Skip to main content
SpringerLink
Log in

Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis

  • Chapter
  • First Online:
Uterine Fibroids and Adenomyosis

Part of the book series: Comprehensive Gynecology and Obstetrics ((CGO))

  • 726 Accesses

Abstract

The exact pathogenesis of adenomyosis is still elusive. Among different reported concepts, direct invagination of gland cells from basalis endometrium deep into myometrium is the most widely accepted opinion in the development of adenomyosis. To address the mechanistic basis of this accepted concept, we investigated the role of hepatocyte growth factor (HGF) and estrogen in the occurrence of epithelial-mesenchymal transition (EMT) in human adenomyosis. Biopsy specimens from endometrium to myometrium were collected after hysterectomy from women with and without adenomyosis. The relationship between HGF and E-cadherin (epithelial cell marker)/N-cadherin (mesenchymal cell marker) was examined using endometrial epithelial cells (EECs) and tissues by qRT-PCR and immunohistochemistry. The gene and protein expressions of two transcriptional repressors of E-cadherin, SLUG and SNAIL, were examined using Ishikawa cells. HGF downregulated E-cadherin and upregulated N-cadherin mRNA expression in EECs, and an inverse relationship between HGF and E-cadherin was observed in basalis endometria of women with adenomyosis. HGF induced morphological changes and promoted migration of EECs. Ishikawa cells exhibited upregulation of SLUG/SNAIL gene expression in response to HGF and estrogen with an additive effect between them. HGF- and estrogen-promoted SLUG/SNAIL gene expression was significantly abrogated after pretreatment of cells with anti-HGF antibody or ICI 182720, an estrogen receptor antagonist. Our findings suggested that HGF either alone or in combination with estrogen may be involved in gland invagination deep into myometrium by inducing EMT in women with adenomyosis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bergeron C, Amant F, Ferenczy A. Pathology and pathophysiology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):511–21.

    Article  PubMed  Google Scholar 

  2. Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update. 1998;4(4):312–22.

    Article  CAS  PubMed  Google Scholar 

  3. Wang PH, Fuh JL, Chao HT, Liu WM, Cheng MH, Chao KC. Is the surgical approach beneficial to subfertile women with symptomatic extensive adenomyosis? J Obstet Gynecol Res. 2009;35:495–502.

    Article  Google Scholar 

  4. Ridley JH. The histogenesis of endometriosis: a review of facts and fancies. Obstet Gynecol Surv. 1968;23:1–35.

    Article  Google Scholar 

  5. Hay ED. Organization and fine structure of epithelium and mesenchyme in the development of chick embryo. In: Fleischmajer R, Billingham RE, editors. Epithelial-mesenchymal interactions. Baltimore: Williams & Wilkins; 1968. p. 31–55.

    Google Scholar 

  6. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als-Nielsen J, Colman DR, Hendrickson WA. Structural basis of cell-cell adhesion by cadherins. Nature. 1995;374:327–37.

    Article  CAS  PubMed  Google Scholar 

  7. Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Nonmalignant epithelial cells, potentially invasive in human endometriosis, lacks the tumor suppressor molecule E-cadherin. Am J Pathol. 1997;150:461–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Hiscox S, Jiang WG. HGF/SF regulates the phosphorylation of β-catenin and cell-cell adhesion in cancer cells. Proc Am Assoc Cancer Res. 1998;39:500–1.

    Google Scholar 

  9. Chen YJ, Li HY, Huang CH, Twu NF, Yen MS, Wang PH, Chou TY, Liu YN, Chao KC, Yang MH. Estrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol. 2010;222:261–70.

    Article  CAS  PubMed  Google Scholar 

  10. Park SH, Cheung LWT, Wong AST, Leung PCK. Estrogen regulates Snail and Slug in the down-regulation of E-cadherin and induces mestastatic potential of ovarian cancer cells through estrogen receptorα. Mol Endocrinol. 2008;22:2085–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA. The transcriptional factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.

    Article  CAS  Google Scholar 

  12. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499–511.

    Article  CAS  PubMed  Google Scholar 

  13. Hendrickson MR, et al. Normal histology of the uterus and fallopian tubes. In: Sternberg SS, editor. Histology for pathologists. 2nd ed. Philadelphia: Lippincott-Raven; 1997. p. 894–7.

    Google Scholar 

  14. Setoguchi T. Histology of endometrium (in Japanese). In: Suzuku S, editor. Textbook of practical histology. Tokyo: Nanzando Co. Ltd.; 1979. p. 218–41.

