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Epithelial–mesenchymal transition

December 15, 2023

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 in cancer progression.

Epithelial-mesenchymal transition
Diagram showing the epithelial-mesenchymal transition
Details
Precursorendoderm
Identifiers
MeSHD058750
Anatomical terminology
[edit on Wikidata]

Introduction edit

 
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 by Betty Hay in the 1980s.[1][2] 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, secondary palate development, and myogenesis.[3] Epithelial and mesenchymal cells differ in phenotype as well as function, though both share inherent plasticity.[2] 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.[4] 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.[5]

Based on the biological context, EMT has been categorized into 3 types: developmental (Type I), fibrosis[6] and wound healing (Type II), and cancer (Type III).[7][8][9]

Inducers edit

 
Key inducers of the epithelial to mesenchymal transition process.
 
Epithelial to mesenchymal cell transition – loss of cell adhesion leads to constriction and extrusion of newly mesenchymal cell.

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, TCF3 and KLF8 (Kruppel-like factor 8) can bind to the E-cadherin promoter and repress its transcription, whereas factors such as Twist, Goosecoid, TCF4 (also known as E2.2), homeobox protein SIX1 and FOXC2 (fork-head box protein C2) repress E-cadherin indirectly.[10][11] 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 and are found to actively drive MET when overexpressed in mesenchymal cells.[12][13] Since EMT in cancer progression recaptures EMT in developmental programs, many of the EMT-TFs are involved in promoting metastatic events.[14][15]

Several signaling pathways (TGF-β, FGF, EGF, HGF, Wnt/beta-catenin and Notch) and hypoxia may induce EMT.[7][16][17] In particular, Ras-MAPK has been shown to activate Snail and Slug.[18][19][20] 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,[21] which includes the induction of cell motility, repression of the cytokeratin expression, and activation of vimentin expression.[22] Snail and Slug are known to regulate the expression of p63 isoforms, another transcription factor that is required for proper development of epithelial structures.[23] 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.[24] Some of them are known to regulate the expression of cytokeratins.[25] The phosphatidylinositol 3' kinase (PI3K)/AKT axis, Hedgehog signaling pathway, nuclear factor-kappaB and Activating Transcription Factor 2 have also been implicated to be involved in EMT.[26][27][28][29]

Wnt signaling pathway regulates EMT in gastrulation, cardiac valve formation and cancer.[30] 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-β activates the expression of SNAIL and ZEB to regulate EMT in heart development, palatogenesis, and cancer. The breast cancer bone metastasis has activated TGF-β signaling, which contributes to the formation of these lesions.[31] 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.[32]

In development and wound healing edit

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.[33] 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.[34] 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.[34][35]

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.[36]

In cancer progression and metastasis edit

Initiation of metastasis requires invasion, which is enabled by EMT.[37][38] Carcinoma cells in a 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 micro-metastases, they undergo MET for clonal outgrowth at these metastatic sites. Thus, EMT and MET form the initiation and completion of the invasion-metastasis cascade.[39] At this new metastatic site, the tumor may undergo other processes to optimize growth. For example, EMT has been associated with PD-L1 expression, particularly in lung cancer. Increased levels of PD-L1 suppresses the immune system which allows the cancer to spread more easily. [40]

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, TGF-β can promote tumor invasion and evasion of immune surveillance at advanced stages. When TGF-β acts on activated Ras-expressing mammary epithelial cells, EMT is favored and apoptosis is inhibited.[41] This effect can be reversed by inducers of epithelial differentiation, such as GATA-3.[42]

EMT has been shown to be induced by androgen deprivation therapy in metastatic prostate cancer.[14] 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.[14] Oncogenic PKC-iota can promote melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted an increase E-cadherin and RhoA levels while decreasing total Vimentin, phosphorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma.[43][44]

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.[45] 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.[46] Consequently, EMT enables cells to gain a migratory phenotype, as well as induce multiple immunosuppression, drug resistance, evasion of apoptosis mechanisms.

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.[47] Also, ZEB1 is capable of conferring stem cell-like properties, thus strengthening the relationship between EMT and stemness. Thus, EMT may present increased danger to cancer patients, as EMT not only enables the carcinoma cells to enter the bloodstream, but also endows them with properties of stemness which increases tumorigenic and proliferative potential.[48]

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 in cells' metastatic potential upon acquisition of EMT.[49][50] 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.[51] The effects of EMT and its relationship to invasion and metastasis may therefore be highly context specific.

In urothelial carcinoma cell lines overexpression of HDAC5 inhibits long-term proliferation but can promote epithelial-to-mesenchymal transition (EMT).[52]

Platelets in cancer EMT edit

 
Cancer cells enter the bloodstream after undergoing EMT induced by TGF-β released from platelets. Once in the bloodstream, metastatic cancer cells recruit platelets for use as a physical barrier that helps protect these cells from elimination by immune cells. The metastatic cancer cell can use the attached platelets to adhere to P-selectin expressed by activated endothelial cells lining the blood vessel walls. Following adhesion to the endothelium, the metastatic cancer cell exits the bloodstream at the secondary site to begin formation of a new tumor.

Platelets in the blood have the ability to initiate the induction of EMT in cancer cells. When platelets are recruited to a site in the blood vessel they can release a variety of growth factors (PDGF,[53] VEGF,[54] Angiopoietin-1[55]) and cytokines including the EMT inducer TGF-β.[56] The release of TGF-β by platelets in blood vessels near primary tumors enhances invasiveness and promotes metastasis of cancer cells in the tumor.[57] Studies looking at defective platelets and reduced platelet counts in mouse models have shown that impaired platelet function is associated with decreased metastatic formation.[58][59] In humans, platelet counts and thrombocytosis within the upper end of the normal range have been associated with advanced, often metastatic, stage cancer in cervical cancer,[60] ovarian cancer,[61] gastric cancer,[62] and esophageal cancer.[63] Although a great deal of research has been applied to studying interactions between tumor cells and platelets, a cancer therapy targeting this interaction has not yet been established.[64] This may be in part due to the redundancy of prothrombotic pathways which would require the use of multiple therapeutic approaches in order to prevent pro-metastatic events via EMT induction in cancer cells by activated platelets.

To improve the chances for the development of a cancer metastasis, a cancer cell must avoid detection and targeting by the immune system once it enters the bloodstream. Activated platelets have the ability to bind glycoproteins and glycolipids (P-selectin ligands such as PSGL-1) on the surface of cancer cells to form a physical barrier that protects the cancer cell from natural killer cell-mediated lysis in the bloodstream.[65] Furthermore, activated platelets promote the adhesion of cancer cells to activated endothelial cells lining blood vessels using adhesion molecules present on platelets.[66][64] P-selectin ligands on the surface of cancer cells remain to be elucidated and may serve as potential biomarkers for disease progression in cancer.[64]

Therapeutics targeting cancer EMT edit

Many studies have proposed that induction of EMT is the primary mechanism by which epithelial cancer cells acquire malignant phenotypes that promote metastasis.[67] Drug development targeting the activation of EMT in cancer cells has thus become an aim of pharmaceutical companies.[68]

Small molecule inhibitors edit

Small molecules that are able to inhibit TGF-β induced EMT are under development.[68] Silmitasertib (CX-4945) is a small molecule inhibitor of protein kinase CK2, which has been supported to be linked with TGF-β induced EMT, and is currently in clinical trials for cholangiocarcinoma (bile duct cancer), as well as in preclinical development for hematological and lymphoid malignancies.[69][70] In January 2017, Silmitasertib was granted orphan drug status by the U.S. Food and Drug Administration for cholangiocarcinoma and is currently in phase II study. Silmitasertib is being developed by Senhwa Biosciences.[71] Another small molecule inhibitor Galunisertib (LY2157299) is a potent TGF-β type I receptor kinase inhibitor that was demonstrated to reduce the size, the growth rate of tumors, and the tumor forming potential in triple negative breast cancer cell lines using mouse xenografts.[72] Galunisertib is currently being developed by Lilly Oncology and is in phase I/II clinical trials for hepatocellular carcinoma, unresectable pancreatic cancer, and malignant glioma.[73] Small molecule inhibitors of EMT are suggested to not act as a replacement for traditional chemotherapeutic agents but are likely to display the greatest efficacy in treating cancers when used in conjunction with them.

