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The Role of Epithelial-mesenchymal Transition in the Development of Adenomyosis

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Published: 9th Dec 2019

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The role of epithelial-mesenchymal transition in the development of adenomyosis


The growth of organ system begins with single layers of epithelial cells, this results in primary building block for constructing organismic complexity(Lamouille, Xu and Derynck, 2014). Epithelial cells form layers of cells which is tightly connected by specialized junction structures such as adherence junctions, desmosomes, tight junctions, and gap junctions.

According Hay, (1995) adherence junction play important role in connecting and developing lateral cell-cell adhesions in epithelial cell sheets. As epithelial cells establish apical-basal polarity through their connection with a lamina layer at the basal surface, called basement membrane.

This basement membrane secures the epithelial cells can only move horizontally along the basal surface, which results in keeping their positioning within the epithelium and preventing their entrance into the underlying extracellular matrix(Hay, 2005).According Zeisberg et al., (2003) the early embryogenesis of most metazoans mesenchymal cells arise from the primitive epithelium. In comparison to epithelial cells, mesenchymal cells shows a front-back end polarity and it is uncommon a direct contact with neighboring mesenchymal cells (Acloque et al., 2009).

In contrast to epithelial cells , mesenchymal cells can invade as distinct cells through ECM( extracellular matrix) formed by epithelial sheets and mesenchymal cells(Iwatsuki et al., 2010)Although epithelial and mesenchymal cells types have been known in earlier embryos, the conversion of epithelial cells into mesenchymal cell was defined as a distinctive cellular program in 1980s.Furthermore Greenburg and Hay confirmed this in a series of experiments, where epithelial cells from embryogenic and adult anterior were cultured in 3D collagen gels, these cells were starched, detached from the explants, and migrated as individual cells(Bilozur and Hay, 1988).

According Acloque et al., (2009) Based on the mesenchyal morphology and the pseudopodia and filopodia structures of these migrating cells, it was concluded that disitinguished epithelial cells could be converted into mesenchymal cells through a cellular programme they named Epithelial mesenchymal transformation (EMT). EMT is important in development, cell behavior, wound healing and contributes pathologically to fibrosis and cancer progression (Lamouille, Xu and Derynck, 2014). 


There are three different types of EMT. Type 1 EMT is linked to gastrulation and implantation, results in giving rise to the mesoderm, endoderm and mobile neural crest cells (Tanimizu and Miyajima, 2007). This happens when a fertilized egg undergoes gastrulation by generating three germ layers. Firstly a primitive streak is formed in the epiblast layer(Moustakas and Heldin, 2007). Secondly the epithelial cells in this tissue form E-cadherin and exhibit apical-basal polarity. This leads in turn to the formation of the three germ layers that makes all types of body tissues.

The formed primitive streak in the epiblast layer forms the lower extremity of the embryo and later on extends in the direction of future head(Kalluri and Weinberg, 2009). The epithelial-like cells of the epiblast undergo programmed changes which is dictated by specific protein expression related with cell differentiation and migration (Thiery and Sleeman, 2006). After the formation of embryonic mesoderm between epiblas and hypoblast ,it gives rise to primary mesenchyme related associated with axial, paraxial, intermediate, and lateral plate mesodermal layer(Tanimizu and Miyajima, 2007).

Type 2 EMT is associate with tissue regeneration and organ fibrosis (Carew, Wang and Kantharidis, 2012).  Organ fibrosis takes place in various epithelial tissues, this is mediated by inflammatory cells and fibroblasts which release a number of inflammatory signals as well as componenets of Extra cellular Matrix(ECM). This includes collagens, laminins,elastin, and tenancins(Koike et al., 2013).

Furthermore EMT’s are found to be associate with fiborisis occurring in liver,lung,intestine and kidney((Kim et al., 2006).According Zeisberg et al.,( 2003) fibroblast-specific protein 1(FSP1) which is an S100 class of cytoskeletal protein, a-SMA, and collagen are markers that characterize the mesenchymal production by the EMTs during the development of fibrosis in various organs (Carew, Wang and Kantharidis, 2012). Other markers such as decoidin domain receptor tyrosin kinase 2 (DDR2) ,vitamentin,desmin along with these markers have been used to classify epithelial cells of the liver,lung,kidney and intestine that are in process of undergoing an EMT associated with chronic inflammation (Chen et al., 2010)

According (Mira et al., 2017) type 3 EMT is associated with cancer progression and metastasis, where excessive epithelial cell proliferation and angiogenesis are hallmarks of initiation and early growth of primary epithelial cancers.

Various studies and cell culture experiments have shown that carcinoma cells can develop a mesenchymal phenotype and express mesenchymal markers that include A-SMA,FSP1,vimentin and desmin (Yang and Weinberg, 2008).

These cells are specially observed at the invasive front of primary tumors and enter into subsequent steps of invasion metastasis cascade such as transport through the circulation, intravasation, extravasation, and formation of micrometasitases(Thiery, 2002).