    Google Scholar 

  15. Khan KN, Fujishita A, Kitajima M, Masuzaki H, Nakashima M, Kitawaki J. Biological differences between functionalis and basalis endometria in women with and without adenomyosis. Eur J Obstet Gynecol Reprod Biol. 2016;203:49–55.

    Article  PubMed  Google Scholar 

  16. Khan KN, Kitajima M, Imamura T, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Toll-like receptor 4 (TLR4)-mediated growth of endometriosis by human heat shock protein 70 (Hsp70). Hum Reprod. 2008;23(10):2210–9.

    Article  CAS  PubMed  Google Scholar 

  17. Imamura T, Khan KN, Fujishita A, Kitajima M, Hiraki K, Ishimaru T, Masuzaki H. Effect of GnRH agonist therapy on the expression of human heat shock protein 70 in eutopic and ectopic endometria of women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2014;180:16–23.

    Article  CAS  PubMed  Google Scholar 

  18. Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Masuzaki H. Involvement of hepatocyte growth factor-induced epithelial-mesenchymal transition in human adenomyosis. Biol Reprod. 2015;92(2):35.

    Article  CAS  PubMed  Google Scholar 

  19. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Ishimaru T. Immunoexpression of hepatocyte growth factor and c-Met receptor in the eutopic endometrium predicts the activity of ectopic endometrium. Fertil Steril. 2003;79(1):173–81.

    Article  PubMed  Google Scholar 

  20. Khan KN, Kitajima M, Hiraki H, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Immunopathogenesis of pelvic endometriosis: role of hepatocyte growth factor, macrophages and ovarian steroids. Am J Reprod Immunol. 2008;60:383–404.

    Article  CAS  PubMed  Google Scholar 

  21. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Kohno T, Sekine I, Matsuyama T, Ishimaru T. Regulation of hepatocyte growth factor by basal and stimulated-macrophages in women with endometriosis. Hum Reprod. 2005;20:49–60.

    Article  CAS  PubMed  Google Scholar 

  22. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Matsuyama T, Ishimaru T. Estrogen and progesterone receptor expression in macrophages and regulation of hepatocyte growth factor by ovarian steroids in women with endometriosis. Hum Reprod. 2005;20:2004–13.

    Article  CAS  PubMed  Google Scholar 

  23. Fujishita A, Nakane PK, Koji T, Masuzaki H, Chavez RO, Yamabe T, Ishimaru T. Expression of estrogen and progesterone in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study. Fertil Steril. 1997;67:856–64.

    Article  CAS  PubMed  Google Scholar 

  24. Khan KN, Kitajima M, Fujishita A, Ishimaru T, Sekine I, Masuzaki H. Multifunctional role of hepatocyte growth factor in the development of pelvic endometriosis. WES E-J. 2008;13–20.

    Google Scholar 

  25. Hannan NJ, Paiva P, Dimitriadis E, Salamonsen LA. Models for study of human embryo implantation: choice of cell lines? Biol Reprod. 2010;82:235–45.

    Article  CAS  PubMed  Google Scholar 

  26. Castelbaum AJ, Ying L, Samkuti SG, Sun J, IIesanmi AO, Lessey BA. Characterization of integrin expression in a well differentiated endometrial adenocarcinoma cell line (Ishikawa). J Clin Endocrinol Metab. 1997;82:136–42.

    PubMed  CAS  Google Scholar 

  27. Montserrat N, Mozos A, Llobet D, Dolcet X, Pons C, Garcia de Herreros A, Matias-Guiu X, Prat J. Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma. Hum Pathol. 2012;43:632–43.

    Article  PubMed  Google Scholar 

  28. Zeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. Am J Pathol. 2001;159:1839–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009;119:1438–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

This work was supported in part by Grants-in-Aid for Scientific Research (grants 21592101 and 24592474) from the Japan Society of the Promotion of Science (to K.N.K.).

I gratefully thank Dr. Akira Fujishita and Dr. Koichi Hiraki of Saikeikai Nagasaki Hospital and Dr. Michio Kitajima of Nagasaki University Hospital for their kind assistance in sample collection and Prof. Masahiro Nakashima for his experimental advice. K.N.K. designed and supervised the project and edited/wrote the complete draft.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Khaleque N. Khan M.D., Ph.D.

Authors
  1. Khaleque N. Khan M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Khaleque N. Khan M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan

    Norihiro Sugino

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Khan, K.N. (2018). Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis. In: Sugino, N. (eds) Uterine Fibroids and Adenomyosis. Comprehensive Gynecology and Obstetrics. Springer, Singapore. https://doi.org/10.1007/978-981-10-7167-6_9

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-7167-6_9

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-7166-9

  • Online ISBN: 978-981-10-7167-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation