the nucleus, where it acts as a transcriptional co-activator of EMT-associated gene expression.

In the recent years, the role of small, non-coding RNAs in the EMT process has also been further elucidated. Methylation-depedent expression changes in levels of miR-200c and miR-141, for example, regulate invasion and metastasis in colorectal cancer via altered miR-200c target gene expression; miR-375 is downregulated in tamoxifen-resistant breast cancer cells with EMT-like properties, and its reexpression partly reverses EMT. Other miRNAs that have been discussed to play a central role in EMT are, among others, miR-1, 9, 24, 29b, 30a, 31, 124, 155, 192/215 and 661 (reviewed in). Their mechanisms of action include post-transcriptional regulation of “EMT master genes” or of genes defining the epithelial or mesenchymal phenotype of the cell (such as E-/N-cadherin or vimentin). However, a thorough review of the role of miRNAs in EMT and their clinical significance would lie beyond the scope of this text, where we would like focus on the role of well-characterized proteins in EMT.

Tissue markers of EMT

Unlike the various mechanisms that are known to initiate or repress EMT, the observed hallmarks of established or ongoing EMT are quite consistent. As previously mentioned, loss or degradation of proteins associated with epithelial homeostasis, cell polarity and cell adhesion, such as E-cadherin, RhoA or Plakophilin 2 is frequently observed in EMT (Figure 1A); some proteins that play key roles in cell-cell adhesion when attached to the membrane, such as β-catenin, are redistributed to the cytoplasm. Moreover, cells undergoing EMT show decreased expression of epithelial cytokeratin filaments, such as keratins 8 and 18. On the other hand, the intermediate filament protein Vimentin is frequently overexpressed and contributes to cell migration as well as invasion-associated gene expression by stabilizing the phosphorylated state of MAPK and is thus regarded as a stable marker of EMT; moreover, its presence is a prerequisite for the maturation of invadopodia which are indispensable for cell invasion. Dysregulated expression of transcription factors, such as Notch1, Slug, Snail, Twist or Zeb1 has been described in invasive tumors displaying EMT; these markers are therefore designated as “EMT master genes”. Table 1 provides an overview over selected dysregulated protein markers that have been and still are frequently used in the assessment of EMT.

EMT, tumor invasion and metastasis

The highest clinical significance of the EMT process is linked to its role in tumor cell invasion and metastasis. In a transgenic mouse model of pancreatic beta-cell carcinogenesis, the switch from noninvasive adenoma to invasive carcinoma is associated with a loss of E-cadherin expression; moreover, it has been shown that loss of membraneous β-catenin is associated with tumor cell budding, a morphologic hallmark of invasive tumor phenotype and tumor aggressivity in colorectal cancer tissue specimens. In samples from 49 breast cancer patients, the single-cell infiltration pattern that is observed in some lobular carcinomas has been linked to protein truncation mutations in the CDH1 gene encoding for E-cadherin, and hypoxia-induced upregulation of Slug and Snail is associated with increased breast cancer cell migration and invasion in vitro. Accordingly, expression of Vimentin can be found in many aggressive breast cancer cell lines. As mentioned above, to allow for tumor cell invasion into the vasculature as a prerequisite for metastatic seeding, EMT cooperates with invadopodia formation and MMP activity; circulating tumor cells (CTCs) obtained from peripheral blood of breast cancer patients frequently show an EMT-like phenotype. In human and murine malignant melanoma cells, metastatic dissemination is enhanced and accelerated via Snail-induced EMT, and bone metastases of human prostate carcinomas show significant overexpression of Notch-1 compared to the primary tumors. In lung carcinoma surgical specimens, tumor dedifferentiation as well as lymphogenous metastasis are also associated with reduced E-cadherin expression.

However, as mentioned above, some authors also reported reexpression of epithelial markers, such as E-cadherin, along with loss of EMT-associated transcription factors in established metastases. This apparent reversal of EMT, often referred to as mesenchymal-epithelial transition (MET), has been described for metastases of colorectal carcinoma, non-small cell lung cancer and transitional cell carcinoma. There is an ongoing debate regarding the extent to which these findings reflect a basic mechanism in the establishment of metastases or if they are restricted to certain tumor entities or reflect distinct circumjacent conditions. There are also critical voices that doubt the role of EMT in invasion at all, since in most histopathologic specimens, many tumors invade and metastasize by cohesive and multicellular rather than single-cell migration, and histopathologists rarely see abundant mesenchymal-like tumor cells in routine surgical specimens. This apparent contradiction might in part be explained by regarding EMT as a transient state of a small proportion of migrating tumor cells, with only single tumor cells or small clusters of cells obtaining the ideal dynamic configuration for different stages of invasion and metastasis; this reasonable compromise has been referred to as “spatial and temporal heterogeneity of EMT” by Voulgari et al. (Figure 1).

Notably, there is another controversy regarding the point whether the EMT program is associated with enhanced or attenuated proliferative activity of the cell. While under normal circumstances TGF-β signaling exerts an anti-proliferative and pro-apoptotic effect, there is experimental evidence that tumor cells having undergone EMT do in fact show enhanced proliferation and resistance to apoptosis. This apparent contradiction might also be explained by a possible heterogeneity in the course and the extent of EMT, with specialized cell populations exerting different roles during invasion and metastasis; this is in line with findings that highly metastatic breast cancer cells in fact show strong activity of the TGF-β signaling pathway. It has also been proposed that the two oppositional endpoints of TGF-β signaling might be distinguished by loss of Smad4 in tumor tissue, which promotes TGF-β-mediated tumorigenesis, while in parallel abolishing its tumor-suppressive functions. Additionally, as described above, signaling along various non-TGF-β-dependent pathways might be capable of overcoming the original anti-tumorigenic effect of TGF-β in the course of an “unfriendly takeover” of central TGF-β signaling nodes and target genes; concurrent PI3K/AKT signaling, for example, thwarts the pro-apoptotic effect of TGF-β, thus selectively allowing for the pro-metastatic effects of the pathway to occur.

