Perfil de miRNAs relacionados con la Transición Epitelio-Mesenquimal y la formación de células madre tumorales en glioblastoma

Los tumores en el encéfalo y en el sistema nervioso central (SNC), dada su localización, tienen una alta morbilidad. En 2012, se identificaron 256.000 nuevos casos de cáncer de encéfalo y SNC en el mundo, ocasionando 198.000 muertes. Sin embargo, estos valores pueden estar subestimados, debido a que hay una alta variabilidad en la incidencia y mortalidad en el mundo, principalmente causada por la disponibilidad de métodos de diagnóstico o a la inexactitud cuando se asigna la causa de muerte subyacente. La presencia de metástasis en este tipo de tumores es frecuente y es la principal causa de muerte en el cáncer avanzado siendo responsable del 90% de las causas de muerte por cáncer. Aunque ha sido objeto de intensa investigación, la comprensión actual de las vías de señalización molecular que impulsan el proceso metastásico sigue siendo fragmentado e insuficiente ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nbt.1618","ISSN":"10870156","abstract":"MicroRNAs (miRNAs) are increasingly implicated in the regulation of metastasis. Despite their potential as targets for anti-metastatic therapy, miRNAs have only been silenced in normal tissues of rodents and nonhuman primates. Therefore, the development of effective approaches for sequence-specific inhibition of miRNAs in tumors remains a scientific and clinical challenge. Here we show that systemic treatment of tumor-bearing mice with miR-10b antagomirs-a class of chemically modified anti-miRNA oligonucleotide-suppresses breast cancer metastasis. Both in vitro and in vivo, silencing of miR-10b with antagomirs significantly decreases miR-10b levels and increases the levels of a functionally important miR-10b target, Hoxd10. Administration of miR-10b antagomirs to mice bearing highly metastatic cells does not reduce primary mammary tumor growth but markedly suppresses formation of lung metastases in a sequence-specific manner. The miR-10b antagomir, which is well tolerated by normal animals, appears to be a promising candidate for the development of new anti-metastasis agents.","author":[{"dropping-particle":"","family":"Ma","given":"Li","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reinhardt","given":"Ferenc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pan","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soutschek","given":"Jürgen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhat","given":"Balkrishen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marcusson","given":"Eric G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teruya-Feldstein","given":"Julie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bell","given":"George W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weinberg","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Biotechnology","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"title":"Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model","type":"article-journal"},"uris":["http://www.mendeley.com/documents/?uuid=db564589-e4f4-4474-b610-308a615a7391"]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cell.2009.03.047","ISSN":"00928674","abstract":"MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis. © 2009 Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Valastyan","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reinhardt","given":"Ferenc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benaich","given":"Nathan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calogrias","given":"Diana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szász","given":"Attila M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Zhigang C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brock","given":"Jane E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richardson","given":"Andrea L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weinberg","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell","id":"ITEM-2","issued":{"date-parts":[["2009"]]},"title":"A Pleiotropically Acting MicroRNA, miR-31, Inhibits Breast Cancer Metastasis","type":"article-journal"},"uris":["http://www.mendeley.com/documents/?uuid=22531283-04fd-4003-bd26-924cea196de8"]}],"mendeley":{"formattedCitation":"(1,2)","plainTextFormattedCitation":"(1,2)","previouslyFormattedCitation":"(1,2)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(1,2). Transformar una célula epitelial normal en una célula tumoral es un proceso estocástico. En los carcinomas, la organización de las capas de células epiteliales en los tejidos normales es incompatible con la movilidad y la invasividad de las células tumorales. En este caso, el primero de muchos pasos que conducen a la metástasis (invasión de un sitio diferente al del origen del tumor) implica el intercambio de fenotipos celulares (epitelio à mesenquima à epitelio) dentro del tumor primario ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nrc1098","ISSN":"1474175X","abstract":"Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?","author":[{"dropping-particle":"","family":"Fidler","given":"Isaiah J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Cancer","id":"ITEM-1","issued":{"date-parts":[["2003"]]},"title":"The pathogenesis of cancer metastasis: The 'seed and soil' hypothesis