関: EMT、epithelial mesenchymal transformation、epithelial-to-mesenchymal transition

WordNet

make or undergo a transition (from one state or system to another); "The airline transitioned to more fuel-efficient jets"; "The adagio transitioned into an allegro"
a musical passage moving from one key to another (同)modulation
a change from one place or state or subject or stage to another
a passage that connects a topic to one that follows
cause to convert or undergo a transition; "the company had to transition the old practices to modern technology"
of or belonging to the epithelium; "epithelial layer"

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(…から…へ)移り変わること,変遷;(…から…への)過渡期《+from+名+to+名》

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/02/21 19:26:52」(JST)

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Epithelial to Mesenchmyal Cell Transition – loss of cell adhesion leads to constriction and extrusion of newly mesenchymal cell.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis for cancer progression.

Introduction

Human embryo—length, 2 mm. Dorsal view, with the amnion laid open. X 30.

Epithelial–mesenchymal transition was first recognized as a feature of embryogenesis.^[1] EMT, and its reverse process, MET (mesenchymal-epithelial transition) are critical for development of many tissues and organs in the developing embryo, and numerous embryonic events such as gastrulation, neural crest formation, heart valve formation, palatogenesis and myogenesis.^[2] Epithelial and mesenchymal cells differ in phenotype as well as function. Epithelial cells are closely connected to each other by tight junctions, gap junctions and adherens junctions, have an apico-basal polarity, polarization of the actin cytoskeleton and are bound by a basal lamina at their basal surface. Mesenchymal cells, on the other hand, lack this polarization, have a spindle-shaped morphology and interact with each other only through focal points.^[3] Epithelial cells express high levels of E-cadherin, whereas mesenchymal cells express those of N-cadherin, fibronectin and vimentin. Thus, EMT entails profound morphological and phenotypic changes to a cell. Based on the biological context, EMT has been categorized into 3 types - developmental (Type I), fibrosis^[4] and wound healing (Type II), and cancer (Type III).^[5]

Inducers

Loss of E-cadherin is considered to be a fundamental event in EMT. Many transcription factors (TFs) that can repress E-cadherin directly or indirectly can be considered as EMT-TF (EMT inducing TFs). SNAI1/Snail 1, SNAI2/Snail 2 (also known as Slug), ZEB1, ZEB2, E47 and KLF8 (Kruppel-like factor 8) can bind to E-cadherin promoter and repress its transcription, whereas factors such as Twist, Goosecoid, E2.2 (also known as TCF4), homeobox protein SIX1 and FOXC2 (fork-head box protein C2) repress E-cadherin indirectly.^[6]^[7] SNAIL and ZEB factors bind to E-box consensus sequences on the promoter region, while KLF8 binds to promoter through GT boxes. These EMT-TFs not only directly repress E-cadherin, but also repress transcriptionally other junctional proteins, including claudins and desmosomes, thus facilitating EMT. On the other hand, transcription factors such as grainyhead-like protein 2 homologue (GRHL2), and ETS-related transcription factors ELF3 and ELF5 are downregulated during EMT - rather they actively drive MET when overexpressed in mesenchymal cells.^[8]^[9] Since EMT in cancer progression recaptures EMT in developmental programs, many of the EMT-TFs are involved in promoting metastasis.^[10]

Several signaling pathways (TGF-beta, FGF, EGF, HGF, Wnt/beta-catenin and Notch) and hypoxia may induce EMT. In particular, Ras-MAPK has been shown to activate Snail and Slug. Slug triggers the steps of desmosomal disruption, cell spreading, and partial separation at cell–cell borders, which comprise the first and necessary phase of the EMT process. On the other hand, Slug cannot trigger the second phase,^[11] which includes the induction of cell motility, repression of the cytokeratin expression, and activation of vimentin expression.^[12] Snail and Slug are known to regulate the expression of isoforms of another transcription factor p63 that is required for proper development of epithelial structures.^[13] The altered expression of p63 isoforms reduced cell–cell adhesion and increased the migratory properties of cancer cells. The p63 factor is involved in inhibiting EMT and reduction of certain p63 isoforms may be important in the development of epithelial cancers.^[14] Some of them are known to regulate the expression of cytokeratins.^[15] Recently, activation of the phosphatidylinositol 3' kinase (PI3K)/AKT axis is emerging as a central feature of EMT. Similarly, Hedgehog, nuclear factor-kappaB and Activating Transcription Factor 2 have been implicated to be involved in EMT.^[16]^[17]^[18]