EMT, cancer stem cells and therapy resistance

Concerning the role of EMT in antitumoral therapies, it has been shown that an EMT-like cellular phenotype in both surgical specimens and cell lines is associated with increased resistance to most conventional approaches, such as chemotherapy, radiotherapy or hormone withdrawal. The observed changes in gene expression during EMT show striking similarity to a rather dedifferentiated state of the cell; in immortalized mammary epithelial cells, induction of EMT not only leads to the gain of a mesenchymal phenotype, but also induces the expression of certain stem cell markers (CD44+/CD24−). This generation of breast cancer cells with both cancer stem cell and mesenchymal-like characteristics has again been shown to be dependent on an activation Ras/MAPK signaling, and the link between EMT and cancer cell “stemness” is supported by the fact that genes associated with angiogenesis, invasion and metastasis are overexpressed in stem cell- like CD44+/CD24− breast cancer cells; notably, after chemotherapy for breast cancer, residual tumor cells frequently display a stem cell-like phenotype and increased mammosphere formation efficiency. The sensitivity of non-small cell lung cancer cells to EGFR kinase inhibition depends on their respective EMT phenotype, with mesenchymal-like cells (that express Vimentin or Fibronectin) being less sensitive to EGFR inhibition. In the NSCLC model, it has also been shown that this resistance might be mediated via EGFR-independent MEK-Erk pathway activation and PDGFR, FGFR and TGF-β receptor acquisition in mesenchymal-like tumor cells. An EMT-like gene expression profile in lung cancer cell lines is in fact associated with increased resistance to both EGFR and PI3K/Akt pathway inhibitors, a finding that could even be confirmed in a small patient cohort. Thus, the mechanisms of resistance to antineoplastic therapies might be due to stem-cell like properties of tumor cells that have undergone EMT, allowing for self-renewing of a proportion of cells within the tumor based on the activation of central signaling pathways that are common to both processes, such as TGF-β, wnt, Notch and Hedgehog. Associations between EMT-like properties and a stem-cell like cellular phenotype have not only been described in carcinoma of the breast and in NSCLC, but also in urinary bladder, head and neck, pancreas, and colorectal carcinoma; here, increased resistance to anti-epithelial growth factor receptor (EGFR)-directed therapy is also associated with an EMT-like phenotype of the tumor cells.

EMT and patient prognosis

Since the metastatic spread of malignant tumors accounts for the majority of cancer-specific deaths, possible correlations between EMT markers and patient prognosis have been intensely studied in multiple tumor entities. However, there is still controversy regarding the impact of the EMT concept on the actual situation in human malignancies. Therefore, much effort has been put into linking the expression of EMT markers to data on patient survival. In colon cancer, the upregulation of genes involved in EMT/matrix remodeling defines a molecularly distinct subtype with very unfavorable prognosis; downregulation of E-cadherin in patient samples, on the other hand, seems to be associated with high TNM stages and distant metastasis. Accordingly, basal-like, triple-negative breast cancers that show upregulation of Vimentin have a poor prognosis. In a meta-analysis of 1107 breast cancer samples, Tobin et al. showed reduced recurrence free survival in tumors displaying increased gene expression of EMT markers SNAI2, TWIST1 and VIM, and decreased levels of CDH1 (encoding for E-cadherin). In contrast, only recently Lee et al. were unable to confirm an impact of the tissue expression of EMT markers on disease-free survival or overall survival in breast cancer patients. In prostate cancer, expression levels of EMT markers Twist and Vimentin - as assessed by immunohistochemistry in radical prostatectomy specimens - are independent predictors for biochemical recurrence as defined by a resurgence in serum prostate-specific antigen (PSA) levels following surgery. Additionally, loss of membraneous E-cadherin staining seems to be associated with increased Gleason score, advanced clinical stage, and poor prognosis in prostate cancer. In tissue samples from 354 primary tumors and 30 metastases of endometrial carcinomas, Tanaka et al. reported that EMT status (E-cadherin-negative/ Snail-positive immunostaining) correlated with histological type, FIGO stage, myometrial invasion and positive peritoneal cytology while it was inversely associated with both progression-free survival (HR = 0.443) and overall survival (HR = 0.366).

Taken together, numerous studies in a variety of tumor entities show statistical correlations between patient prognosis and alterations of various markers compatible with EMT. However, it may be difficult to yield reliable prognostic information for an individual patient from the expression pattern of EMT markers in surgical specimens; this is in part due to high variability of marker expression patterns in different tumor areas in a heterogeneous sample. Moreover, artificial induction of EMT in vitro (under certain cell culture conditions) as well as in vivo (in surgical specimens subjected to ischemia) has been shown. Another key problem is the lack of a standardized diagnostic definition of which gene or which extent of expression changes is sufficient to determine EMT; in many reports, expression changes of one or two genes are already referred to as EMT or “partial EMT”, thus impairing the comparability of studies. Furthermore, as has already been discussed above, it is still unclear whether the gene expression changes observed in EMT reflect “passenger mutations” caused by genetic instability during tumor dedifferentiation rather than a real mesenchymal transdifferentiation state of the cell. From this point of view, the expression of EMT markers simply represents a more primitive differentiation state of the cancer cell that is associated with oncogenic activation of a variety of signaling molecules.