Furthermore Mira et al.,( 2017) states that EMT plays role in preventing senescence induced by oncogene, therefore enabling constant aggressive dissemintation.In many carcinomas, the EMT-inducing signals emiting from tumor-associated stroma, specially HGF,EGF,PDGF, and TGF-β is responsible for the functional activation or general in cancer cells of various EMT-inducing transcription factors (Mechsner et al., 2010). These are remarkably Snail,Slug,Zinc Finger E-Box binding homeobox 1(ZEB1), Twist, Gooscoid and FOXC2 (Kokudo et al., 2008).


Adenomyosis is the presence of endometrial mucosa within the myometrium. This appears due to invagination of basalis endometrium into the myometrium (Koike et al., 2013). This process is facilitated by the non-cyclic, anti-apoptopic activity of the basalis connected with virtual hyper-oestrogenic states. Adenomyosis cases are common in multiparous women during the “transitional” year, which is 40-50(Oh et al., 2013) .Furthermore this condition is associate with menorrhagia ,dymensnorrhoea, endometrial polyps and leiomyomata uteri (Matsuzaki and Darcha, 2013).

According Chen et al., (2010)epithelial-mesenchymal transition(EMT) plays an important role in development of adenomyosis, which results in an increased invasive tendency of adenomyotic epithelial cells. Nevertheless Oh et al., (2013) states that an increased level of nuclearcatenin in adenomyosis found in mouse, stabilized catenin expression which resulted in changed expression of EMT markers, that include E-cadherin, SNAIL, and ZEB1 assoiciated with occurrence of adenomyosis. Moreover Khan et al., (2015) narrated that increased level of hepatocyte growth factor (HGF) in the endometrial-myometrial junction in adenomyosis, HGF-mediated EMT along with increased level of migratory ability in HGF-treated endometrial epithelial cells, and the signs of EMT in Ishikawa cells treated with HGF as well.

References :

Acloque, H. et al. (2009) ‘Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease’, Journal of Clinical Investigation, 119(6), pp. 1438–1449. doi: 10.1172/JCI38019.

Bilozur, M. E. and Hay, E. D. (1988) ‘Neural crest migration in 3D extracellular matrix utilizes laminin, fibronectin, or collagen’, Developmental Biology, 125(1), pp. 19–33. doi: 10.1016/0012-1606(88)90055-3.

Carew, R. M., Wang, B. and Kantharidis, P. (2012) ‘The role of EMT in renal fibrosis’, Cell and Tissue Research, 347(1), pp. 103–116. doi: 10.1007/s00441-011-1227-1.

Chen, Y.-J. et al. (2010) ‘Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis’, The Journal of Pathology, 222(3), pp. 261–270. doi: 10.1002/path.2761.

Hay, E. D. (1995) ‘An Overview of Epithelio-Mesenchymal Transformation’, Cells Tissues Organs, 154(1), pp. 8–20. doi: 10.1159/000147748.

Hay, E. D. (2005) ‘The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it’, Developmental Dynamics, 233(3), pp. 706–720. doi: 10.1002/dvdy.20345.

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Kalluri, R. and Weinberg, R. A. (2009) ‘The basics of epithelial-mesenchymal transition’, The Journal of Clinical Investigation, 119(6), pp. 1420–1428. doi: 10.1172/JCI39104.

Khan, K. N. et al. (2015) ‘Involvement of Hepatocyte Growth Factor-Induced Epithelial-Mesenchymal Transition in Human Adenomyosis1’, Biology of Reproduction, 92(2). doi: 10.1095/biolreprod.114.124891.

Kim, K. K. et al. (2006) ‘Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix’, Proceedings of the National Academy of Sciences of the United States of America, 103(35), pp. 13180–13185. doi: 10.1073/pnas.0605669103.

Koike, N. et al. (2013) ‘Pathogenesis and malignant transformation of adenomyosis (Review)’, Oncology Reports, 29(3), pp. 861–867. doi: 10.3892/or.2012.2184.

Kokudo, T. et al. (2008) ‘Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells’, Journal of Cell Science, 121(Pt 20), pp. 3317–3324. doi: 10.1242/jcs.028282.

Lamouille, S., Xu, J. and Derynck, R. (2014) ‘Molecular mechanisms of epithelial–mesenchymal transition’, Nature reviews. Molecular cell biology, 15(3), pp. 178–196. doi: 10.1038/nrm3758.

Matsuzaki, S. and Darcha, C. (2013) ‘Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis’, PloS One, 8(10), p. e76808. doi: 10.1371/journal.pone.0076808.

Mechsner, S. et al. (2010) ‘Possible roles of oxytocin receptor and vasopressin-1α receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri’, Fertility and Sterility, 94(7), pp. 2541–2546. doi: 10.1016/j.fertnstert.2010.03.015.

Mira, A. et al. (2017) ‘Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors’, Oncotarget, 8(24), pp. 38193–38213. doi: 10.18632/oncotarget.16942.

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Oh, S. J. et al. (2013) ‘β-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition’, The Journal of Pathology, 231(2), pp. 210–222. doi: 10.1002/path.4224.

Tanimizu, N. and Miyajima, A. (2007) ‘Molecular mechanism of liver development and regeneration’, International Review of Cytology, 259, pp. 1–48. doi: 10.1016/S0074-7696(06)59001-1.

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Zeisberg, M. et al. (2003) ‘BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury’, Nature Medicine, 9(7), pp. 964–968. doi: 10.1038/nm888.

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