Antagomirs and microRNA mimics have gained interest as a potential source of therapeutics to target EMT induced metastasis in cancer as well as treating many other diseases.[74] Antagomirs were first developed to target miR-122, a microRNA that was abundant and specific to the liver, and this discovery has led to the development of other antagomirs that can pair with specific microRNAs present in the tumor microenvironment or in the cancer cells.[75][73] A microRNA mimic to miR-655 was found to suppress EMT through the targeting of EMT inducing transcription factor ZEB1 and TGF-β receptor 2 in a pancreatic cancer cell line. Overexpression of the miR-655 mimic in the Panc1 cancer cell line upregulated the expression of E-cadherin and suppressed the migration and invasion of mesenchymal-like cancer cells.[76] The use of microRNA mimics to suppress EMT has expanded to other cancer cell lines and holds potential for clinical drug development.[74] However, microRNA mimics and antagomirs suffer from a lack of stability in vivo and lack an accurate delivery system to target these molecules to the tumor cells or tissue for treatment.[77] Improvements to antagomir and microRNA mimic stability through chemical modifications such as locked nucleic acid (LNA) oligonucleotides or peptide nucleic acids (PNA) can prevent the fast clearing of these small molecules by RNases.[77][74] Delivery of antagomirs and microRNA mimics into cells by enclosing these molecules in liposome-nanoparticles has generated interest however liposome structures suffer from their own drawbacks that will need to be overcome for their effective use as a drug delivery mechanism.[77] These drawbacks of liposome-nanoparticles include nonspecific uptake by cells and induction of immune responses.[78] The role that microRNAs play in cancer development and metastasis is under much scientific investigation and it is yet to be demonstrated whether microRNA mimics or antagomirs may serve as standard clinical treatments to suppress EMT or oncogenic microRNAs in cancers.[74]

Generation of endocrine progenitor cells from pancreatic islets edit

Similar to generation of Cancer Stem Cells, EMT was demonstrated to generate endocrine progenitor cells from human pancreatic islets.[79] 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.[80] 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 in 2007.[81][82][83]

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.[84][85] 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.[86] 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 inhibition of EMT in cancer.[86]

Partial EMT or a hybrid E/M phenotype edit

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.[51][87][88][30][89][90][91][92] Two mathematical models have been proposed, attempting to explain the emergence of this hybrid E/M phenotype,[89][91] and its highly likely that different cell lines adopt different hybrid state(s), as shown by experiments in MCF10A, HMLE and H1975 cell lines.[90][93] 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.[94]

See also edit

References edit

  1. ^ Kong D, Li Y, Wang Z, Sarkar FH (February 2011). "Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins?". Cancers. 3 (1): 716–29. doi:10.3390/cancers30100716. PMC 3106306. PMID 21643534.
  2. ^ a b Lamouille S, Xu J, Derynck R (March 2014). "Molecular mechanisms of epithelial-mesenchymal transition". Nature Reviews. Molecular Cell Biology. 15 (3): 178–96. doi:10.1038/nrm3758. PMC 4240281. PMID 24556840.
  3. ^ Thiery JP, Acloque H, Huang RY, Nieto MA (November 2009). "Epithelial-mesenchymal transitions in development and disease". Cell. 139 (5): 871–90. doi:10.1016/j.cell.2009.11.007. PMID 19945376. S2CID 10874320.
  4. ^ Thiery JP, Sleeman JP (February 2006). "Complex networks orchestrate epithelial-mesenchymal transitions". Nature Reviews. Molecular Cell Biology. 7 (2): 131–42. doi:10.1038/nrm1835. PMID 16493418. S2CID 8435009.
  5. ^ Francou A, Anderson KV (2020). "The Epithelial-to-Mesenchymal Transition in Development and Cancer". Annual Review of Cancer Biology. 4: 197–220. doi:10.1146/annurev-cancerbio-030518-055425. PMC 8189433. PMID 34113749.
  6. ^ Phua YL, Martel N, Pennisi DJ, Little MH, Wilkinson L (April 2013). "Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins". The Journal of Pathology. 229 (5): 685–96. doi:10.1002/path.4155. PMID 23224993. S2CID 22837861.
  7. ^ a b Kalluri R, Weinberg RA (June 2009). "The basics of epithelial-mesenchymal transition". The Journal of Clinical Investigation. 119 (6): 1420–8. doi:10.1172/JCI39104. PMC 2689101. PMID 19487818.
  8. ^ Sciacovelli M, Frezza C (October 2017). "Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer". The FEBS Journal. 284 (19): 3132–3144. doi:10.1111/febs.14090. PMC 6049610. PMID 28444969.
  9. ^ Li L, Li W (June 2015). "Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation". Pharmacology & Therapeutics. 150: 33–46. doi:10.1016/j.pharmthera.2015.01.004. PMID 25595324.
  10. ^ Peinado H, Olmeda D, Cano A (2007). "Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?". Nature Reviews Cancer. 7 (6): 415–428. doi:10.1038/nrc2131. hdl:10261/81769. PMID 17508028. S2CID 25162191.
  11. ^ Yang J, Weinberg RA (2008). "Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis". Dev Cell. 14 (6): 818–829. doi:10.1016/j.devcel.2008.05.009. PMID 18539112.
  12. ^ De Craene B, Berx G (2013). "Regulatory networks defining EMT during cancer initiation and progression". Nature Reviews Cancer. 13 (2): 97–110. doi:10.1038/nrc3447. PMID 23344542. S2CID 13619676.
  13. ^ Chakrabarti R, Hwang J, Andres Blanco M, Wei Y, Lukačišin M, Romano RA, Smalley K, Liu S, Yang Q, Ibrahim T, Mercatali L, Amadori D, Haffty BG, Sinha S, Kang Y (2012). "Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2". Nat Cell Biol. 14 (11): 1212–1222. doi:10.1038/ncb2607. PMC 3500637. PMID 23086238.
  14. ^ a b c Nouri M, Ratther E, Stylianou N, Nelson CC, Hollier BG, Williams ED (2014). "Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention". Front Oncol. 4: 370. doi:10.3389/fonc.2014.00370. PMC 4274903. PMID 25566507.
  15. ^ Puisieux A, Brabletz T, Caramel J (June 2014). "Oncogenic roles of EMT-inducing transcription factors". Nature Cell Biology. 16 (6): 488–94. doi:10.1038/ncb2976. PMID 24875735. S2CID 5226347.
  16. ^ Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, et al. (March 2013). "Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1α in hepatocellular carcinoma". BMC Cancer. 13: 108. doi:10.1186/1471-2407-13-108. PMC 3614870. PMID 23496980.
  17. ^ "Epithelial-Mesenchymal Transition | GeneTex". www.genetex.com. Retrieved 28 October 2019.
  18. ^ Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M (January 2009). "Role of Ras signaling in the induction of snail by transforming growth factor-beta". The Journal of Biological Chemistry. 284 (1): 245–53. doi:10.1074/jbc.m804777200. PMID 19010789.
  19. ^ Ciruna B, Rossant J (July 2001). "FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak". Developmental Cell. 1 (1): 37–49. doi:10.1016/s1534-5807(01)00017-x. PMID 11703922.
  20. ^ Lu Z, Ghosh S, Wang Z, Hunter T (December 2003). "Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion". Cancer Cell. 4 (6): 499–515. doi:10.1016/s1535-6108(03)00304-0. PMID 14706341.
  21. ^ Savagner P, Yamada KM, Thiery JP (June 1997). "The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition". The Journal of Cell Biology. 137 (6): 1403–19. doi:10.1083/jcb.137.6.1403. PMC 2132541. PMID 9182671.
  22. ^ Boyer B, Tucker GC, Vallés AM, Franke WW, Thiery JP (October 1989). "Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells". The Journal of Cell Biology. 109 (4 Pt 1): 1495–509. doi:10.1083/jcb.109.4.1495. PMC 2115780. PMID 2677020.
  23. ^ Herfs M, Hubert P, Suarez-Carmona M, Reschner A, Saussez S, Berx G, et al. (April 2010). "Regulation of p63 isoforms by snail and slug transcription factors in human squamous cell carcinoma". The American Journal of Pathology. 176 (4): 1941–9. doi:10.2353/ajpath.2010.090804. PMC 2843482. PMID 20150431.
  24. ^ Lindsay J, McDade SS, Pickard A, McCloskey KD, McCance DJ (February 2011). "Role of DeltaNp63gamma in epithelial to mesenchymal transition". The Journal of Biological Chemistry. 286 (5): 3915–24. doi:10.1074/jbc.M110.162511. PMC 3030392. PMID 21127042.
  25. ^ Boldrup L, Coates PJ, Gu X, Nylander K (December 2007). "DeltaNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck". The Journal of Pathology. 213 (4): 384–91. doi:10.1002/path.2237. PMID 17935121. S2CID 21891189.
  26. ^ Larue L, Bellacosa A (November 2005). "Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways". Oncogene. 24 (50): 7443–54. doi:10.1038/sj.onc.1209091. PMID 16288291.
  27. ^ Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (April 2008). "The role of ATF-2 in oncogenesis". BioEssays. 30 (4): 314–27. doi:10.1002/bies.20734. PMID 18348191. S2CID 678541.
  28. ^ Huber MA, Beug H, Wirth T (December 2004). "Epithelial-mesenchymal transition: NF-kappaB takes center stage". Cell Cycle. 3 (12): 1477–80. doi:10.4161/cc.3.12.1280. PMID 15539952.
  29. ^ Katoh Y, Katoh M (September 2008). "Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review)". International Journal of Molecular Medicine. 22 (3): 271–5. PMID 18698484.
  30. ^ a b Micalizzi DS; Farabaugh SM; Ford HL (2010). "Epithelial-Mesenchymal Transition in Cancer: Parallels between Normal Development and Tumor Progression". J Mammary Gland Biol Neoplasia. 15 (2): 117–134. doi:10.1007/s10911-010-9178-9. PMC 2886089. PMID 20490631.
  31. ^ Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, Manova-Todorova K, Blasberg R, Gerald WL, Massagué J (2005). "Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway". PNAS. 102 (39): 13909–14. Bibcode:2005PNAS..10213909K. doi:10.1073/pnas.0506517102. PMC 1236573. PMID 16172383.
  32. ^ Chang C, Chao C, Xia W, Yang J, Xiong Y, Li C, Yu W, Rehman SK, Hsu JL, Lee H, Liu M, Chen C, Yu D, Hung M (2011). "p53 regulates epithelial-mesenchymal transition (EMT) and stem cell properties through modulating miRNAs". Nat Cell Biol. 13 (3): 317–323. doi:10.1038/ncb2173. PMC 3075845. PMID 21336307.
  33. ^ Lim R, Thiery JP (2012). "Epithelial-mesenchymal transitions: insights from development". Development. 139 (19): 3471–3486. doi:10.1242/dev.071209. PMID 22949611.
  34. ^ a b Hay ED (2005). "The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it". Dev. Dyn. 233 (3): 706–20. doi:10.1002/dvdy.20345. PMID 15937929. S2CID 22368548.
  35. ^ Kerosuo L, Bronner-Fraser M (2012). "What is bad in cancer is good in the embryo: Importance of EMT in neural crest development". Seminars in Cell and Developmental Biology. 23 (3): 320–332. doi:10.1016/j.semcdb.2012.03.010. PMC 3345076. PMID 22430756.
  36. ^ Ahmed N, Maines-Bandiera S, Quinn MA, Unger WG, Dedhar S, Auersperg N (2006). "Molecular pathways regulating EGF-induced epithelio- mesenchymal transition in human ovarian surface epithelium". Am J Physiol Cell Physiol. 290 (6): C1532–C1542. doi:10.1152/ajpcell.00478.2005. PMID 16394028. S2CID 35196500.
  37. ^ Hanahan D, Weinberg RA (January 2000). "The hallmarks of cancer". Cell. 100 (1): 57–70. doi:10.1016/s0092-8674(00)81683-9. PMID 10647931. S2CID 1478778.
  38. ^ Hanahan D, Weinberg RA (March 2011). "Hallmarks of cancer: the next generation". Cell. 144 (5): 646–74. doi:10.1016/j.cell.2011.02.013. PMID 21376230.
  39. ^ Chaffer CL, Weinberg RA (March 2011). "A perspective on cancer cell metastasis". Science. 331 (6024): 1559–64. Bibcode:2011Sci...331.1559C. doi:10.1126/science.1203543. PMID 21436443. S2CID 10550070.
  40. ^ Ye X, Weinberg RA (November 2015). "Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression". Trends in Cell Biology. 25 (11): 675–686. doi:10.1016/j.tcb.2015.07.012. PMC 4628843. PMID 26437589.
  41. ^ Massague J (2008). "TGFβ in cancer". Cell. 134 (2): 215–229. doi:10.1016/j.cell.2008.07.001. PMC 3512574. PMID 18662538.
  42. ^ Chu IM, Lai WC, Aprelikova O, El Touny LH, Kouros-Mehr H, Green JE (2013). "Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFß". PLOS ONE. 8 (4): e61125. Bibcode:2013PLoSO...861125C. doi:10.1371/journal.pone.0061125. PMC 3620110. PMID 23577196.
  43. ^ Ratnayake WS, Apostolatos AH, Ostrov DA, Acevedo-Duncan M (2017). "Two novel atypical PKC inhibitors; ACPD and DNDA effectively mitigate cell proliferation and epithelial to mesenchymal transition of metastatic melanoma while inducing apoptosis". Int. J. Oncol. 51 (5): 1370–1382. doi:10.3892/ijo.2017.4131. PMC 5642393. PMID 29048609.
  44. ^ Ratnayake WS, Apostolatos CA, Apostolatos AH, Schutte RJ, Huynh MA, Ostrov DA, Acevedo-Duncan M (2018). "Oncogenic PKC-ι activates Vimentin during epithelial-mesenchymal transition in melanoma; a study based on PKC-ι and PKC-ζ specific inhibitors". Cell Adhes. Migr. 12 (5): 447–463. doi:10.1080/19336918.2018.1471323. PMC 6363030. PMID 29781749.
  45. ^ Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A, Kikkawa F (August 2007). "Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells". International Journal of Oncology. 31 (2): 277–83. doi:10.3892/ijo.31.2.277. PMID 17611683.
  46. ^ Ricciardi M, Zanotto M, Malpeli G, Bassi G, Perbellini O, Chilosi M, et al. (March 2015). "Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells". British Journal of Cancer. 112 (6): 1067–75. doi:10.1038/bjc.2015.29. PMC 4366889. PMID 25668006.
  47. ^ Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008). "The epithelial-mesenchymal transition generates cells with properties of stem cells". Cell. 133 (4): 704–15. doi:10.1016/j.cell.2008.03.027. PMC 2728032. PMID 18485877.
  48. ^ Singh A, Settleman J (2010). "EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer". Oncogene. 29 (34): 4741–4751. doi:10.1038/onc.2010.215. PMC 3176718. PMID 20531305.
  49. ^ Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. (November 2015). "Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance". Nature. 527 (7579): 472–6. Bibcode:2015Natur.527..472F. doi:10.1038/nature15748. PMC 4662610. PMID 26560033.
  50. ^ Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. (November 2015). "Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer". Nature. 527 (7579): 525–530. Bibcode:2015Natur.527..525Z. doi:10.1038/nature16064. PMC 4849281. PMID 26560028.
  51. ^ a b Shamir ER, Pappalardo E, Jorgens DM, Coutinho K, Tsai WT, Aziz K, et al. (March 2014). "Twist1-induced dissemination preserves epithelial identity and requires E-cadherin". The Journal of Cell Biology. 204 (5): 839–56. doi:10.1083/jcb.201306088. PMC 3941052. PMID 24590176.
  52. ^ Jaguva Vasudevan AA, Hoffmann MJ, Beck ML, Poschmann G, Petzsch P, Wiek C, et al. (April 2019). "HDAC5 Expression in Urothelial Carcinoma Cell Lines Inhibits Long-Term Proliferation but Can Promote Epithelial-to-Mesenchymal Transition". International Journal of Molecular Sciences. 20 (9): 2135. doi:10.3390/ijms20092135. PMC 6539474. PMID 31052182.
  53. ^ Kepner N, Lipton A (February 1981). "A mitogenic factor for transformed fibroblasts from human platelets". Cancer Research. 41 (2): 430–2. PMID 6256066.
  54. ^ Möhle R, Green D, Moore MA, Nachman RL, Rafii S (January 1997). "Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets". Proceedings of the National Academy of Sciences of the United States of America. 94 (2): 663–8. Bibcode:1997PNAS...94..663M. doi:10.1073/pnas.94.2.663. PMC 19570. PMID 9012841.
  55. ^ Li JJ, Huang YQ, Basch R, Karpatkin S (February 2001). "Thrombin induces the release of angiopoietin-1 from platelets". Thrombosis and Haemostasis. 85 (2): 204–6. doi:10.1055/s-0037-1615677. PMID 11246533. S2CID 33522255.
  56. ^ Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (June 1983). "Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization". The Journal of Biological Chemistry. 258 (11): 7155–60. doi:10.1016/S0021-9258(18)32345-7. PMID 6602130.
  57. ^ Oft M, Heider KH, Beug H (November 1998). "TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis". Current Biology. 8 (23): 1243–52. doi:10.1016/s0960-9822(07)00533-7. PMID 9822576. S2CID 18536979.
  58. ^ Bakewell SJ, Nestor P, Prasad S, Tomasson MH, Dowland N, Mehrotra M, et al. (November 2003). "Platelet and osteoclast beta3 integrins are critical for bone metastasis". Proceedings of the National Academy of Sciences of the United States of America. 100 (24): 14205–10. Bibcode:2003PNAS..10014205B. doi:10.1073/pnas.2234372100. PMC 283570. PMID 14612570.
  59. ^ Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR (July 2004). "Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis". Blood. 104 (2): 397–401. doi:10.1182/blood-2004-02-0434. PMID 15031212.
  60. ^ Hernandez E, Lavine M, Dunton CJ, Gracely E, Parker J (June 1992). "Poor prognosis associated with thrombocytosis in patients with cervical cancer". Cancer. 69 (12): 2975–7. doi:10.1002/1097-0142(19920615)69:12<2975::aid-cncr2820691218>3.0.co;2-a. PMID 1591690.
  61. ^ Zeimet AG, Marth C, Müller-Holzner E, Daxenbichler G, Dapunt O (February 1994). "Significance of thrombocytosis in patients with epithelial ovarian cancer". American Journal of Obstetrics and Gynecology. 170 (2): 549–54. doi:10.1016/s0002-9378(94)70225-x. PMID 8116711.
  62. ^ Ikeda M, Furukawa H, Imamura H, Shimizu J, Ishida H, Masutani S, et al. (April 2002). "Poor prognosis associated with thrombocytosis in patients with gastric cancer". Annals of Surgical Oncology. 9 (3): 287–91. doi:10.1245/aso.2002.9.3.287. PMID 11923136.
  63. ^ Shimada H, Oohira G, Okazumi S, Matsubara H, Nabeya Y, Hayashi H, et al. (May 2004). "Thrombocytosis associated with poor prognosis in patients with esophageal carcinoma". Journal of the American College of Surgeons. 198 (5): 737–41. doi:10.1016/j.jamcollsurg.2004.01.022. PMID 15110807.
  64. ^ a b c Erpenbeck L, Schön MP (April 2010). "Deadly allies: the fatal interplay between platelets and metastasizing cancer cells". Blood. 115 (17): 3427–36. doi:10.1182/blood-2009-10-247296. PMC 2867258. PMID 20194899.
  65. ^ Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, et al. (January 2005). "Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells". Blood. 105 (1): 178–85. doi:10.1182/blood-2004-06-2272. PMID 15367435. S2CID 279285.
  66. ^ Gay LJ, Felding-Habermann B (February 2011). "Contribution of platelets to tumour metastasis". Nature Reviews. Cancer. 11 (2): 123–34. doi:10.1038/nrc3004. PMC 6894505. PMID 21258396.
  67. ^ Thiery JP (June 2002). "Epithelial-mesenchymal transitions in tumour progression". Nature Reviews. Cancer. 2 (6): 442–54. doi:10.1038/nrc822. PMID 12189386. S2CID 5236443.
  68. ^ a b Yingling JM, Blanchard KL, Sawyer JS (December 2004). "Development of TGF-beta signalling inhibitors for cancer therapy". Nature Reviews. Drug Discovery. 3 (12): 1011–22. doi:10.1038/nrd1580. PMID 15573100. S2CID 42237691.
  69. ^ Zou J, Luo H, Zeng Q, Dong Z, Wu D, Liu L (June 2011). "Protein kinase CK2α is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT-related genes". Journal of Translational Medicine. 9: 97. doi:10.1186/1479-5876-9-97. PMC 3132712. PMID 21702981.
  70. ^ Gowda C, Sachdev M, Muthusami S, Kapadia M, Petrovic-Dovat L, Hartman M, et al. (2017). "Casein Kinase II (CK2) as a Therapeutic Target for Hematological Malignancies". Current Pharmaceutical Design. 23 (1): 95–107. doi:10.2174/1381612822666161006154311. PMID 27719640.
  71. ^ "CX-4945 Granted Orphan Drug Designation". Oncology Times. 39 (5): 23. 10 March 2017. doi:10.1097/01.cot.0000514203.35081.69. ISSN 0276-2234.
  72. ^ Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, et al. (March 2013). "TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer". The Journal of Clinical Investigation. 123 (3): 1348–58. doi:10.1172/JCI65416. PMC 3582135. PMID 23391723.
  73. ^ a b Kothari AN, Mi Z, Zapf M, Kuo PC (15 October 2014). "Novel clinical therapeutics targeting the epithelial to mesenchymal transition". Clinical and Translational Medicine. 3: 35. doi:10.1186/s40169-014-0035-0. PMC 4198571. PMID 25343018.
  74. ^ a b c d Rupaimoole R, Slack FJ (March 2017). "MicroRNA therapeutics: towards a new era for the management of cancer and other diseases". Nature Reviews. Drug Discovery. 16 (3): 203–222. doi:10.1038/nrd.2016.246. PMID 28209991. S2CID 22956490.
  75. ^ Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (December 2005). "Silencing of microRNAs in vivo with 'antagomirs'". Nature. 438 (7068): 685–9. Bibcode:2005Natur.438..685K. doi:10.1038/nature04303. PMID 16258535. S2CID 4414240.
  76. ^ Harazono Y, Muramatsu T, Endo H, Uzawa N, Kawano T, Harada K, et al. (14 May 2013). "miR-655 Is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2". PLOS ONE. 8 (5): e62757. Bibcode:2013PLoSO...862757H. doi:10.1371/journal.pone.0062757. PMC 3653886. PMID 23690952.
  77. ^ a b c Rothschild SI (4 March 2014). "microRNA therapies in cancer". Molecular and Cellular Therapies. 2: 7. doi:10.1186/2052-8426-2-7. PMC 4452061. PMID 26056576.
  78. ^ Lv H, Zhang S, Wang B, Cui S, Yan J (August 2006). "Toxicity of cationic lipids and cationic polymers in gene delivery". Journal of Controlled Release. 114 (1): 100–9. doi:10.1016/j.jconrel.2006.04.014. PMID 16831482.
  79. ^ Gershengorn MC, Hardikar AA, Wei C, et al. (2004). "Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells". Science. 306 (5705): 2261–2264. Bibcode:2004Sci...306.2261G. doi:10.1126/science.1101968. PMID 15564314. S2CID 22304970.
  80. ^ Gershengorn MC, Geras-Raaka E, Hardikar AA, et al. (2005). "Are better islet cell precursors generated by epithelial-to-mesenchymal transition?". Cell Cycle. 4 (3): 380–382. doi:10.4161/cc.4.3.1538. PMID 15711124.
  81. ^ Atouf F, Park CH, Pechhold K, et al. (2007). "No evidence for mouse pancreatic beta-cell epithelial-mesenchymal transition in vitro". Diabetes. 56 (3): 699–702. doi:10.2337/db06-1446. PMID 17327438.
  82. ^ Chase LG, Ulloa-Montoya F, Kidder BL, et al. (2007). "Islet-derived fibroblast-like cells are not derived via epithelial-mesenchymal transition from Pdx-1 or insulin-positive cells". Diabetes. 56 (1): 3–7. doi:10.2337/db06-1165. PMID 17110468.
  83. ^ Morton RA, Geras-Raaka E, Wilson LM, et al. (2007). "Endocrine precursor cells from mouse islets are not generated by epithelial-to-mesenchymal transition of mature beta cells". Mol Cell Endocrinol. 270 (1–2): 87–93. doi:10.1016/j.mce.2007.02.005. PMC 1987709. PMID 17363142.
  84. ^ Russ HA, Bar Y, Ravassard P, et al. (2008). "In vitro proliferation of cells derived from adult human beta-cells revealed by cell-lineage tracing". Diabetes. 57 (6): 1575–1583. doi:10.2337/db07-1283. PMID 18316362.
  85. ^ Russ HA, Ravassard P, Kerr-Conte J, et al. (2009). "Epithelial-mesenchymal transition in cells expanded in vitro from lineage-traced adult human pancreatic beta cells". PLOS ONE. 4 (7): e6417. Bibcode:2009PLoSO...4.6417R. doi:10.1371/journal.pone.0006417. PMC 2712769. PMID 19641613.
  86. ^ a b Joglekar MV, Joglekar VM, Joglekar SV, et al. (2009). "Human fetal pancreatic insulin-producing cells proliferate in vitro". J Endocrinol. 201 (1): 27–36. doi:10.1677/joe-08-0497. PMID 19171567.
  87. ^ Jolly MK, Boareto M, Huang B, Jia D, Lu M, Ben-Jacob E, et al. (1 January 2015). "Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis". Frontiers in Oncology. 5: 155. arXiv:1505.07494. Bibcode:2015arXiv150507494J. doi:10.3389/fonc.2015.00155. PMC 4507461. PMID 26258068.
  88. ^ Nakaya Y, Sheng G (November 2013). "EMT in developmental morphogenesis". Cancer Letters. 341 (1): 9–15. doi:10.1016/j.canlet.2013.02.037. PMID 23462225.
  89. ^ a b Tian XJ, Zhang H, Xing J (August 2013). "Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition". Biophysical Journal. 105 (4): 1079–89. arXiv:1307.4732. Bibcode:2013BpJ...105.1079T. doi:10.1016/j.bpj.2013.07.011. PMC 3752104. PMID 23972859.
  90. ^ a b Zhang J, Tian XJ, Zhang H, Teng Y, Li R, Bai F, et al. (September 2014). "TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops". Science Signaling. 7 (345): ra91. doi:10.1126/scisignal.2005304. PMID 25270257. S2CID 19143040.
  91. ^ a b Lu M, Jolly MK, Levine H, Onuchic JN, Ben-Jacob E (November 2013). "MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination". Proceedings of the National Academy of Sciences of the United States of America. 110 (45): 18144–9. Bibcode:2013PNAS..11018144L. doi:10.1073/pnas.1318192110. PMC 3831488. PMID 24154725.
  92. ^ Savagner P (October 2010). "The epithelial-mesenchymal transition (EMT) phenomenon". Annals of Oncology. 21 (Suppl 7): vii89-92. doi:10.1093/annonc/mdq292. PMC 3379967. PMID 20943648.
  93. ^ Jia D, Jolly MK, Tripathi SC, Den Hollander P, Huang B, Lu M, et al. (2017). "Distinguishing mechanisms underlying EMT tristability". Cancer Convergence. 1 (1): 2. arXiv:1701.01746. Bibcode:2017arXiv170101746J. doi:10.1186/s41236-017-0005-8. PMC 5876698. PMID 29623961.
  94. ^ Jolly MK, Tripathi SC, Jia D, Mooney SM, Celiktas M, Hanash SM, et al. (May 2016). "Stability of the hybrid epithelial/mesenchymal phenotype". Oncotarget. 7 (19): 27067–84. doi:10.18632/oncotarget.8166. PMC 5053633. PMID 27008704.

External links edit

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

December 15, 2023
epithelial, mesenchymal, transition, this, article, needs, more, reliable, medical, references, verification, relies, heavily, primary, sources, please, review, contents, article, appropriate, references, unsourced, poorly, sourced, material, challenged, remov. This article needs more reliable medical references for verification or relies too heavily on primary sources Please review the contents of the article and add the appropriate references if you can Unsourced or poorly sourced material may be challenged and removed Find sources Epithelial mesenchymal transition news newspapers books scholar JSTOR January 2017 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 in cancer progression Epithelial mesenchymal transitionDiagram showing the epithelial mesenchymal transitionDetailsPrecursorendodermIdentifiersMeSHD058750Anatomical terminology edit on Wikidata Contents 1 Introduction 2 Inducers 3 In development and wound healing 4 In cancer progression and metastasis 5 Platelets in cancer EMT 6 Therapeutics targeting cancer EMT 6 1 Small molecule inhibitors 7 Generation of endocrine progenitor cells from pancreatic islets 8 Partial EMT or a hybrid E M phenotype 9 See also 10 References 11 External linksIntroduction edit nbsp 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 by Betty Hay in the 1980s 1 2 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 secondary palate development and myogenesis 3 Epithelial and mesenchymal cells differ in phenotype as well as function though both share inherent plasticity 2 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 4 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 5 Based on the biological context EMT has been categorized into 3 types developmental Type I fibrosis 6 and wound healing Type II and cancer Type III 7 8 9 Inducers edit nbsp Key inducers of the epithelial to mesenchymal transition process nbsp Epithelial to mesenchymal cell transition loss of cell adhesion leads to constriction and extrusion of newly mesenchymal cell 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 TCF3 and KLF8 Kruppel like factor 8 can bind to the E cadherin promoter and repress its transcription whereas factors such as Twist Goosecoid TCF4 also known as E2 2 homeobox protein SIX1 and FOXC2 fork head box protein C2 repress E cadherin indirectly 10 11 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 and are found to actively drive MET when overexpressed in mesenchymal cells 12 13 Since EMT in cancer progression recaptures EMT in developmental programs many of the EMT TFs are involved in promoting metastatic events 14 15 Several signaling pathways TGF b FGF EGF HGF Wnt beta catenin and Notch and hypoxia may induce EMT 7 16 17 In particular Ras MAPK has been shown to activate Snail and Slug 18 19 20 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 21 which includes the induction of cell motility repression of the cytokeratin expression and activation of vimentin expression 22 Snail and Slug are known to regulate the expression of p63 isoforms another transcription factor that is required for proper development of epithelial structures 23 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 24 Some of them are known to regulate the expression of cytokeratins 25 The phosphatidylinositol 3 kinase PI3K AKT axis Hedgehog signaling pathway nuclear factor kappaB and Activating Transcription Factor 2 have also been implicated to be involved in EMT 26 27 28 29 Wnt signaling pathway regulates EMT in gastrulation cardiac valve formation and cancer 30 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 b activates the expression of SNAIL and ZEB to regulate EMT in heart development palatogenesis and cancer The breast cancer bone metastasis has activated TGF b signaling which contributes to the formation of these lesions 31 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 32 In development and wound healing editAfter 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 33 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 34 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 34 35 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 36 In cancer progression and metastasis editInitiation of metastasis requires invasion which is enabled by EMT 37 38 Carcinoma cells in a 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 micro metastases they undergo MET for clonal outgrowth at these metastatic sites Thus EMT and MET form the initiation and completion of the invasion metastasis cascade 39 At this new metastatic site the tumor may undergo other processes to optimize growth For example EMT has been associated with PD L1 expression particularly in lung cancer Increased levels of PD L1 suppresses the immune system which allows the cancer to spread more easily 40 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 TGF b can promote tumor invasion and evasion of immune surveillance at advanced stages When TGF b acts on activated Ras expressing mammary epithelial cells EMT is favored and apoptosis is inhibited 41 This effect can be reversed by inducers of epithelial differentiation such as GATA 3 42 EMT has been shown to be induced by androgen deprivation therapy in metastatic prostate cancer 14 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 14 Oncogenic PKC iota can promote melanoma cell invasion by activating Vimentin during EMT PKC iota inhibition or knockdown resulted an increase E cadherin and RhoA levels while decreasing total Vimentin phosphorylated Vimentin S39 and Par6 in metastatic melanoma cells These results suggested that PKC i is involved in signaling pathways which upregulate EMT in melanoma 43 44 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 45 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 46 Consequently EMT enables cells to gain a migratory phenotype as well as induce multiple immunosuppression drug resistance evasion of apoptosis mechanisms 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 47 Also ZEB1 is capable of conferring stem cell like properties thus strengthening the relationship between EMT and stemness Thus EMT may present increased danger to cancer patients as EMT not only enables the carcinoma cells to enter the bloodstream but also endows them with properties of stemness which increases tumorigenic and proliferative potential 48 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 in cells metastatic potential upon acquisition of EMT 49 50 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 51 The effects of EMT and its relationship to invasion and metastasis may therefore be highly context specific In urothelial carcinoma cell lines overexpression of HDAC5 inhibits long term proliferation but can promote epithelial to mesenchymal transition EMT 52 Platelets in cancer EMT edit nbsp Cancer cells enter the bloodstream after undergoing EMT induced by TGF b released from platelets Once in the bloodstream metastatic cancer cells recruit platelets for use as a physical barrier that helps protect these cells from elimination by immune cells The metastatic cancer cell can use the attached platelets to adhere to P selectin expressed by activated endothelial cells lining the blood vessel walls Following adhesion to the endothelium the metastatic cancer cell exits the bloodstream at the secondary site to begin formation of a new tumor Platelets in the blood have the ability to initiate the induction of EMT in cancer cells When platelets are recruited to a site in the blood vessel they can release a variety of growth factors PDGF 53 VEGF 54 Angiopoietin 1 55 and cytokines including the EMT inducer TGF b 56 The release of TGF b by platelets in blood vessels near primary tumors enhances invasiveness and promotes metastasis of cancer cells in the tumor 57 Studies looking at defective platelets and reduced platelet counts in mouse models have shown that impaired platelet function is associated with decreased metastatic formation 58 59 In humans platelet counts and thrombocytosis within the upper end of the normal range have been associated with advanced often metastatic stage cancer in cervical cancer 60 ovarian cancer 61 gastric cancer 62 and esophageal cancer 63 Although a great deal of research has been applied to studying interactions between tumor cells and platelets a cancer therapy targeting this interaction has not yet been established 64 This may be in part due to the redundancy of prothrombotic pathways which would require the use of multiple therapeutic approaches in order to prevent pro metastatic events via EMT induction in cancer cells by activated platelets To improve the chances for the development of a cancer metastasis a cancer cell must avoid detection and targeting by the immune system once it enters the bloodstream Activated platelets have the ability to bind glycoproteins and glycolipids P selectin ligands such as PSGL 1 on the surface of cancer cells to form a physical barrier that protects the cancer cell from natural killer cell mediated lysis in the bloodstream 65 Furthermore activated platelets promote the adhesion of cancer cells to activated endothelial cells lining blood vessels using adhesion molecules present on platelets 66 64 P selectin ligands on the surface of cancer cells remain to be elucidated and may serve as potential biomarkers for disease progression in cancer 64 Therapeutics targeting cancer EMT editMany studies have proposed that induction of EMT is the primary mechanism by which epithelial cancer cells acquire malignant phenotypes that promote metastasis 67 Drug development targeting the activation of EMT in cancer cells has thus become an aim of pharmaceutical companies 68 Small molecule inhibitors edit Small molecules that are able to inhibit TGF b induced EMT are under development 68 Silmitasertib CX 4945 is a small molecule inhibitor of protein kinase CK2 which has been supported to be linked with TGF b induced EMT and is currently in clinical trials for cholangiocarcinoma bile duct cancer as well as in preclinical development for hematological and lymphoid malignancies 69 70 In January 2017 Silmitasertib was granted orphan drug status by the U S Food and Drug Administration for cholangiocarcinoma and is currently in phase II study Silmitasertib is being developed by Senhwa Biosciences 71 Another small molecule inhibitor Galunisertib LY2157299 is a potent TGF b type I receptor kinase inhibitor that was demonstrated to reduce the size the growth rate of tumors and the tumor forming potential in triple negative breast cancer cell lines using mouse xenografts 72 Galunisertib is currently being developed by Lilly Oncology and is in phase I II clinical trials for hepatocellular carcinoma unresectable pancreatic cancer and malignant glioma 73 Small molecule inhibitors of EMT are suggested to not act as a replacement for traditional chemotherapeutic agents but are likely to display the greatest efficacy in treating cancers when used in conjunction with them Antagomirs and microRNA mimics have gained interest as a potential source of therapeutics to target EMT induced metastasis in cancer as well as treating many other diseases 74 Antagomirs were first developed to target miR 122 a microRNA that was abundant and specific to the liver and this discovery has led to the development of other antagomirs that can pair with specific microRNAs present in the tumor microenvironment or in the cancer cells 75 73 A microRNA mimic to miR 655 was found to suppress EMT through the targeting of EMT inducing transcription factor ZEB1 and TGF b receptor 2 in a pancreatic cancer cell line Overexpression of the miR 655 mimic in the Panc1 cancer cell line upregulated the expression of E cadherin and suppressed the migration and invasion of mesenchymal like cancer cells 76 The use of microRNA mimics to suppress EMT has expanded to other cancer cell lines and holds potential for clinical drug development 74 However microRNA mimics and antagomirs suffer from a lack of stability in vivo and lack an accurate delivery system to target these molecules to the tumor cells or tissue for treatment 77 Improvements to antagomir and microRNA mimic stability through chemical modifications such as locked nucleic acid LNA oligonucleotides or peptide nucleic acids PNA can prevent the fast clearing of these small molecules by RNases 77 74 Delivery of antagomirs and microRNA mimics into cells by enclosing these molecules in liposome nanoparticles has generated interest however liposome structures suffer from their own drawbacks that will need to be overcome for their effective use as a drug delivery mechanism 77 These drawbacks of liposome nanoparticles include nonspecific uptake by cells and induction of immune responses 78 The role that microRNAs play in cancer development and metastasis is under much scientific investigation and it is yet to be demonstrated whether microRNA mimics or antagomirs may serve as standard clinical treatments to suppress EMT or oncogenic microRNAs in cancers 74 Generation of endocrine progenitor cells from pancreatic islets editSimilar to generation of Cancer Stem Cells EMT was demonstrated to generate endocrine progenitor cells from human pancreatic islets 79 Initially the human islet derived progenitor cells hIPCs were proposed to be better precursors since b cell progeny in these hIPCs inherit epigenetic marks that define an active insulin promoter region 80 However later another set of experiments suggested that labelled b cells de differentiate to a mesenchymal like phenotype in vitro but fail to proliferate thus initiating a debate in 2007 81 82 83 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 b cells it was convincingly demonstrated that adult human islet b cells undergo EMT and proliferate in vitro 84 85 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 86 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 inhibition of EMT in cancer 86 Partial EMT or a hybrid E M phenotype editNot 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 51 87 88 30 89 90 91 92 Two mathematical models have been proposed attempting to explain the emergence of this hybrid E M phenotype 89 91 and its highly likely that different cell lines adopt different hybrid state s as shown by experiments in MCF10A HMLE and H1975 cell lines 90 93 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 94 See also editCollective cell migration Collective amoeboid transition Mesenchymal epithelial transition c Met inhibitors Vasculogenic MimicryReferences edit Kong D Li Y Wang Z Sarkar FH February 2011 Cancer Stem Cells and Epithelial to Mesenchymal Transition EMT Phenotypic Cells Are They Cousins or Twins Cancers 3 1 716 29 doi 10 3390 cancers30100716 PMC 3106306 PMID 21643534 a b Lamouille S Xu J Derynck R March 2014 Molecular mechanisms of epithelial mesenchymal transition Nature Reviews Molecular Cell Biology 15 3 178 96 doi 10 1038 nrm3758 PMC 4240281 PMID 24556840 Thiery JP Acloque H Huang RY Nieto MA November 2009 Epithelial mesenchymal transitions in development and disease Cell 139 5 871 90 doi 10 1016 j cell 2009 11 007 PMID 19945376 S2CID 10874320 Thiery JP Sleeman JP February 2006 Complex networks orchestrate epithelial mesenchymal transitions Nature Reviews Molecular Cell Biology 7 2 131 42 doi 10 1038 nrm1835 PMID 16493418 S2CID 8435009 Francou A Anderson KV 2020 The Epithelial to Mesenchymal Transition in Development and Cancer Annual Review of Cancer Biology 4 197 220 doi 10 1146 annurev cancerbio 030518 055425 PMC 8189433 PMID 34113749 Phua YL Martel N Pennisi DJ Little MH Wilkinson L April 2013 Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins The Journal of Pathology 229 5 685 96 doi 10 1002 path 4155 PMID 23224993 S2CID 22837861 a b Kalluri R Weinberg RA June 2009 The basics of epithelial mesenchymal transition The Journal of Clinical Investigation 119 6 1420 8 doi 10 1172 JCI39104 PMC 2689101 PMID 19487818 Sciacovelli M Frezza C October 2017 Metabolic reprogramming and epithelial to mesenchymal transition in cancer The FEBS Journal 284 19 3132 3144 doi 10 1111 febs 14090 PMC 6049610 PMID 28444969 Li L Li W June 2015 Epithelial mesenchymal transition in human cancer comprehensive reprogramming of metabolism epigenetics and differentiation Pharmacology amp Therapeutics 150 33 46 doi 10 1016 j pharmthera 2015 01 004 PMID 25595324 Peinado H Olmeda D Cano A 2007 Snail Zeb and bHLH factors in tumour progression an alliance against the epithelial phenotype Nature Reviews Cancer 7 6 415 428 doi 10 1038 nrc2131 hdl 10261 81769 PMID 17508028 S2CID 25162191 Yang J Weinberg RA 2008 Epithelial mesenchymal transition at the crossroads of development and tumor metastasis Dev Cell 14 6 818 829 doi 10 1016 j devcel 2008 05 009 PMID 18539112 De Craene B Berx G 2013 Regulatory networks defining EMT during cancer initiation and progression Nature Reviews Cancer 13 2 97 110 doi 10 1038 nrc3447 PMID 23344542 S2CID 13619676 Chakrabarti R Hwang J Andres Blanco M Wei Y Lukacisin M Romano RA Smalley K Liu S Yang Q Ibrahim T Mercatali L Amadori D Haffty BG Sinha S Kang Y 2012 Elf5 inhibits the epithelial mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2 Nat Cell Biol 14 11 1212 1222 doi 10 1038 ncb2607 PMC 3500637 PMID 23086238 a b c Nouri M Ratther E Stylianou N Nelson CC Hollier BG Williams ED 2014 Androgen targeted therapy induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer an opportunity for intervention Front Oncol 4 370 doi 10 3389 fonc 2014 00370 PMC 4274903 PMID 25566507 Puisieux A Brabletz T Caramel J June 2014 Oncogenic roles of EMT inducing transcription factors Nature Cell Biology 16 6 488 94 doi 10 1038 ncb2976 PMID 24875735 S2CID 5226347 Zhang L Huang G Li X Zhang Y Jiang Y Shen J et al March 2013 Hypoxia induces epithelial mesenchymal transition via activation of SNAI1 by hypoxia inducible factor 1a in hepatocellular carcinoma BMC Cancer 13 108 doi 10 1186 1471 2407 13 108 PMC 3614870 PMID 23496980 Epithelial Mesenchymal Transition GeneTex www genetex com Retrieved 28 October 2019 Horiguchi K Shirakihara T Nakano A Imamura T Miyazono K Saitoh M January 2009 Role of Ras signaling in the induction of snail by transforming growth factor beta The Journal of Biological Chemistry 284 1 245 53 doi 10 1074 jbc m804777200 PMID 19010789 Ciruna B Rossant J July 2001 FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak Developmental Cell 1 1 37 49 doi 10 1016 s1534 5807 01 00017 x PMID 11703922 Lu Z Ghosh S Wang Z Hunter T December 2003 Downregulation of caveolin 1 function by EGF leads to the loss of E cadherin increased transcriptional activity of beta catenin and enhanced tumor cell invasion Cancer Cell 4 6 499 515 doi 10 1016 s1535 6108 03 00304 0 PMID 14706341 Savagner P Yamada KM Thiery JP June 1997 The zinc finger protein slug causes desmosome dissociation an initial and necessary step for growth factor induced epithelial mesenchymal transition The Journal of Cell Biology 137 6 1403 19 doi 10 1083 jcb 137 6 1403 PMC 2132541 PMID 9182671 Boyer B Tucker GC Valles AM Franke WW Thiery JP October 1989 Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells The Journal of Cell Biology 109 4 Pt 1 1495 509 doi 10 1083 jcb 109 4 1495 PMC 2115780 PMID 2677020 Herfs M Hubert P Suarez Carmona M Reschner A Saussez S Berx G et al April 2010 Regulation of p63 isoforms by snail and slug transcription factors in human squamous cell carcinoma The American Journal of Pathology 176 4 1941 9 doi 10 2353 ajpath 2010 090804 PMC 2843482 PMID 20150431 Lindsay J McDade SS Pickard A McCloskey KD McCance DJ February 2011 Role of DeltaNp63gamma in epithelial to mesenchymal transition The Journal of Biological Chemistry 286 5 3915 24 doi 10 1074 jbc M110 162511 PMC 3030392 PMID 21127042 Boldrup L Coates PJ Gu X Nylander K December 2007 DeltaNp63 isoforms regulate CD44 and keratins 4 6 14 and 19 in squamous cell carcinoma of head and neck The Journal of Pathology 213 4 384 91 doi 10 1002 path 2237 PMID 17935121 S2CID 21891189 Larue L Bellacosa A November 2005 Epithelial mesenchymal transition in development and cancer role of phosphatidylinositol 3 kinase AKT pathways Oncogene 24 50 7443 54 doi 10 1038 sj onc 1209091 PMID 16288291 Vlahopoulos SA Logotheti S Mikas D Giarika A Gorgoulis V Zoumpourlis V April 2008 The role of ATF 2 in oncogenesis BioEssays 30 4 314 27 doi 10 1002 bies 20734 PMID 18348191 S2CID 678541 Huber MA Beug H Wirth T December 2004 Epithelial mesenchymal transition NF kappaB takes center stage Cell Cycle 3 12 1477 80 doi 10 4161 cc 3 12 1280 PMID 15539952 Katoh Y Katoh M September 2008 Hedgehog signaling epithelial to mesenchymal transition and miRNA review International Journal of Molecular Medicine 22 3 271 5 PMID 18698484 a b Micalizzi DS Farabaugh SM Ford HL 2010 Epithelial Mesenchymal Transition in Cancer Parallels between Normal Development and Tumor Progression J Mammary Gland Biol Neoplasia 15 2 117 134 doi 10 1007 s10911 010 9178 9 PMC 2886089 PMID 20490631 Kang Y He W Tulley S Gupta GP Serganova I Chen CR Manova Todorova K Blasberg R Gerald WL Massague J 2005 Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway PNAS 102 39 13909 14 Bibcode 2005PNAS 10213909K doi 10 1073 pnas 0506517102 PMC 1236573 PMID 16172383 Chang C Chao C Xia W Yang J Xiong Y Li C Yu W Rehman SK Hsu JL Lee H Liu M Chen C Yu D Hung M 2011 p53 regulates epithelial mesenchymal transition EMT and stem cell properties through modulating miRNAs Nat Cell Biol 13 3 317 323 doi 10 1038 ncb2173 PMC 3075845 PMID 21336307 Lim R Thiery JP 2012 Epithelial mesenchymal transitions insights from development Development 139 19 3471 3486 doi 10 1242 dev 071209 PMID 22949611 a b Hay ED 2005 The mesenchymal cell its role in the embryo and the remarkable signaling mechanisms that create it Dev Dyn 233 3 706 20 doi 10 1002 dvdy 20345 PMID 15937929 S2CID 22368548 Kerosuo L Bronner Fraser M 2012 What is bad in cancer is good in the embryo Importance of EMT in neural crest development Seminars in Cell and Developmental Biology 23 3 320 332 doi 10 1016 j semcdb 2012 03 010 PMC 3345076 PMID 22430756 Ahmed N Maines Bandiera S Quinn MA Unger WG Dedhar S Auersperg N 2006 Molecular pathways regulating EGF induced epithelio mesenchymal transition in human ovarian surface epithelium Am J Physiol Cell Physiol 290 6 C1532 C1542 doi 10 1152 ajpcell 00478 2005 PMID 16394028 S2CID 35196500 Hanahan D Weinberg RA January 2000 The hallmarks of cancer Cell 100 1 57 70 doi 10 1016 s0092 8674 00 81683 9 PMID 10647931 S2CID 1478778 Hanahan D Weinberg RA March 2011 Hallmarks of cancer the next generation Cell 144 5 646 74 doi 10 1016 j cell 2011 02 013 PMID 21376230 Chaffer CL Weinberg RA March 2011 A perspective on cancer cell metastasis Science 331 6024 1559 64 Bibcode 2011Sci 331 1559C doi 10 1126 science 1203543 PMID 21436443 S2CID 10550070 Ye X Weinberg RA November 2015 Epithelial Mesenchymal Plasticity A Central Regulator of Cancer Progression Trends in Cell Biology 25 11 675 686 doi 10 1016 j tcb 2015 07 012 PMC 4628843 PMID 26437589 Massague J 2008 TGFb in cancer Cell 134 2 215 229 doi 10 1016 j cell 2008 07 001 PMC 3512574 PMID 18662538 Chu IM Lai WC Aprelikova O El Touny LH Kouros Mehr H Green JE 2013 Expression of GATA3 in MDA MB 231 triple negative breast cancer cells induces a growth inhibitory response to TGFss PLOS ONE 8 4 e61125 Bibcode 2013PLoSO 861125C doi 10 1371 journal pone 0061125 PMC 3620110 PMID 23577196 Ratnayake WS Apostolatos AH Ostrov DA Acevedo Duncan M 2017 Two novel atypical PKC inhibitors ACPD and DNDA effectively mitigate cell proliferation and epithelial to mesenchymal transition of metastatic melanoma while inducing apoptosis Int J Oncol 51 5 1370 1382 doi 10 3892 ijo 2017 4131 PMC 5642393 PMID 29048609 Ratnayake WS Apostolatos CA Apostolatos AH Schutte RJ Huynh MA Ostrov DA Acevedo Duncan M 2018 Oncogenic PKC i activates Vimentin during epithelial mesenchymal transition in melanoma a study based on PKC i and PKC z specific inhibitors Cell Adhes Migr 12 5 447 463 doi 10 1080 19336918 2018 1471323 PMC 6363030 PMID 29781749 Kajiyama H Shibata K Terauchi M Yamashita M Ino K Nawa A Kikkawa F August 2007 Chemoresistance to paclitaxel induces epithelial mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells International Journal of Oncology 31 2 277 83 doi 10 3892 ijo 31 2 277 PMID 17611683 Ricciardi M Zanotto M Malpeli G Bassi G Perbellini O Chilosi M et al March 2015 Epithelial to mesenchymal transition EMT induced by inflammatory priming elicits mesenchymal stromal cell like immune modulatory properties in cancer cells British Journal of Cancer 112 6 1067 75 doi 10 1038 bjc 2015 29 PMC 4366889 PMID 25668006 Mani SA Guo W Liao MJ Eaton EN Ayyanan A Zhou AY Brooks M Reinhard F Zhang CC Shipitsin M Campbell LL Polyak K Brisken C Yang J Weinberg RA 2008 The epithelial mesenchymal transition generates cells with properties of stem cells Cell 133 4 704 15 doi 10 1016 j cell 2008 03 027 PMC 2728032 PMID 18485877 Singh A Settleman J 2010 EMT cancer stem cells and drug resistance an emerging axis of evil in the war on cancer Oncogene 29 34 4741 4751 doi 10 1038 onc 2010 215 PMC 3176718 PMID 20531305 Fischer KR Durrans A Lee S Sheng J Li F Wong ST et al November 2015 Epithelial to mesenchymal transition is not required for lung metastasis but contributes to chemoresistance Nature 527 7579 472 6 Bibcode 2015Natur 527 472F doi 10 1038 nature15748 PMC 4662610 PMID 26560033 Zheng X Carstens JL Kim J Scheible M Kaye J Sugimoto H et al November 2015 Epithelial to mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer Nature 527 7579 525 530 Bibcode 2015Natur 527 525Z doi 10 1038 nature16064 PMC 4849281 PMID 26560028 a b Shamir ER Pappalardo E Jorgens DM Coutinho K Tsai WT Aziz K et al March 2014 Twist1 induced dissemination preserves epithelial identity and requires E cadherin The Journal of Cell Biology 204 5 839 56 doi 10 1083 jcb 201306088 PMC 3941052 PMID 24590176 Jaguva Vasudevan AA Hoffmann MJ Beck ML Poschmann G Petzsch P Wiek C et al April 2019 HDAC5 Expression in Urothelial Carcinoma Cell Lines Inhibits Long Term Proliferation but Can Promote Epithelial to Mesenchymal Transition International Journal of Molecular Sciences 20 9 2135 doi 10 3390 ijms20092135 PMC 6539474 PMID 31052182 Kepner N Lipton A February 1981 A mitogenic factor for transformed fibroblasts from human platelets Cancer Research 41 2 430 2 PMID 6256066 Mohle R Green D Moore MA Nachman RL Rafii S January 1997 Constitutive production and thrombin induced release of vascular endothelial growth factor by human megakaryocytes and platelets Proceedings of the National Academy of Sciences of the United States of America 94 2 663 8 Bibcode 1997PNAS 94 663M doi 10 1073 pnas 94 2 663 PMC 19570 PMID 9012841 Li JJ Huang YQ Basch R Karpatkin S February 2001 Thrombin induces the release of angiopoietin 1 from platelets Thrombosis and Haemostasis 85 2 204 6 doi 10 1055 s 0037 1615677 PMID 11246533 S2CID 33522255 Assoian RK Komoriya A Meyers CA Miller DM Sporn MB June 1983 Transforming growth factor beta in human platelets Identification of a major storage site purification and characterization The Journal of Biological Chemistry 258 11 7155 60 doi 10 1016 S0021 9258 18 32345 7 PMID 6602130 Oft M Heider KH Beug H November 1998 TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis Current Biology 8 23 1243 52 doi 10 1016 s0960 9822 07 00533 7 PMID 9822576 S2CID 18536979 Bakewell SJ Nestor P Prasad S Tomasson MH Dowland N Mehrotra M et al November 2003 Platelet and osteoclast beta3 integrins are critical for bone metastasis Proceedings of the National Academy of Sciences of the United States of America 100 24 14205 10 Bibcode 2003PNAS 10014205B doi 10 1073 pnas 2234372100 PMC 283570 PMID 14612570 Camerer E Qazi AA Duong DN Cornelissen I Advincula R Coughlin SR July 2004 Platelets protease activated receptors and fibrinogen in hematogenous metastasis Blood 104 2 397 401 doi 10 1182 blood 2004 02 0434 PMID 15031212 Hernandez E Lavine M Dunton CJ Gracely E Parker J June 1992 Poor prognosis associated with thrombocytosis in patients with cervical cancer Cancer 69 12 2975 7 doi 10 1002 1097 0142 19920615 69 12 lt 2975 aid cncr2820691218 gt 3 0 co 2 a PMID 1591690 Zeimet AG Marth C Muller Holzner E Daxenbichler G Dapunt O February 1994 Significance of thrombocytosis in patients with epithelial ovarian cancer American Journal of Obstetrics and Gynecology 170 2 549 54 doi 10 1016 s0002 9378 94 70225 x PMID 8116711 Ikeda M Furukawa H Imamura H Shimizu J Ishida H Masutani S et al April 2002 Poor prognosis associated with thrombocytosis in patients with gastric cancer Annals of Surgical Oncology 9 3 287 91 doi 10 1245 aso 2002 9 3 287 PMID 11923136 Shimada H Oohira G Okazumi S Matsubara H Nabeya Y Hayashi H et al May 2004 Thrombocytosis associated with poor prognosis in patients with esophageal carcinoma Journal of the American College of Surgeons 198 5 737 41 doi 10 1016 j jamcollsurg 2004 01 022 PMID 15110807 a b c Erpenbeck L Schon MP April 2010 Deadly allies the fatal interplay between platelets and metastasizing cancer cells Blood 115 17 3427 36 doi 10 1182 blood 2009 10 247296 PMC 2867258 PMID 20194899 Palumbo JS Talmage KE Massari JV La Jeunesse CM Flick MJ Kombrinck KW et al January 2005 Platelets and fibrin ogen increase metastatic potential by impeding natural killer cell mediated elimination of tumor cells Blood 105 1 178 85 doi 10 1182 blood 2004 06 2272 PMID 15367435 S2CID 279285 Gay LJ Felding Habermann B February 2011 Contribution of platelets to tumour metastasis Nature Reviews Cancer 11 2 123 34 doi 10 1038 nrc3004 PMC 6894505 PMID 21258396 Thiery JP June 2002 Epithelial mesenchymal transitions in tumour progression Nature Reviews Cancer 2 6 442 54 doi 10 1038 nrc822 PMID 12189386 S2CID 5236443 a b Yingling JM Blanchard KL Sawyer JS December 2004 Development of TGF beta signalling inhibitors for cancer therapy Nature Reviews Drug Discovery 3 12 1011 22 doi 10 1038 nrd1580 PMID 15573100 S2CID 42237691 Zou J Luo H Zeng Q Dong Z Wu D Liu L June 2011 Protein kinase CK2a is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT related genes Journal of Translational Medicine 9 97 doi 10 1186 1479 5876 9 97 PMC 3132712 PMID 21702981 Gowda C Sachdev M Muthusami S Kapadia M Petrovic Dovat L Hartman M et al 2017 Casein Kinase II CK2 as a Therapeutic Target for Hematological Malignancies Current Pharmaceutical Design 23 1 95 107 doi 10 2174 1381612822666161006154311 PMID 27719640 CX 4945 Granted Orphan Drug Designation Oncology Times 39 5 23 10 March 2017 doi 10 1097 01 cot 0000514203 35081 69 ISSN 0276 2234 Bhola NE Balko JM Dugger TC Kuba MG Sanchez V Sanders M et al March 2013 TGF b inhibition enhances chemotherapy action against triple negative breast cancer The Journal of Clinical Investigation 123 3 1348 58 doi 10 1172 JCI65416 PMC 3582135 PMID 23391723 a b Kothari AN Mi Z Zapf M Kuo PC 15 October 2014 Novel clinical therapeutics targeting the epithelial to mesenchymal transition Clinical and Translational Medicine 3 35 doi 10 1186 s40169 014 0035 0 PMC 4198571 PMID 25343018 a b c d Rupaimoole R Slack FJ March 2017 MicroRNA therapeutics towards a new era for the management of cancer and other diseases Nature Reviews Drug Discovery 16 3 203 222 doi 10 1038 nrd 2016 246 PMID 28209991 S2CID 22956490 Krutzfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M Stoffel M December 2005 Silencing of microRNAs in vivo with antagomirs Nature 438 7068 685 9 Bibcode 2005Natur 438 685K doi 10 1038 nature04303 PMID 16258535 S2CID 4414240 Harazono Y Muramatsu T Endo H Uzawa N Kawano T Harada K et al 14 May 2013 miR 655 Is an EMT suppressive microRNA targeting ZEB1 and TGFBR2 PLOS ONE 8 5 e62757 Bibcode 2013PLoSO 862757H doi 10 1371 journal pone 0062757 PMC 3653886 PMID 23690952 a b c Rothschild SI 4 March 2014 microRNA therapies in cancer Molecular and Cellular Therapies 2 7 doi 10 1186 2052 8426 2 7 PMC 4452061 PMID 26056576 Lv H Zhang S Wang B Cui S Yan J August 2006 Toxicity of cationic lipids and cationic polymers in gene delivery Journal of Controlled Release 114 1 100 9 doi 10 1016 j jconrel 2006 04 014 PMID 16831482 Gershengorn MC Hardikar AA Wei C et al 2004 Epithelial to mesenchymal transition generates proliferative human islet precursor cells Science 306 5705 2261 2264 Bibcode 2004Sci 306 2261G doi 10 1126 science 1101968 PMID 15564314 S2CID 22304970 Gershengorn MC Geras Raaka E Hardikar AA et al 2005 Are better islet cell precursors generated by epithelial to mesenchymal transition Cell Cycle 4 3 380 382 doi 10 4161 cc 4 3 1538 PMID 15711124 Atouf F Park CH Pechhold K et al 2007 No evidence for mouse pancreatic beta cell epithelial mesenchymal transition in vitro Diabetes 56 3 699 702 doi 10 2337 db06 1446 PMID 17327438 Chase LG Ulloa Montoya F Kidder BL et al 2007 Islet derived fibroblast like cells are not derived via epithelial mesenchymal transition from Pdx 1 or insulin positive cells Diabetes 56 1 3 7 doi 10 2337 db06 1165 PMID 17110468 Morton RA Geras Raaka E Wilson LM et al 2007 Endocrine precursor cells from mouse islets are not generated by epithelial to mesenchymal transition of mature beta cells Mol Cell Endocrinol 270 1 2 87 93 doi 10 1016 j mce 2007 02 005 PMC 1987709 PMID 17363142 Russ HA Bar Y Ravassard P et al 2008 In vitro proliferation of cells derived from adult human beta cells revealed by cell lineage tracing Diabetes 57 6 1575 1583 doi 10 2337 db07 1283 PMID 18316362 Russ HA Ravassard P Kerr Conte J et al 2009 Epithelial mesenchymal transition in cells expanded in vitro from lineage traced adult human pancreatic beta cells PLOS ONE 4 7 e6417 Bibcode 2009PLoSO 4 6417R doi 10 1371 journal pone 0006417 PMC 2712769 PMID 19641613 a b Joglekar MV Joglekar VM Joglekar SV et al 2009 Human fetal pancreatic insulin producing cells proliferate in vitro J Endocrinol 201 1 27 36 doi 10 1677 joe 08 0497 PMID 19171567 Jolly MK Boareto M Huang B Jia D Lu M Ben Jacob E et al 1 January 2015 Implications of the Hybrid Epithelial Mesenchymal Phenotype in Metastasis Frontiers in Oncology 5 155 arXiv 1505 07494 Bibcode 2015arXiv150507494J doi 10 3389 fonc 2015 00155 PMC 4507461 PMID 26258068 Nakaya Y Sheng G November 2013 EMT in developmental morphogenesis Cancer Letters 341 1 9 15 doi 10 1016 j canlet 2013 02 037 PMID 23462225 a b Tian XJ Zhang H Xing J August 2013 Coupled reversible and irreversible bistable switches underlying TGFb induced epithelial to mesenchymal transition Biophysical Journal 105 4 1079 89 arXiv 1307 4732 Bibcode 2013BpJ 105 1079T doi 10 1016 j bpj 2013 07 011 PMC 3752104 PMID 23972859 a b Zhang J Tian XJ Zhang H Teng Y Li R Bai F et al September 2014 TGF b induced epithelial to mesenchymal transition proceeds through stepwise activation of multiple feedback loops Science Signaling 7 345 ra91 doi 10 1126 scisignal 2005304 PMID 25270257 S2CID 19143040 a b Lu M Jolly MK Levine H Onuchic JN Ben Jacob E November 2013 MicroRNA based regulation of epithelial hybrid mesenchymal fate determination Proceedings of the National Academy of Sciences of the United States of America 110 45 18144 9 Bibcode 2013PNAS 11018144L doi 10 1073 pnas 1318192110 PMC 3831488 PMID 24154725 Savagner P October 2010 The epithelial mesenchymal transition EMT phenomenon Annals of Oncology 21 Suppl 7 vii89 92 doi 10 1093 annonc mdq292 PMC 3379967 PMID 20943648 Jia D Jolly MK Tripathi SC Den Hollander P Huang B Lu M et al 2017 Distinguishing mechanisms underlying EMT tristability Cancer Convergence 1 1 2 arXiv 1701 01746 Bibcode 2017arXiv170101746J doi 10 1186 s41236 017 0005 8 PMC 5876698 PMID 29623961 Jolly MK Tripathi SC Jia D Mooney SM Celiktas M Hanash SM et al May 2016 Stability of the hybrid epithelial mesenchymal phenotype Oncotarget 7 19 27067 84 doi 10 18632 oncotarget 8166 PMC 5053633 PMID 27008704 External links editCommentary Epithelial to mesenchymal transition in pancreatic islet b cells Retrieved from https en wikipedia org w index php title Epithelial mesenchymal transition amp oldid 1189569838, wikipedia, wiki, book, 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