EMT as a potential target for antineoplastic therapies

Since the population of stem cell-like tumor cells will always bear considerable resistance to conventional therapies and since the hallmarks of EMT have been identified in a significant proportion of these cells as described above, efforts have been made to develop antineoplastic therapies that directly target EMT. The aim of most therapeutic approaches is to block or slow down invasion and metastasis in tumors or, in benign conditions associated with EMT, impede fibrotic organ remodeling. Table 2 shows some current therapeutic approaches that are aiming at EMT, most of them targeting kinase signaling pathways upstream EMT master gene expression. In mouse hepatocytes that have undergone EMT, it has been shown that inhibition of STAT3 signaling, for example, reduces EMT-like changes; in renal tubular epithelium, ALK receptor activation via recombinant BMP-7 acts antagonistically to TGF-β and leads to reexpression of E-cadherin. Inhibition of kinase signaling downstream FGFR3, ILK, Ras/MAPK or PI3K/AKT downregulates tumor formation, EMT master gene expression and invasive potential in colorectal, lung and pancreatic carcinoma cells in vitro, while in some models, re-expression of E-cadherin could be shown upon treatment with kinase inhibitors. In a mouse model of hepatocellular carcinoma, transformation with kinase-inactivated integrin-linked kinase (KI-ILK) partially restored the sensitivity to anti-EGFR treatment. Accordingly, our own group showed that Ras-driven EMT is attenuated via Sorafenib-mediated inhibition of Urokinase plasminogen activator (uPA) expression in RT112 urothelial carcinoma cells.

From the knowledge of the diverse kinase-dependent signaling pathways that are activated during EMT, it is not surprising that the application of multi-kinase inhibitors such as Sorafenib is capable of reversing the process to a certain extent. Up to now, concepts that are directly targeting EMT master genes or their effectors are rare. Interesting new approaches include the previously mentioned vaccination against Brachyury-positive tumor cells and the transcriptional repression of EMT master gene expression by the anti-diabetic drug Metformin (Table 2). Resveratol, a dietary polyphenol, downregulated expression of EMT master genes Zeb1, Snail and Slug and impaired CSC self-renewal capacity, tumor growth and invasion in a mouse model of pancreatic ductal adenocarcinoma. However, despite the abundance of literature on effectors of EMT, there is a lack of studies that show a solid effect of a specific compound in an in vivo system additionally to cell culture data, and to our best knowledge, a study that rescued the EMT phenotype after application of a certain compound - for example by overexpressing an EMT-inducing transcription factor - has so far not been conducted. Therefore, most of the data on drugs targeting EMT has to be regarded as preliminary, and further research is needed to identify valuable pharmacologic targets during the induction or progression of the EMT process.

Conclusions

Taken together, the concept of EMT is a valuable model for the morphologic and molecular changes observed in tumor cell invasion as well as tissue fibrosis. However, it is still unclear whether or to which extent cells in fact do undergo a complete conversion of cell type or show only transient changes in cellular morphology and protein expression patterns that are supportive of a migratory phenotype. Despite the controversies dealing with the definition and extent of EMT, the association between an EMT-like cellular phenotype - as shown by changes in marker protein expression - and tumor aggressivity has been well-proven in a variety of malignancies. In recent years, first promising results have been reported concerning a possible use of the EMT process as a pharmacological target, especially with multi-kinase inhibitors such as Sorafenib. However, since most of these results are actually derived from in vitro data and definite proof of druggable EMT in vivo is still missing, the clinical utility of these approaches remains to be elucidated in future studies.

Abbreviations

AJ: Adherens junction; CXCR-1: CXC motif chemokine receptor 1/Interleukin-8-receptor alpha; ECM: Extracellular matrix; EMT: Epithelial-mesenchymal transition; FGFR: Fibroblast growth factor receptor; FIGO: Fédération internationale de Gynécologie et d’Obstétrique; GSK3β: Glycogen synthase kinase 3β; HDAC: Histone deacetylase; HIF: Hypoxia-inducible factor; MAPK: Mitogen-associated protein kinase; MEK: Mitogen-associated protein kinase kinase; MET: Mesenchymal-epithelial transition; MMP: Matrix metalloproteinase; NSCLC: Non-small cell lung cancer; PAR: Partitioning defective; PDGFR: Platelet-derived growth factor receptor; PI3K: Phosphatidylinositol-3-kinase; RTK: Receptor tyrosine kinase; TGF-β: Transforming growth factor β; TNM: Tumor/Nodes/Metastasis (clinical classification system for tumor spread); uPA: Urokinase plasminogen activator; ZO-1: Zonula occludens 1.

Competing interests

Prof AJ Schrader receives compensation as a consultant for Bayer Healthcare AG, which manufactures Sorafenib (Nexavar®) for clinical application.

Authors’ contributions

All authors participated in the design of this review. KS, SE and JS reviewed literature on the molecular basis of EMT, on EMT markers and on EMT in tumor invasion and metastasis; KS and AJS reviewed literature on the association between EMT and cancer stem cells, therapy resistance and patient prognosis as well as on EMT as a pharmaceutical target. All authors read and approved the final manuscript.

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    Deryugina E Behrendt NExperimental approaches for understanding the role of matrix metalloproteinases in cancer invasionMatrix Proteases in Health and Disease2012 Weinheim: Wiley-VCH Verlag181211

    Not in our library

  34. 34.