Wnt signaling pathway regulates EMT in gastrulation, cardiac valve formation and cancer.^[19] Activation of Wnt pathway in breast cancer cells induces the EMT regulator SNAIL and upregulates the mesenchymal marker, vimentin. Also, active Wnt/beta-catenin pathway correlates with poor prognosis in breast cancer patients in the clinic. Similarly, TGF-beta activates the expression of SNAIL and ZEB to regulate EMT in heart development, palatogenesis and cancer. The breast cancer bone metastasis has activated TGF-beta signaling, which contributes to the formation of these lesions.^[20] However, on the other hand, p53, a well-known tumor suppressor, represses EMT by activating the expression of various microRNAs - miR-200 and miR-34 that inhibit the production of protein ZEB and SNAIL, and thus maintain the epithelial phenotype.^[21]

In development and wound healing

After the initial stage of embryogenesis, the implantation of the embryo and the initiation of placenta formation are associated with EMT. The trophoectoderm cells undergo EMT to facilitate the invasion of endometrium and appropriate placenta placement, thus enabling nutrient and gas exchange to the embryo. Later in embryogenesis, during gastrulation, EMT allows the cells to ingress in a specific area of the embryo - the primitive streak in amniotes, and the ventral furrow in Drosophila. The cells in this tissue express E-cadherin and apical-basal polarity.^[22] Since gastrulation is a very rapid process, E-cadherin is repressed transcriptionally by Twist and SNAI1 (commonly called Snail), and at the protein level by P38 interacting protein. The primitive streak, through invagination, further generates mesoendoderm, which separates to form a mesoderm and an endoderm, again through EMT. Mesenchymal cells from the primitive streak participate also in the formation of many epithelial mesodermal organs, such as notochord as well as somites, through the reverse of EMT, i.e. mesenchymal–epithelial transition. Amphioxus forms an epithelial neural tube and dorsal notochord but does not have the EMT potential of the primitive streak. In higher chordates, the mesenchyme originates out of the primitive streak migrates anteriorly to form the somites and participate with neural crest mesenchyme in formation of the heart mesoderm.

In vertebrates, epithelium and mesenchyme are the basic tissue phenotypes. During embryonic development, migratory neural crest cells are generated by EMT involving the epithelial cells of the neuroectoderm. As a result, these cells dissociate from neural folds, gain motility, and disseminate to various parts of the embryo, where they differentiate to many other cell types. Also, craniofacial crest mesenchyme that forms the connective tissue forming the head and face, is formed by neural tube epithelium by EMT.^[23] EMT takes place during the construction of the vertebral column out of the extracellular matrix, which is to be synthesized by fibroblasts and osteoblasts that encircle the neural tube. The major source of these cells are sclerotome and somite mesenchyme as well as primitive streak. Mesenchymal morphology allows the cells to travel to specific targets in the embryo, where they differentiate and/or induce differentiation of other cells.^[23]^[24]

During wound healing, keratinocytes at the border of the wound undergo EMT and undergo re-epithelialization or MET when the wound is closed. Snail2 expression at the migratory front influences this state, as its overexpression accelerates wound healing. Similarly, in each menstrual cycle, the ovarian surface epithelium undergoes EMT during post-ovulatory wound healing.^[25]

In cancer progression and metastasis

Initiation of metastasis requires invasion, which is enabled by EMT. Carcinoma cells in primary tumor lose cell-cell adhesion mediated by E-cadherin repression and break through the basement membrane with increased invasive properties, and enter the bloodstream through intravasation. Later, when these circulating tumor cells (CTCs) exit the bloodstream to form micrometastases, they undergo MET for clonal outgrowth at these metastatic sites. Thus, EMT and MET form the initiation and completion of the invasion-metastasis cascade.^[26]

EMT confers resistance to oncogene-induced premature senescence. Twist1 and Twist2, as well as ZEB1 protects human cells and mouse embryonic fibroblasts from senescence. Similarly, TGFβ can promote tumor invasion and evasion of immune surveillance at advanced stages. When TGFβ acts on activated Ras-expressing mammary epithelial cells, EMT is favored and apoptosis is inhibited.^[27] This effect can be reversed by inducers of epithelial differentiation, such as GATA-3.^[28]

EMT has been shown to be induced by androgen deprivation therapy in metastatic prostate cancer.^[10] Activation of EMT programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications.^[10]

EMT has been indicated to be involved in acquiring drug resistance. Gain of EMT markers was found to be associated with the resistance of ovarian carcinoma epithelial cell lines to paclitaxel. Similarly, SNAIL also confers resistance to paclitaxel, adriamycin and radiotherapy by inhibiting p53-mediated apoptosis.^[29] Furthermore, inflammation, that has been associated with the progression of cancer and fibrosis, was recently shown to be related to cancer through inflammation-induced EMT. Thus, EMT not only enables cells the migratory phenotype, but also acts on multiple immunosuppression, drug resistance, evasion of apoptosis, thus showing an altered response of the host to the tumor.

Some evidence suggests that cells that undergo EMT gain stem cell-like properties, thus giving rise to Cancer Stem Cells (CSCs). Upon transfection by activated Ras, a subpopulation of cells exhibiting the putative stem cell markers CD44high/CD24low increases with the concomitant induction of EMT.^[30] Also, ZEB1 is capable of conferring stem cell-like properties, thus strengthening the relationship between EMT and stemness. This property conferred by EMT is thus doubly dangerous duo for the patient, as it not only enables the carcinoma cells to enter the bloodstream, but also endows them with properties of stemness by virtue of which these cells have increased tumorigenic and proliferative potential.^[31]

However, recent studies have further shifted the primary effects of EMT away from invasion and metastasis, toward resistance to chemotherapeutic agents. Research on breast cancer and pancreatic cancer both demonstrated no difference cells' in metastatic potential upon acquisition of EMT.^[32]^[33] These are in agreement with another study showing that the EMT transcription factor TWIST actually requires intact adherens junctions in order to mediate local invasion in breast cancer.^[34] The effects of EMT and its relationship to invasion and metastasis may therefore be highly context specific.

Generation of endocrine progenitor cells from pancreatic islets

Similar to generation of Cancer Stem Cells, EMT was demonstrated to generate endocrine progenitor cells from human pancreatic islets.^[35] Initially, the human islet-derived progenitor cells (hIPCs) were proposed to be better precursors since β-cell progeny in these hIPCs inherit epigenetic marks that define an active insulin promoter region.^[36] However, later, another set of experiments suggested that labelled β-cells de-differentiate to a mesenchymal-like phenotype in vitro, but fail to proliferate; thus initiating a debate.^[37]^[38]^[39]

Since these studies in human islets lacked lineage-tracing analysis, these findings from irreversibly tagged beta cells in mice were extrapolated to human islets. Thus, using a dual lentiviral and genetic lineage tracing system to label β-cells, it was convincingly demonstrated that adult human islet β-cells undergo EMT and proliferate in vitro.^[40]^[41] Also, these findings were confirmed in human fetal pancreatic insulin-producing cells, and the mesenchymal cells derived from pancreatic islets can undergo the reverse of EMT - MET - to generate islet-like cell aggregates.^[42]

Thus, the concept of generating progenitors from insulin-producing cells by EMT or generation of Cancer Stem Cells during EMT in cancer may have potential for replacement therapy in diabetes, and call for drugs targeting inhibiting EMT in cancer.

Partial EMT or a hybrid E/M phenotype

Not all cells undergo a complete EMT, i.e. losing their cell-cell adhesion and gaining solitary migration characteristics. Instead, most cells undergo partial EMT, a state in which they retain some epithelial traits such as cell-cell adhesion or apico-basal polarity, and gain migratory traits, thus cells in this hybrid epithelial/mesenchymal (E/M) phenotype are endowed with special properties such as collective cell migration.^[34]^[43]^[44]^[45]^[46]^[47]^[48]^[49] Two mathematical models have been proposed, attempting to explain the emergence of this hybrid E/M phenotype,^[46]^[50] and its highly likely that different cell lines adopt different hybrid state(s), as shown by experiments in MCF10A, HMLE and H1975 cell lines.^[47]^[51] Although a hybrid E/M state has been referred to as 'metastable' or transient, recent experiments in H1975 cells suggest that this state can be stably maintained by cells.^[52]

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Commentary: Epithelial-to-mesenchymal transition in pancreatic islet β cells

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English Journal

Synergistic effect of lung tumor-associated dendritic cell-derived HB-EGF and CXCL5 on cancer progression.

Kuo PL1, Huang MS, Hung JY, Chou SH, Chiang SY, Huang YF, Yang CJ, Tsai MJ, Chang WA, Hsu YL.Author information 1Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.AbstractThe interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and its effect on cancer development. The combination of HB-EGF (heparin-binding EGF-like growth factor) and CXCL5 (CXCL5/epithelial neutrophil-activating peptide-78) produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB-EGF plus CXCL5-mediated tumor spheroid formation in a three-dimensional culture system, suggesting that AKT/HSP27 was required for HB-EGF/CXCL5-mediated cancer progression. Inhibiting RSK also reduces the modulation of c-Fos phosphorylation, Snail upregulation and cell migration by HB-EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB-EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross-points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemotherapy or immunotherapy.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Jul 1;135(1):96-108. doi: 10.1002/ijc.28673. Epub 2014 Jan 8.
The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and it
PMID 24346967

Protumorigenic effects of Snail-expression fibroblasts on colon cancer cells.

Herrera A1, Herrera M, Alba-Castellón L, Silva J, García V, Loubat-Casanovas J, Alvarez-Cienfuegos A, Miguel García J, Rodriguez R, Gil B, Ma Jesús Citores, Ma Jesús Larriba, Ignacio Casal J, de Herreros AG, Bonilla F, Peña C.Author information 1Department of Medical Oncology, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain.AbstractSnail1 is a transcriptional factor that plays an important role in epithelial-mesenchymal transition and in the acquisition of invasive properties by epithelial cells. In colon tumors, Snail1 expression in the stroma correlates with lower specific survival of cancer patients. However, the role(s) of Snail1 expression in stroma and its association with patients' survival have not been determined. We used human primary carcinoma-associated fibroblasts (CAFs) or normal fibroblasts (NFs) and fibroblast cell lines to analyze the effects of Snail1 expression on the protumorigenic capabilities in colon cancer cells. Snail1 expression was higher in CAFs than in NFs and, as well as α-SMA, a classic marker of activated CAFs. Moreover, in tumor samples from 50 colon cancer patients, SNAI1 expression was associated with expression of other CAF markers, such as α-SMA and fibroblast activation protein. Interestingly, coculture of CAFs with colon cells induced a significant increase in epithelial cell migration and proliferation, which was associated with endogenous SNAI1 expression levels. Ectopic manipulation of Snail1 in fibroblasts demonstrated that Snail1 expression controlled migration as well as proliferation of cocultured colon cancer cells in a paracrine manner. Furthermore, expression of Snail1 in fibroblasts was required for the coadjuvant effect of these cells on colon cancer cell growth and invasion when coxenografted in nude mice. Finally, cytokine profile changes, particularly MCP-3 expression, in fibroblasts are put forward as mediators of Snail1-derived effects on colon tumor cell migration. In summary, these studies demonstrate that Snail1 is necessary for the protumorigenic effects of fibroblasts on colon cancer cells.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Jun 15;134(12):2984-90. doi: 10.1002/ijc.28613. Epub 2013 Nov 29.
Snail1 is a transcriptional factor that plays an important role in epithelial-mesenchymal transition and in the acquisition of invasive properties by epithelial cells. In colon tumors, Snail1 expression in the stroma correlates with lower specific survival of cancer patients. However, the role(s) of
PMID 24242829

GPI/AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids.

Gallardo-Pérez JC1, Rivero-Segura NA1, Marín-Hernández A1, Moreno-Sánchez R1, Rodríguez-Enríquez S2.Author information 1Departamento de Bioquímica, Instituto Nacional de Cardiología, Tlalpan, México DF 14080, México.2Departamento de Bioquímica, Instituto Nacional de Cardiología, Tlalpan, México DF 14080, México; Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, México. Electronic address: saren960201@hotmail.com.AbstractEpithelial-mesenchymal transition (EMT) and cellular invasiveness are two pivotal processes for the development of metastatic tumor phenotypes. The metastatic profile of non-metastatic MCF-7 cells growing as multi-cellular tumor microspheroids (MCTSs) was analyzed by determining the contents of the EMT, invasive and migratory proteins, as well as their migration and invasiveness potential and capacity to secrete active cytokines such as the glucose phosphate isomerase/AMF (GPI/AMF). As for the control, the same analysis was also performed in MCF-7 and MDA-MB-231 (highly metastatic, MDA) monolayer cells, and in stage IIIB and IV human metastatic breast biopsies. The proliferative cell layers (PRL) of mature MCF-7 MCTSs, MDA monolayer cells and metastatic biopsies exhibited increased cellular contents (2-15 times) of EMT (β-catenin, SNAIL), migratory (vimentin, cytokeratin, and fibronectin) and invasive (MMP-1, VEGF) proteins versus MCF-7 monolayer cells, quiescent cell layers of mature MCF-7 MCTS and non-metastatic breast biopsies. The increase in metastatic proteins correlated with substantially elevated cellular abilities for migration (18-times) and invasiveness (13-times) and with the higher level (6-times) of the cytokine GPI/AMF in the extracellular medium of PRL, as compared to MCF-7 monolayer cells. Interestingly, the addition of the GPI/AMF inhibitors erythrose-4-phosphate or 6-phosphogluconate at micromolar doses significantly decreased its extracellular activity (>80%), with a concomitant diminution in the metastatic protein content and migratory tumor cell capacity, and with no inhibitory effect on tumor lactate production or toxicity on 3T3 mouse fibroblasts. The present findings provide new insights into the discovery of metabolic inhibitors to be used as complementary therapy against metastatic and aggressive tumors.
Biochimica et biophysica acta.Biochim Biophys Acta.2014 Jun;1843(6):1043-53. doi: 10.1016/j.bbamcr.2014.01.013. Epub 2014 Jan 16.
Epithelial-mesenchymal transition (EMT) and cellular invasiveness are two pivotal processes for the development of metastatic tumor phenotypes. The metastatic profile of non-metastatic MCF-7 cells growing as multi-cellular tumor microspheroids (MCTSs) was analyzed by determining the contents of the
PMID 24440856

Japanese Journal

Induction of palate epithelial mesenchymal transition by transforming growth factor β3 signaling

Jalali Azadeh,Zhu Xiujuan,Liu ChangChih [他]
Development, growth & differentiation 54(6), 633-648, 2012-08
NAID 40019395360

腹膜透析液の生体適合性

樋口千恵子
東京女子医科大学雑誌 82(E2), E388-E393, 2012-07-31
… 動物実験では低pH, GDPの一つである3-deoxyglucosoneは腹膜中皮細胞のepithelial mesenchymal transition(EMT)を引き起こし、腹膜のコラーゲン産生亢進、腹膜肥厚を引き起こす。 …
NAID 110009435918

Related Pictures

★リンクテーブル★

リンク元	「上皮間葉転換」「EMT」「上皮間充織転換」
関連記事	「transition」「mesenchyma」「epithelial」「mesenchymal」「epithelia」

「上皮間葉転換」

　　[★]

英: epithelial-to-mesenchymal transition、epithelial mesenchymal transformation、epithelial mesenchymal transition、epithelial-to-mesenchymal transitions、EMT
関: 上皮間充織変移、上皮間充織転換

[show details]

上皮間葉転換 EMT : 約 29,400 件
上皮間充織変移 EMT : 12 件

上皮間葉転換 : 約 69,600 件
上皮間充織変移 : 13 件

「EMT」

　　[★]

「上皮間充織転換」

　　[★]

英: epithelial-to-mesenchymal transition、epithelial mesenchymal transformation、epithelial mesenchymal transition
関: 上皮間充織変移、上皮間葉転換

「transition」

　　[★]

n.

(相の)転移、移行、推移、移行期、遷移、変遷、トランジション

関: dissemination、entry、immigration、metastases、metastasis、metastasize、shift、succession、transfer、transference、transit、transition state、transitional、transitional period、translocation、travel

「mesenchyma」

　　[★]

間葉

関: dorsal mesoderm、intermediate mesoderm、lateral plate mesoderm、mesenchymal、mesenchyme、mesoderm、paraxial mesoderm

「epithelial」

　　[★]

上皮の、上皮系の、上皮性の、上皮型の

関: epidermal、epithelia、epithelium

「mesenchymal」

　　[★]

adj.

間葉系の、間葉の、間充織の

関: mesenchyma、mesenchyme

「epithelia」

　　[★]

n.

epitheliumの複数形
上皮

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案内

epithelial mesenchymal transition