Formation of the heart valves is one of critical steps in vertebrate cardiac development. Valvular heart anomaly can induce severe cardiac impairment, which is one of most common symptoms for congenital heart defects (CHD). The canonical Wnt/β-catenin signaling pathway, which is essential for numerous developmental processes, has also been suggested to be involved in the regulation of proliferation, differentiation, and migration of myocardium, endocardium and valve primordia at different stages. The canonical Wnt signaling also regulates the endocardial-mesenchymal transformation (EMT) process during the endocardial cushion formation. This paper reviews current knowledge about the canonical Wnt signaling pathway in heart valve development, including the functional diversities of Wnt activity in heart valve development at different stages and its interaction with other valve-relevant signaling pathways and the potential role of canonical Wnt activity in heart valve mesenchymal stem cells at the late developmental stage.
Cell Differentiation ; Cell Proliferation ; Epithelial-Mesenchymal Transition ; Heart Valves ; embryology ; Humans ; Wnt Signaling Pathway ; physiology

Epithelial-mesenchymal transition (EMT) is a process by which fully differentiated epithelial cells undergo a phenotypic conversion and assume a mesenchymal cell phenotype, including elongated morphology, enhanced migratory and invasiveness capacity, and greatly increased production of extracellular matrix (ECM) components. The EMTs associated with wound healing, tissue regeneration, and organ fibrosis are termed as type 2 EMT. Over the past two decades, emerging evidence suggested that injured epithelial cells, via type 2 EMT, may serve as important sources of fibroblasts and contribute to organ fibrosis, such as kidney, liver, lung and eyes. There is perhaps no doubt that adult epithelial cells can undergo EMT in vitro in response to transforming growth factor (TGF)-β1 and other inflammatory or pro-fibrotic stimuli. However, whether type 2 EMT really occurs in vivo, whethers it is actually a source of functional and activated interstitial fibroblasts and whether it contributes to tissue fibrosis have already been the subjects of heated debate. In this review, we will describe the main features of EMT, the major findings of type 2 EMT in vitro, the evidences for and against type 2 EMT in vivo and discuss the heterogeneity and pitfalls of the techniques used to detect EMT during fibrotic diseases. We suggest that in order to ascertain the existence of type 2 EMT in vivo, different proper phenotype markers of epithelial and mesenchymal cells should be jointly used and cell lineage tracking techniques should be standardized and avoid false positives. Finally, we believe that if EMT really occurs and contributes to tissue fibrosis, efforts should be made to block or reverse EMT to attenuate fibrotic process.
Animals ; Epithelial-Mesenchymal Transition ; physiology ; Fibroblasts ; cytology ; metabolism ; Fibrosis ; metabolism ; pathology ; Humans

Metastasis is the main cause of cancer mortality. One of the initiating events of cancer metastasis of epithelial tumors is epithelial-to-mesenchymal transition (EMT), during which cells dedifferentiate from a relatively rigid cell structure/morphology to a flexible and changeable structure/morphology often associated with mesenchymal cells. The presence of EMT in human epithelial tumors is reflected by the increased expression of genes and levels of proteins that are preferentially present in mesenchymal cells. The combined presence of these genes forms the basis of mesenchymal gene signatures, which are the foundation for classifying a mesenchymal subtype of tumors. Indeed, tumor classification schemes that use clustering analysis of large genomic characterizations, like The Cancer Genome Atlas (TCGA), have defined mesenchymal subtype in a number of cancer types, such as high-grade serous ovarian cancer and glioblastoma. However, recent analyses have shown that gene expression-based classifications of mesenchymal subtypes often do not associate with poor survival. This "paradox" can be ameliorated using integrated analysis that combines multiple data types. We recently found that integrating mRNA and microRNA (miRNA) data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer. This network consists of 8 major miRNAs and 214 mRNAs. Among the 8 miRNAs, 4 are known to be regulators of EMT. This review provides a summary of these 8 miRNAs, which were associated with the integrated mesenchymal subtype of serous ovarian cancer.
Cystadenocarcinoma, Serous ; genetics ; pathology ; Epithelial-Mesenchymal Transition ; Female ; Humans ; MicroRNAs ; physiology ; Ovarian Neoplasms ; genetics ; pathology

The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.
Carcinogenesis ; metabolism ; pathology ; Disease Progression ; Epithelial-Mesenchymal Transition ; physiology ; Humans ; Neoplasm Metastasis

Epithelial mesenchymal transition (EMT) is a process of normal cell physiological development, in which epithelial cells transform into mesenchyme cells through a specific program. EMT plays a key role in inflammatory reaction, cell development, tumor invasion, and metastasis and has an interrelation with prostate cancer stem cells. Recent researches show the involvement of EMT in the development and metastasis of prostate cancer. This article reviews the specific roles and action mechanisms of EMT in the progression of prostate cancer.
Biomedical Research ; Cell Differentiation ; Disease Progression ; Epithelial Cells ; physiology ; Epithelial-Mesenchymal Transition ; physiology ; Humans ; Male ; Mesenchymal Stromal Cells ; Neoplastic Stem Cells ; physiology ; Prostatic Neoplasms ; pathology

Epithelial-mesenchymal transition (EMT) refers to tne transition during which epithelial cells undergo the loss of apical-basal polarity, acquisition of migration capability and transformation into mesenchymal cells. EMT induces breast cancer in situ to developing into metastasis and associates with the drug resistence. The multiple elements including signal pathways, transcriptional factors and downstream genes orchestrate the transition. Among them, the transforming growth factor β (TGF-β) signaling pathway plays a key role in the regulation of EMT in breast cancer. And this paper reviews the development of TGF-β signaling pathway induced EMT in breast cancer.
Breast Neoplasms ; metabolism ; Epithelial Cells ; Epithelial-Mesenchymal Transition ; Humans ; Signal Transduction ; Transcription Factors ; Transforming Growth Factor beta ; physiology

Epithelial-mesenchymal transition plays an important role in the development and progression of endometriosis. Mesenchymal-epithelial transition is involved in forming localized lesions of endometriosis, while EMT is involved in the injury, repair and fibrosis induced by local inflammation of endometriosis and the process of cell invasion and metastasis. The studies of signal transduction pathway and related proteins of epithelial-mesenchymal transition in the process of endometriosis may provide new targets for diagnosis and treatment of endometriosis.
Endometriosis ; complications ; etiology ; pathology ; physiopathology ; Epithelial-Mesenchymal Transition ; physiology ; Female ; Fibrosis ; complications ; Humans ; Inflammation ; complications ; Signal Transduction ; physiology

Erythropoietin-producing hepatoma (EPH) receptors are considered the largest family of receptor tyrosine kinases and play key roles in physiological and pathologic processes in development and disease. EPH receptors are often overexpressed in human malignancies and are associated with poor prognosis. However, the functions of EPH receptors in epithelial-mesenchymal transition (EMT) remain largely unknown. This review depicts the relationship between EPH receptors and the EMT marker E-cadherin as well as the crosstalk between EPH receptors and the signaling pathways involved EMT. Further discussion is focused on the clinical significance of EPH receptors as candidates for targeting in cancer therapeutics. Finally, we summarize how targeted inhibition of both EPH receptors and EMT-related signaling pathways represents a novel strategy for cancer treatment.
Antineoplastic Agents ; Cadherins ; Epithelial-Mesenchymal Transition ; Humans ; Neoplasms ; Receptor Protein-Tyrosine Kinases ; Receptors, Eph Family ; physiology ; Signal Transduction

PURPOSE: Tuberculous pleurisy is the most frequent extrapulmonary manifestation of tuberculosis. In spite of adequate treatment, pleural fibrosis is a common complication, but the mechanism has not been elucidated. This study is to determine whether epithelial to mesenchymal transition (EMT) of mesothelial cells occurs in tuberculous pleurisy. MATERIALS AND METHODS: Normal pleural mesothelial cells, isolated from irrigation fluids during operations for primary spontaneous pneumothorax, were characterized by immunofluorescence and reverse transcription polymerase chain reaction (RT-PCR). These cells were treated in vitro with various cytokines, which were produced in the effluents of tuberculous pleurisy. The isolated cells from the effluents of tuberculous pleurisy were analyzed by immunofluorescence and RT-PCR analysis. RESULTS: The isolated cells from the irrigation fluid of primary spontaneous pneumothorax had epithelial characteristics. These cells, with transforming growth factor-beta1 and/or interleukin-1beta treatment, underwent phenotypic transition from epithelial to mesenchymal cells, with the loss of epithelial morphology and reduction in cytokeratin and E-cadherin expression. Effluent analysis from tuberculous pleurisy using immunofluorescence and RT-PCR demonstrated two phenotypes that showed mesenchymal characteristics and both epithelial & mesencymal characteristics. CONCLUSION: Our results suggest that pleural mesothelial cells in tuberculous pleurisy have been implicated in pleural fibrosis through EMT.
Cells, Cultured ; Epithelial Cells/*pathology ; Epithelial-Mesenchymal Transition/*physiology ; Fluorescent Antibody Technique ; Humans ; Pleura/*pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Tuberculosis, Pleural/*pathology

OBJECTIVEThe objective of this paper was to study the expression of related protein and Twist transcription factor of epithelial-mesenchymal transition in oral squamous cell carcinoma (OSCC) tissue and the correlations of OSCC and oral squamous cell carcino-metastasis. The paper also investigated the clinical significance of expression on OSCC.

METHODSThe labels of epithelium materialization (E-cadherin and cytokeratin), stromal labels (N-cadherin), transcription factor Twist protein, and mRNA expression in 30 OSCC tissues were investigated via immunohistochemistry and in situ hybridization. The paper also conducted contrast analysis with clinicopathology.

RESULTSImmunization result showed that the expressions of Twist and N-cadherin in the OSCC group were more significant than those of the normal group (P<0.05). The expressions of E-cadherin and keratin in OSCC were significantly lower than those of the normal group (P<0.05). In the moderate- and low-differentiated group of OSCC, the expressions of Twist and N-cadherin were higher than those of the high-differentiated group (P<0.05). The expressions of E-cadherin and keratin were lower than those in the high-differentiated group (P<0.05). In the lymphatic metastasis group, the expressions of Twist and N-cadherin were higher than those of no-lymphatic metastasis group (P<0.05). The expressions of E-cadherin and keratin were lower than those of the no-lymphatic metastasis group (P< 0.05). Results of in situ hybridization showed that the expression of Twist mRNA in the moderate- and low-differentiated groups of OSCC, T3, and T4 groups as well as that of the lymphatic metastasis group were higher than those of the high-differentiated, T1 and T2 groups, and no-separate lymphatic metastasis group, and the differences were statistically significant (P<0.05).

CONCLUSIONEpithelium materialization exists in OSCC tissue. Twist can enhance the invasiveness of tumor cell and promote the infiltration and metastasis of OSCC. The combined detection of Twist, E-cadherin, and N-cadherin expressions can effectively predict and estimate OSCC metastasis.

Cadherins ; Carcinoma, Squamous Cell ; metabolism ; Epithelial Cells ; Epithelial-Mesenchymal Transition ; physiology ; Epithelium ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Mouth Neoplasms ; metabolism ; RNA, Messenger ; Twist-Related Protein 1 ; metabolism