    Lin CY Tsai PH Kandaswami CC Lee PP Huang CJ Hwang JJ Lee MT Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial–mesenchymal transitionCancer Sci2011 3815827

    Not in our library10.1111/j.1349-7006.2011.01861.x

  35. 35.

    Shah PP Fong MY Kakar SS PTTG induces EMT through integrin αVβ3-focal adhesion kinase signaling in lung cancer cellsOncogene2011 331243135

    Not in our library10.1038/onc.2011.488

  36. 36.

    Yoo YA Kang MH Lee HJ B-h K Park JK Kim HK Kim JS Oh SC Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancerCancer Res2011 370617070

    Not in our library10.1158/0008-5472.can-11-1338

  37. 37.

    Karihtala P Auvinen P Kauppila S Haapasaari K-M Jukkola-Vuorinen A Soini Y Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotypeBreast Cancer Res Treat2013 38190

    Not in our library10.1007/s10549-013-2442-0

  38. 38.

    Nisticò P Bissell MJ Radisky DC Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinasesCold Spring Harb Perspect Biol2012 3a011908

    Not in our library10.1101/cshperspect.a011908

  39. 39.

    Radisky DC Levy DD Littlepage LE Liu H Nelson CM Fata JE Leake D Godden EL Albertson DG Nieto MA Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instabilityNature2005 3123127

    Not in our library10.1038/nature03688

  40. 40.

    Ocaña Oscar H Córcoles R Fabra Á Moreno-Bueno G Acloque H Vega S Barrallo-Gimeno A Cano A Nieto MA Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1Cancer Cell2012 3709724

    Not in our library10.1016/j.ccr.2012.10.012

  41. 41.

    Tsai Jeff H Donaher Joana L Murphy Danielle A Chau S Yang J Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasisCancer Cell2012 3725736

    Not in our library10.1016/j.ccr.2012.09.022

  42. 42.

    Higgins DF Kimura K Bernhardt WM Shrimanker N Akai Y Hohenstein B Saito Y Johnson RS Kretzler M Cohen CD Eckardt KU Iwano M Haase VH Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transitionJ Clin Invest2007 338103820

    Not in our library10.1172/jci30487

  43. 43.

    Sahlgren C Gustafsson MV Jin S Poellinger L Lendahl U Notch signaling mediates hypoxia-induced tumor cell migration and invasionProc Natl Acad Sci U S A2008 363926397

    Not in our library10.1073/pnas.0802047105

  44. 44.

    Kaidi A Williams AC Paraskeva C Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxiaNat Cell Biol2007 3210217

    Not in our library10.1038/ncb1534

  45. 45.

    Yang F Sun L Li Q Han X Lei L Zhang H Shang Y SET8 promotes epithelial–mesenchymal transition and confers TWIST dual transcriptional activitiesEMBO J2012 3110123

    Not in our library10.1038/emboj.2011.364

  46. 46.

    Luo D Wang J Li J Post M Mouse snail is a target gene for HIFMol Cancer Res2011 3234245

    Not in our library10.1158/1541-7786.mcr-10-0214

  47. 47.

    Imai T Horiuchi A Wang C Oka K Ohira S Nikaido T Konishi I Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cellsAm J Pathol2003 314371447

    Not in our library10.1016/s0002-9440(10)63501-8

  48. 48.

    Bates RC DeLeo Iii MJ Mercurio AM The epithelial–mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxisExp Cell Res2004 3315324

    Not in our library10.1016/j.yexcr.2004.05.033

  49. 49.

    Wu Y Ginther C Kim J Mosher N Chung S Slamon D Vadgama JV Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cellsMol Cancer Res2012 315971606

    Not in our library10.1158/1541-7786.mcr-12-0155-t

  50. 50.

    Vincan E Barker N The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progressionClin Exp Metastasis2008 3657663

    Not in our library10.1007/s10585-008-9156-4

  51. 51.

    Hur K Toiyama Y Takahashi M Balaguer F Nagasaka T Koike J Hemmi H Koi M Boland CR Goel A MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasisGut2013 313151326

    Not in our library10.1136/gutjnl-2011-301846

  52. 52.

    Ward A Balwierz A Zhang JD Kublbeck M Pawitan Y Hielscher T Wiemann S Sahin O Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancerOncogene2013 311731182

    Not in our library10.1038/onc.2012.128

  53. 53.

    Fortier A-M Asselin E Cadrin M Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through Claudin1 Up-regulationJ Biol Chem2013 31155511571

    Not in our library10.1074/jbc.m112.428920

  54. 54.

    Vuoriluoto K Haugen H Kiviluoto S Mpindi JP Nevo J Gjerdrum C Tiron C Lorens JB Ivaska J Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancerOncogene2011 314361448

    Not in our library10.1038/onc.2010.509

  55. 55.

    Sohal SS Soltani Abhari A Weston S Wood-Baker R Walters E de Mello RAIntermediate filament vimentin and potential role in epithelial mesenchymal transition (EMT)Vimentin Concepts and Molecular Mechanisms2013 New York: Nova Publishers3761

    Not in our library

  56. 56.

    Hirano S Kimoto N Shimoyama Y Hirohashi S Takeichi M Identification of a neural alpha-catenin as a key regulator of cadherin function and multicellular organizationCell1992 3293301

    Not in our library10.1016/0092-8674(92)90103-j

  57. 57.

    Williams CS Zhang B Smith JJ Jayagopal A Barrett CW Pino C Russ P Presley SH Peng D Rosenblatt DO BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinomaJ Clin Invest2011 34056

    Not in our library10.1172/jci44228

  58. 58.

    Galván JA Astudillo A Vallina A Fonseca PJ Gómez-Izquierdo L García-Carbonero R González MV Epithelial-mesenchymal transition markers in the differential diagnosis of gastroenteropancreatic neuroendocrine tumorsAm J Clin Pathol2013 36172

    Not in our library10.1309/ajcpiv40istbxrax

  59. 59.

    Lioni M Brafford P Andl C Rustgi A El-Deiry W Herlyn M Smalley KS Dysregulation of claudin-7 leads to loss of E-cadherin expression and the increased invasion of esophageal squamous cell carcinoma cellsAm J Pathol2007 3709721

    Not in our library10.2353/ajpath.2007.060343

  60. 60.

    Kominsky SL Argani P Korz D Evron E Raman V Garrett E Rein A Sauter G Kallioniemi OP Sukumar S Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breastOncogene2003 320212033

    Not in our library10.1038/sj.onc.1206199

  61. 61.

    Shi Y Wu H Zhang M Ding L Meng F Fan X Expression of the epithelial-mesenchymal transition-related proteins and their clinical significance in lung adenocarcinomaDiagn Pathol2013 389

    Not in our library10.1186/1746-1596-8-89

  62. 62.

    Kagalwalla AF Akhtar N Woodruff SA Rea BA Masterson JC Mukkada V Parashette KR Du J Fillon S Protheroe CA Eosinophilic esophagitis: epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatmentJ Allergy Clin Immunol2012 313871396e1387

    Not in our library10.1016/j.jaci.2012.03.005

  63. 63.

    van Roy F Beyond E-cadherin: roles of other cadherin superfamily members in cancerNat Rev Cancer2014 3121134

    Not in our library10.1038/nrc3647

  64. 64.

    Pichler M Ress AL Winter E Stiegelbauer V Karbiener M Schwarzenbacher D Scheideler M Ivan C Jahn SW Kiesslich T Gerger A Bauernhofer T Calin GA Hoefler G MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patientsBr J Cancer2014 316141621

    Not in our library10.1038/bjc.2014.51

  65. 65.

    Zheng H Li W Wang Y Xie T Cai Y Wang Z Jiang B miR-23a inhibits E-cadherin expression and is regulated by AP-1 and NFAT4 complex during Fas-induced EMT in gastrointestinal cancerCarcinogenesis2014 3173183

    Not in our library10.1093/carcin/bgt274

  66. 66.

    Shah P Gau Y Sabnis G Histone deacetylase inhibitor entinostat reverses epithelial to mesenchymal transition of breast cancer cells by reversing the repression of E-cadherinBreast Cancer Res Treat2014 399111

    Not in our library10.1007/s10549-013-2784-7

  67. 67.

    Jin L Chen J Li L Li C Chen C Li S CRH suppressed TGFβ1-induced epithelial-mesenchymal transition via induction of E-cadherin in breast cancer cellsCell Signal2014 3757765

    Not in our library10.1016/j.cellsig.2013.12.017

  68. 68.

    Huang RYJ Wong MK Tan TZ Kuay KT Ng AHC Chung VY Chu YS Matsumura N Lai HC Lee YF Sim WJ Chai C Pietschmann E Mori S Low JJH Choolani M Thiery P An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)Cell Death Dis2013 3e915

    Not in our library10.1038/cddis.2013.442

  69. 69.

    Sun Y Wang B-E Leong KG Yue P Li L Jhunjhunwala S Chen D Seo K Modrusan Z Gao W-Q Settleman J Johnson L Androgen deprivation causes epithelial–mesenchymal transition in the prostate: implications for androgen-deprivation therapyCancer Res2012 3527536

    Not in our library10.1158/0008-5472.can-11-3004

  70. 70.

    Lee M-Y Chou C-Y Tang M-J Shen M-R Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulationClin Cancer Res2008 347434750

    Not in our library10.1158/1078-0432.ccr-08-0234

  71. 71.

    Zhu Y Nilsson M Sundfeldt K Phenotypic plasticity of the ovarian surface epithelium: TGF-β1 induction of epithelial to mesenchymal transition (EMT) in vitroEndocrinology2010 354975505

    Not in our library10.1210/en.2010-0486

  72. 72.

    Fernando RI Litzinger M Trono P Hamilton DH Schlom J Palena C The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cellsJ Clin Invest2010 3533

    Not in our library10.1172/jci38379

  73. 73.
    Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters · 2011
    No notice
  74. 74.

    Tanaka H Kono E Tran CP Miyazaki H Yamashiro J Shimomura T Fazli L Wada R Huang J Vessella RL An J Horvath S Gleave M Rettig MB Wainberg ZA Reiter RE Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistanceNat Med2010 314141420

    Not in our library10.1038/nm.2236

  75. 75.

    Sethi S Macoska J Chen W Sarkar FH Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasisAm J Transl Res2011 390

    Not in our library

  76. 76.

    Dawson H Koelzer VH Karamitopoulou E Economou M Hammer C Muller D-E Lugli A Zlobec I The apoptotic and proliferation rate of tumour budding cells in colorectal cancer outlines a heterogeneous population of cells with various impacts on clinical outcomeHistopathology2014 3577584

    Not in our library10.1111/his.12294

  77. 77.
    Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion · 2009
    No notice
  78. 78.

    Lo H-W Hsu S-C Xia W Cao X Shih J-Y Wei Y Abbruzzese JL Hortobagyi GN Hung M-C Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expressionCancer Res2007 390669076

    Not in our library10.1158/0008-5472.can-07-0575

  79. 79.

    Yang Z Zhang X Gang H Li X Li Z Wang T Han J Luo T Wen F Wu X Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expressionBiochem Biophys Res Commun2007 3925930

    Not in our library10.1016/j.bbrc.2007.05.023

  80. 80.

    Sánchez-Tilló E de Barrios O Siles L Amendola PG Darling DS Cuatrecasas M Castells A Postigo A ZEB1 promotes invasiveness of colorectal carcinoma cells through the opposing regulation of uPA and PAI-1Clin Cancer Res2013 310711082

    Not in our library10.1158/1078-0432.ccr-12-2675

  81. 81.

    Lee J Park M Park J Lee H Shin D Kang Y Lee C Kong G Loss of the polycomb protein Mel-18 enhances the epithelial–mesenchymal transition by ZEB1 and ZEB2 expression through the downregulation of miR-205 in breast cancerOncogene2013 313251335

    Not in our library10.1038/onc.2013.53

  82. 82.

    Perl A-K Wilgenbus P Dahl U Semb H Christofori G A causal role for E-cadherin in the transition from adenoma to carcinomaNature1998 3190193

    Not in our library10.1038/32433

  83. 83.

    Kevans D Wang LM Sheahan K Hyland J O’Donoghue D Mulcahy H O’Sullivan J Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein statusInt J Surg Pathol2011 3751760

    Not in our library10.1177/1066896911414566

  84. 84.

    Horcic M Koelzer VH Karamitopoulou E Terracciano L Puppa G Zlobec I Lugli A Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancerHum Pathol2013 3697705

    Not in our library10.1016/j.humpath.2012.07.026

  85. 85.

    Ueno H Murphy J Jass J Mochizuki H Talbot I Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancerHistopathology2002 3127132

    Not in our library10.1046/j.1365-2559.2002.01324.x

  86. 86.

    Berx G Cleton-Jansen A Nollet F De Leeuw W Van de Vijver M Cornelisse C Van Roy F E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancersEMBO J1995 36107

    Not in our library10.1002/j.1460-2075.1995.tb00301.x

  87. 87.

    Neve RM Chin K Fridlyand J Yeh J Baehner FL Fevr T Clark L Bayani N Coppe J-P Tong F Speed T Spellman PT DeVries S Lapuk A Wang NJ Kuo WL Stilwell JL Pinkel D Albertson DG Waldman FM McCormick F Dickson RB Johnson MD Lippman M Ethier S Gazdar A Gray JW A collection of breast cancer cell lines for the study of functionally distinct cancer subtypesCancer Cell2006 3515527

    Not in our library10.1016/j.ccr.2006.10.008

  88. 88.

    Burgess DJ Breast cancer: circulating and dynamic EMTNat Rev Cancer2013 3148149

    Not in our library10.1038/nrc3475

  89. 89.

    Yu M Bardia A Wittner BS Stott SL Smas ME Ting DT Isakoff SJ Ciciliano JC Wells MN Shah AM Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal compositionScience2013 3580584

    Not in our library10.1126/science.1228522

  90. 90.

    Kudo-Saito C Shirako H Takeuchi T Kawakami Y Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer CellsCancer Cell2009 3195206

    Not in our library10.1016/j.ccr.2009.01.023

  91. 91.

    Sulzer MA Leers MPG van Noord JA Bollen ECM Theunissen PHMH Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancerAm J Respir Crit Care Med1998 313191323

    Not in our library10.1164/ajrccm.157.4.9703099

  92. 92.

    Brabletz T Hlubek F Spaderna S Schmalhofer O Hiendlmeyer E Jung A Kirchner T Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and β-cateninCells Tissues Organs2005 35665

    Not in our library10.1159/000084509

  93. 93.

    Soltermann A Tischler V Arbogast S Braun J Probst-Hensch N Weder W Moch H Kristiansen G Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non–small cell lung cancerClin Cancer Res2008 374307437

    Not in our library10.1158/1078-0432.ccr-08-0935

  94. 94.

    Chaffer CL Brennan JP Slavin JL Blick T Thompson EW Williams ED Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2Cancer Res2006 31127111278

    Not in our library10.1158/0008-5472.can-06-2044

  95. 95.

    Ruiter DJ van Krieken JH van Muijen GN de Waal RM Tumour metastasis: is tissue an issue?Lancet Oncol2001 3109112

    Not in our library10.1016/s1470-2045(00)00229-1

  96. 96.

    Garber K Epithelial-to-mesenchymal transition is important to metastasis, but questions remainJ Natl Cancer Inst2008 3232239

    Not in our library10.1093/jnci/djn032

  97. 97.

    Nieto MA Cano A The epithelial–mesenchymal transition under control: global programs to regulate epithelial plasticitySemin Cancer Biol2012 3361368

    Not in our library10.1016/j.semcancer.2012.05.003

  98. 98.

    Voulgari A Pintzas A Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinicBiochim Biophys Acta2009 37590

    Not in our library10.1016/j.bbcan.2009.03.002

  99. 99.

    Bierie B Moses HL Transforming growth factor beta (TGF-β) and inflammation in cancerCytokine Growth Factor Rev2010 34959

    Not in our library10.1016/j.cytogfr.2009.11.008

  100. 100.

    Gore AJ Deitz SL Palam LR Craven KE Korc M Pancreatic cancer–associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferationJ Clin Invest2014 3338352

    Not in our library10.1172/jci71526

  101. 101.

    Shipitsin M Campbell LL Argani P Weremowicz S Bloushtain-Qimron N Yao J Nikolskaya T Serebryiskaya T Beroukhim R Hu M Molecular definition of breast tumor heterogeneityCancer Cell2007 3259273

    Not in our library10.1016/j.ccr.2007.01.013

  102. 102.

    Levy L Hill CS Smad4 dependency defines Two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responsesMol Cell Biol2005 381088125

    Not in our library10.1128/mcb.25.18.8108-8125.2005

  103. 103.

    Hollier BG Evans K Mani SA The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapiesJ Mammary Gland Biol Neoplasia2009 32943

    Not in our library10.1007/s10911-009-9110-3

  104. 104.

    Kajiyama H Shibata K Terauchi M Yamashita M Ino K Nawa A Kikkawa F Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cellsInt J Oncol2007 3277284

    Not in our library

  105. 105.

    Arumugam T Ramachandran V Fournier KF Wang H Marquis L Abbruzzese JL Gallick GE Logsdon CD McConkey DJ Choi W Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancerCancer Res2009 358205828

    Not in our library10.1158/0008-5472.can-08-2819

  106. 106.

    Kurrey NK Jalgaonkar SP Joglekar AV Ghanate AD Chaskar PD Doiphode RY Bapat SA Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cellsStem Cells2009 320592068

    Not in our library10.1002/stem.154

  107. 107.

    Kim MR Choi HK Cho KB Kim HS Kang KW Involvement of Pin1 induction in epithelial–mesenchymal transition of tamoxifen-resistant breast cancer cellsCancer Sci2009 318341841

    Not in our library10.1111/j.1349-7006.2009.01260.x

  108. 108.

    Singh S Sadacharan S Su S Belldegrun A Persad S Singh G Overexpression of vimentin: role in the invasive phenotype in an androgen-independent model of prostate cancerCancer Res2003 323062311

    Not in our library

  109. 109.

    Mani SA Guo W Liao M-J Eaton EN Ayyanan A Zhou AY Brooks M Reinhard F Zhang CC Shipitsin M Campbell LL Polyak K Brisken C Yang J Weinberg RA The epithelial-mesenchymal transition generates cells with properties of stem cellsCell2008 3704715

    Not in our library10.1016/j.cell.2008.03.027

  110. 110.
    Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition · 2008
    No notice
  111. 111.

    Li X Lewis MT Huang J Gutierrez C Osborne CK Wu M-F Hilsenbeck SG Pavlick A Zhang X Chamness GC Wong H Rosen J Chang JC Intrinsic resistance of tumorigenic breast cancer cells to chemotherapyJ Natl Cancer Inst2008 3672679

    Not in our library10.1093/jnci/djn123

  112. 112.

    Thomson S Buck E Petti F Griffin G Brown E Ramnarine N Iwata KK Gibson N Haley JD Epithelial to mesenchymal transition is a determinant of sensitivity of non–small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibitionCancer Res2005 394559462

    Not in our library10.1158/0008-5472.can-05-1058

  113. 113.

    Thomson S Petti F Sujka-Kwok I Epstein D Haley J Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancyClin Exp Metastasis2008 3843854

    Not in our library10.1007/s10585-008-9200-4

  114. 114.

    Byers LA Diao L Wang J Saintigny P Girard L Peyton M Shen L Fan Y Giri U Tumula PK Nilsson MB Gudikote J Tran H Cardnell RJG Bearss DJ Warner SL Foulks JM Kanner SB Gandhi V Krett N Rosen ST Kim ES Herbst RS Blumenschein GR Lee JJ Lippman SM Ang KK Mills GB Hong WK Weinstein JN An epithelial–mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistanceClin Cancer Res2013 3279290

    Not in our library10.1158/1078-0432.ccr-12-1558

  115. 115.

    Barr S Thomson S Buck E Russo S Petti F Sujka-Kwok I Eyzaguirre A Gibson NW Miglarese M Epstein D Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitionsClin Exp Metastasis2008 3685693

    Not in our library10.1007/s10585-007-9121-7

  116. 116.

    Yi JM Dhir M Van Neste L Downing SR Jeschke J Glöckner SC de Freitas Calmon M Hooker CM Funes JM Boshoff C Genomic and epigenomic integration identifies a prognostic signature in colon cancerClin Cancer Res2011 315351545

    Not in our library10.1158/1078-0432.ccr-10-2509

  117. 117.

    de Boer M van Dijck JA Bult P Borm GF Tjan-Heijnen VC Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastasesJ Natl Cancer Inst2010 3410425

    Not in our library10.1093/jnci/djq008

  118. 118.

    Volinia S Galasso M Sana ME Wise TF Palatini J Huebner K Croce CM Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNAProc Natl Acad Sci2012 330243029

    Not in our library10.1073/pnas.1200010109

  119. 119.

    Bastid J EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerationsCancer Metastasis Rev2012 3277283

    Not in our library10.1007/s10555-011-9344-6

  120. 120.

    De Sousa E Melo F Wang X Jansen M Fessler E Trinh A de Rooij LPMH de Jong JH de Boer OJ van Leersum R Bijlsma MF Rodermond H van der Heijden M van Noesel CJM Tuynman JB Dekker E Markowetz F Medema JP Vermeulen L Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesionsNat Med2013 3614618

    Not in our library10.1038/nm.3174

  121. 121.

    Jie D Zhongmin Z Guoqing L Sheng L Yi Z Jing W Liang Z Positive expression of LSD1 and negative expression of E-cadherin correlate with metastasis and poor prognosis of colon cancerDig Dis Sci2013 315811589

    Not in our library10.1007/s10620-012-2552-2

  122. 122.
    Cyclin D1, Id1 and EMT in breast cancer · 2011
    Not checked
  123. 123.