revisited","type":"article"},"uris":["http://www.mendeley.com/documents/?uuid=ed8d90fb-484e-4fff-b2c7-2c7e39f56740"]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/s12935-015-0198-9","ISSN":"14752867","abstract":"© 2015 Chen et al. Background: Mesenchymal stem cells (MSCs) in tumors have emerged as progenitors involved in stroma formation and metastasis of cancers, partially owing to their abilities to differentially express paracrine factors related to the proliferation and invasion of cancer cells. In this regard, increasing evidence has shown that MSCs have impacts on the malignancy of colon cancer, however, the underpi nning mechanisms by which MSCs promote cancer metastasis remain elusive. Methods: To investigate the crosstalk between adipose-derived MSCs (AMSCs) isolated from adipose tissues and colon cancer cells, a co-culture transwell model of AMSCs and colon cancer cells was employed, and the activation of Wnt signaling and paracrine factors in colon cancer cells and AMSCs were measured. Results: The results showed that AMSCs could enhance the metastatic capacity of colon cancer cells with an elevated expression of mesenchymal-epithelial transition (EMT)-associated genes in a contact-dependent manner. Reciprocally, colon cancer cells were able to induce AMSCs to produce metastasis-related factors and cytokines, such as FGF10, VEGFC and matrix metalloproteinases (MMPs) in part through a mechanism of an activation of Wnt signaling, by which these factors in turn activate Wnt signaling of colon cancer cells. Intriguingly, an inhibition of Wnt signaling leads a reduced capacity of invasion and colony formation of colon cancer cells in vitro, and the tumorigenicity of cancer cells in a murine model. Conclusions: These findings thus suggest that the crosstalk between the Wnt signaling of cancer cells and paracrine factors of AMSCs has an implication in colon cancer malignancy. This study thus uncovers a novel Wnt-paracrine factors mediated-crosstalk between colon cancer cells and AMSCs in cancer malignancy.","author":[{"dropping-particle":"","family":"Chen","given":"Dongmei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Shudan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Huiming","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liang","given":"Xueyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Haibin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yan","given":"Xiurui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Bao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wei","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Xiaoming","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Cell International","id":"ITEM-2","issued":{"date-parts":[["2015"]]},"title":"Paracrine factors from adipose-mesenchymal stem cells enhance metastatic capacity through Wnt signaling pathway in a colon cancer cell co-culture model","type":"article-journal"},"uris":["http://www.mendeley.com/documents/?uuid=e62c3e82-ead7-4b96-a278-3d9051bb2b13"]}],"mendeley":{"formattedCitation":"(3,4)","plainTextFormattedCitation":"(3,4)","previouslyFormattedCitation":"(3,4)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(3,4). Para adquirir movilidad e invasividad, las células de carcinoma alteran su fenotipo epitelial, se desprenden de las capas epiteliales y experimentan un cambio drástico, la transición epitelial-mesenquimal (EMT, Epithelial Mesenchymal Transition). El término EMT se refiere a la activación de un complejo programa molecular y celular, en el que las células epiteliales pierden las propiedades de adhesión celular, polaridad apical-basal y de falta de movilidad, y adquieren características mesenquimales como son la motilidad, la invasión y el aumento de la resistencia a la apoptosis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdu439","ISSN":"15698041","abstract":"© The Author 2014. Background: Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-29c has been implicated as a tumor suppressor in several human cancers. However, the role of miR-29c in the progression of colorectal cancer (CRC) metastasis remains largely unknown. Patients and methods: The expression of miR-29c was examined by qRT-PCR in a cohort of primary CRC (PC) and distant liver metastasis (LM) tissues. A series of in vivo and in vitro assays were carried out in order to elucidate the functions of miR-29c and the molecular mechanisms underlying the pathogenesis of metastatic CRC. Results: MiR-29c was markedly downregulated in PCs with distant metastasis and determined to be an independent predictor of shortened patient survival. But LM tissues showed higher levels of miR-29c than that in PC tissues. In CRC cells, miR-29c dramatically suppressed cell migration and invasion abilities in vitro and cancer metastasis in vivo. In addition, miR-29c inhibited EMT and negatively regulated Wnt/β-catenin signaling pathway. Guanine nucleotide binding protein alpha13 (GNA13) and protein tyrosine phosphatase type IVA (PTP4A) were identified as direct targets of miR-29c, which acted through ERK/GSK3β/β-catenin and AKT/GSK3β/β-catenin pathways, respectively, to regulate EMT. Furthermore, significant associations between miR-29c, its target genes (GNA13 and PTP4A) and EMT markers we re validated in both PC and LM tissues. Conclusion: Our findings highlight the important role of miR-29c in regulating CRC EMT via GSK-3β/β-catenin signaling by targeting GNA13 and PTP4A and provide new insights into the metastatic basis of CRC.","author":[{"dropping-particle":"","family":"Zhang","given":"J. X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mai","given":"S. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"X. X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"F. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liao","given":"Y. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kung","given":"H. F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zeng","given":"Y. X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xie","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"title":"MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling","type":"article-journal"},"uris":["http://www.mendeley.com/documents/?uuid=d36a5d4d-b348-483d-99bb-f1b274e426f1"]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/1746-1596-9-66","ISSN":"17461596","abstract":"Background: Metastatic lung cancer is one of the leading causes of cancer death. In recent years, epithelial-to-mesenchymal transition (EMT) has been found to contribute to metastasis, as it enables migratory and invasive properties in cancer cells. Previous genome-wide studies found that DNA methylation was unchanged during EMT induced by TGF-β in AML12 cells. In this study, we aimed to discover EMT-related changes in DNA methylation in cancer cells, which are poorly understood.Methods: We employed a next-generation sequencing-based method, MSCC (methyl-sensitive cut counting), to investigate DNA methylation during EMT in the A549 lung cancer cell line.Results: We found that methylation levels were highly correlated to gene expression, histone modifications and small RNA expression. However, no differentially methylated regions (DMRs) were found in A549 cells treated with TGF-β for 4 h, 12 h, 24 h and 96 h. Additionally, CpG islands (CGIs) showed no overall change in methylation levels, and at the single-base level, almost all of the CpGs showed conservation of DNA methylation levels. Furthermore, we found that the expression of DNA methyltransferase 1, 3a, 3b (DNMT1, DNMT3a, DNMT3b) and ten-eleven translocation 1 (TET1) was altered after EMT. The level of several histone methylations was also changed.Conclusions: DNA methylation-related enzymes and histone methylation might have a role in TGF-β-induced EMT without affecting the whole DNA methylome in cancer cells. Our data provide new insights into the global methylation signature of lung cancer cells and the role of DNA methylation in EMT.Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1112892497119603. © 2014 Liu et al.; licensee BioMed Central Ltd.","author":[{"dropping-particle":"","family":"Liu","given":"Fatao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhou","given":"Yi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhou","given":"Daizhan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kan","given":"Mengyuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Niu","given":"Xiaomin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Zhou","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Di","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tao","given":"Liming","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"He","given":"Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhan","given":"Lixing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yun","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diagnostic Pathology","id":"ITEM-2","issued":{"date-parts":[["2014"]]},"title":"Whole DNA methylome profiling in lung cancer cells before and after epithelial-to-mesenchymal transition","type":"article-journal"},"uris":["http://www.mendeley.com/documents/?uuid=b5687087-4c9f-49c2-8595-54ef6e0c21e3"]}],"mendeley":{"formattedCitation":"(5,6)","plainTextFormattedCitation":"(5,6)","previouslyFormattedCitation":"(5,6)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(5,6). La EMT es de importancia fisiológica, ya que ocurre en etapas críticas del desarrollo embrionario en muchas especies; sin embargo, observaciones en tumores humanos y modelos animales experimentales han producido pruebas convincentes del papel de la EMT en la carcinogénesis. En particular, que contribuye a la invasión de células tumorales, diseminación metastásica y resistencia terapéutica ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI36183","ISSN":"00219738","abstract":"Somatic cells that change from one mature phenotype to another exhibit the property of plasticity. It is increasingly clear that epithelial and endothelial cells enjoy some of this plasticity, which is easily demonstrated by studying the process of epithelial-mesenchymal transition (EMT). Published reports from the literature typically rely on ad hoc criteria for determining EMT events; consequently, there is some uncertainty as to whether the same process occurs under different experimental conditions. As we discuss in this Personal Perspective, we believe that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon - namely, the transition of epithelial and endothelial cells to a motile phenotype","author":[{"dropping-particle":"","family":"Zeisberg","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neilson","given":"Eric G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Investigation","id":"ITEM-1","issued":{"date-parts":[["2009"]]},"title":"Biomarkers for epithelial-mesenchymal transitions","type":"article"},"uris":["http://www.mendeley.com/documents/?uuid=a9c25f14-6562-4e33-8b05-94a27a51021b"]},{"id":"ITEM-2","itemData":{"DOI":"10.1172/JCI39104","ISSN":"00219738","abstract":"The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.","author":[{"dropping-particle":"","family":"Kalluri","given":"Raghu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weinberg","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Investigation","id":"ITEM-2","issued":{"date-parts":[["2009"]]},"title":"The basics of epithelial-mesenchymal transition","type":"article"},"uris":["http://www.mendeley.com/documents/?uuid=fa0bc12a-0062-4e4e-af5c-43030b1f4725"]}],"mendeley":{"formattedCitation":"(7,8)","plainTextFormattedCitation":"(7,8)","previouslyFormattedCitation":"(7,8)"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}(7,8). En la EMT aparecen algunos cambios en las características fenotípicas, tales como: (1) adquisición de morfología fusiforme; (2) represión de marcadores epiteliales (como E-cadherina, citoqueratina) y ganancia de marcadores mesenquimales (N-cadherina, vimentina, fibronectina) y (3) aumento de la motilidad y la capacidad de invadir la matriz extracelular. Todos estos cambios inherentes al EMT en una célula ocurren en respuesta a la activación del programa morfogenético que ya está codificado en su genoma ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.semcdb.2008.02.001","ISSN":"10849521","abstract":"The ancestors of modern Metazoa were constructed in large part by the foldings and distortions of two-dimensional sheets of epithelial cells. This changed ∼600 million years ago with the evolution of mesenchymal cells. These cells arise as the result of epithelial cell delamination through a reprogramming process called an epithelial to mesenchymal transition (EMT) [Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev 2003;120:1351-83; Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42]. Because mesenchymal cells are free to migrate through the body cavity, the evolution of the mesenchyme opened up new avenues for morphological plasticity, as cells evolved the ability to take up new positions within the embryo and to participate in novel cell-cell interactions; forming new types of internal tissues and organs such as muscle and bone [Thiery JP, Sleeman, JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42; Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995;26:678-90]. After migrating to a suitable site, mesenchymal cells coalesce and re-polarize to form secondary epithelia, in a so-called mesenchymal-epithelial transition (MET). Such switches between mesenchymal and epithelial states are a frequent feature of Metazoan gastrulation [Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995;26:678-90] and the neural crest lineage [Duband JL, Monier F, Delannet M, Newgreen D. Epitheliu-mmesenchyme transition during neural crest development. Acta Anat 1995;154:63-78]. Significantly, however, when hijacked during the development of cancer, the ability of cells to undergo EMT, to leave the primary tumor and to undergo MET at secondary sites can have devastating consequences on the organism, allowing tumor cells derived from epithelia to invade surrounding tissues and spread through the host [Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42; Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995;26:678-90]. Thus, the molecular and cellular mechanisms un…","author":[{"dropping-particle":"","family":"Baum","given":"Buzz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Settleman","given":"Jeffrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Quinlan","given":"Margaret P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Seminars in Cell and Developmental Biology","id":"ITEM-1","issued":{"date-parts":[["2008"]]},"title":"Transitions between epithelial and mesenchymal states in development and disease","type":"article"},"uris":["http://www.mendeley.com/documents/?uuid=3b5979e1-c01e-4f23-b0f4-192097aabcf6"]},{"id":"ITEM-2","itemData":{"DOI":"10.1172/JCI200320530","ISSN":"00219738","abstract":"Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.","author":[{"dropping-particle":"","family":"Kalluri","given":"Raghu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neilson","given":"Eric G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Investigation","id":"ITEM-2","issued":{"date-parts":[["2003"]]},"title":"Epithelial-mesenchymal transition and its implications for fibrosis","type":"article"},"uris":["http://www.mendeley.com/documents/?uuid=45c6c1c2-8104-49eb-af9b-d4464d01c7fa"]},{"id":"ITEM-3","itemData":{"DOI":"10.1007/s00428-014-1603-9","ISSN":"14322307","abstract":"Fibromatosis-like metaplastic carcinoma (FLMCa) of the breast is a rare low-grade spindle cell carcinoma, of which the biological characteristics have not been well studied. This study aims to assess, in FLMCa, immunohistochemical expression of claudins (CLDN) and features connected with the claudin-low subtype, such as the presence of tumor initiating cells (TIC), epithelial-mesenchymal transition (EMT) phenotype, as well as EGFR activating mutations. Three cases of FLMCa were retrieved from our hospital archives. Histological and immunohistochemical characteristics were reviewed. Expression of CLDN-1, CLDN-3, CLDN-4 and CLDN-7, CD44 and CD24 (TIC phenotype), and vimentin and E-cadherin (EMT features) were studied. EGFR mutations on exons 18, 19, 20, and 21 were investigated by real-time PCR. In all cases, the low-grade spindle cell component was predominant, with two cases presenting