    Lee J Yang G Paik S Chung M Does E-cadherin or N-cadherin or epithelial-mesenchymal transition have a probability of clinical implication of the prognostic marker in invasive ductal carcinoma?Cancer Res2012 3Abstract nr P2-10-39

    Not in our library

  124. 124.

    Behnsawy HM Miyake H Harada K Fujisawa M Expression patterns of epithelial-mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomyBJU Int2013 33037

    Not in our library10.1111/j.1464-410x.2012.11551.x

  125. 125.

    Whiteland H Spencer-Harty S Thomas DH Davies C Morgan C Kynaston H Bose P Fenn N Lewis PD Bodger O Jenkins S Doak SH Putative prognostic epithelial-to-mesenchymal transition biomarkers for aggressive prostate cancerExp Mol Pathol2013 3220226

    Not in our library10.1016/j.yexmp.2013.07.010

  126. 126.

    Tanaka Y Terai Y Kawaguchi H Fujiwara S Yoo S Tsunetoh S Takai M Kanemura M Tanabe A Ohmichi M Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancerCancer Biol Ther2013 313

    Not in our library10.4161/cbt.22625

  127. 127.

    Rodrıguez-Gonzalez FG Mustafa DAM Mostert B Sieuwerts AM The challenge of gene expression profiling in heterogeneous clinical samplesMethods2013 34758

    Not in our library10.1016/j.ymeth.2012.05.005

  128. 128.

    Alkatout I Wiedermann M Bauer M Wenners A Jonat W Klapper W Transcription factors associated with epithelial–mesenchymal transition and cancer stem cells in the tumor centre and margin of invasive breast cancerExp Mol Pathol2013 3168173

    Not in our library10.1016/j.yexmp.2012.09.003

  129. 129.

    Aoyagi K Tamaoki M Nishumura T Sasaki H Technical considerations for analyzing EMT–MET data from surgical samplesCancer Lett2013 3105110

    Not in our library10.1016/j.canlet.2013.08.001

  130. 130.

    Yeung T Georges PC Flanagan LA Marg B Ortiz M Funaki M Zahir N Ming W Weaver V Janmey PA Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesionCell Motil Cytoskeleton2005 32434

    Not in our library10.1002/cm.20041

  131. 131.

    Nieto MA The ins and outs of the epithelial to mesenchymal transition in health and diseaseAnnu Rev Cell Dev Biol2011 3347376

    Not in our library10.1146/annurev-cellbio-092910-154036

  132. 132.

    Boyer B Vallés AM Edme N Induction and regulation of epithelial–mesenchymal transitionsBiochem Pharmacol2000 310911099

    Not in our library10.1016/s0006-2952(00)00427-5

  133. 133.

    Kalluri R Neilson EG Epithelial-mesenchymal transition and its implications for fibrosisJ Clin Investig2003 317761784

    Not in our library10.1172/jci20530

  134. 134.

    Chen YL Lv J Ye XL Sun MY Xu Q Liu CH Min LH Li HP Liu P Ding X Sorafenib inhibits transforming growth factor beta1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytesHepatology2011 317081718

    Not in our library10.1002/hep.24254

  135. 135.

    Zeisberg M Hanai J-i Sugimoto H Mammoto T Charytan D Strutz F Kalluri R BMP-7 counteracts TGF-[beta] 1-induced epithelial-to-mesenchymal transition and reverses chronic renal injuryNat Med2003 3964968

    Not in our library10.1038/nm888

  136. 136.

    Liu Y Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic interventionJ Am Soc Nephrol2004 3112

    Not in our library10.1097/01.asn.0000106015.29070.e7

  137. 137.
    FGFR4 role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer. · 2013
    Not checked
  138. 138.
    Sorafenib inhibits epithelial-mesenchymal transition through an epigenetic-based mechanism in human lung epithelial cells. · 2013
    Not checked
  139. 139.

    Feldmann G Dhara S Fendrich V Bedja D Beaty R Mullendore M Karikari C Alvarez H Iacobuzio-Donahue C Jimeno A Gabrielson KL Matsui W Maitra A Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancersCancer Res2007 321872196

    Not in our library10.1158/0008-5472.can-06-3281

  140. 140.

    Feldmann G Fendrich V McGovern K Bedja D Bisht S Alvarez H Koorstra JB Habbe N Karikari C Mullendore M Gabrielson KL Sharma R Matsui W Maitra A An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancerMol Cancer Ther2008 327252735

    Not in our library10.1158/1535-7163.mct-08-0573

  141. 141.

    Fuchs BC Fujii T Dorfman JD Goodwin JM Zhu AX Lanuti M Tanabe KK Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cellsCancer Res2008 323912399

    Not in our library10.1158/0008-5472.can-07-2460

  142. 142.

    Choi Y-L Bocanegra M Kwon MJ Shin YK Nam SJ Yang J-H Kao J Godwin AK Pollack JR LYN is a mediator of epithelial-mesenchymal transition and a target of dasatinib in breast cancerCancer Res2010 322962306

    Not in our library10.1158/0008-5472.can-09-3141

  143. 143.

    Menendez JA Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) statusCell Cycle2010 338073814

    Not in our library

  144. 144.
    Resveratrol Inhibits Pancreatic Cancer Stem Cell Characteristics in Human and KrasG12D Transgenic Mice by Inhibiting Pluripotency Maintaining Factors and Epithelial-Mesenchymal Transition · 2011
    No notice
  145. 145.

    Koorstra J Karikari CA Feldmann G Bisht S Rojas PL Offerhaus G Alvarez H Maitra A The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic targetCancer Biol Ther2009 3618626

    Not in our library10.4161/cbt.8.7.7923

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