Role of epithelial–mesenchymal transition factors in the histogenesis of uterine carcinomas

Abstract

Several subtypes of high-grade endometrial carcinomas (ECs) contain an undifferentiated component of non-epithelial morphology, including undifferentiated and dedifferentiated carcinomas and carcinosarcomas (CSs). The mechanism by which an EC undergoes dedifferentiation has been the subject of much debate. The epithelial–mesenchymal transition (EMT) is one of the mechanisms implicated in the transdifferentiation of high-grade carcinomas. To improve our understanding of the role of EMT in these tumors, we studied a series of 89 carcinomas including 14 undifferentiated/dedifferentiated endometrial carcinomas (UECs/DECs), 49 CSs (21 endometrial, 29 tubo-ovarian and peritoneal), 17 endometrioid carcinomas (grade 1–3), and 9 high-grade serous carcinomas of the uterus, using a panel of antibodies targeting known epithelial markers (Pan-Keratin AE1/AE3 and E-cadherin), mesenchymal markers (N-cadherin), EMT transcription factors (TFs) (ZEB1, ZEB2, TWIST1), PAX8, estrogen receptors (ER), progesterone receptors (PR), and the p53 protein. At least one of the three EMT markers (more frequently ZEB1) was positive in the sarcomatous component of 98% (n = 48/49) of CSs and 98% (n = 13/14) of the undifferentiated component of UEC/DEC. In addition, 86% of sarcomatous areas of CSs and 79% of the undifferentiated component of UEC/DEC expressed all three EMT-TFs. The expression of these markers was associated with the loss of or reduction in epithelial markers (Pan-keratin, E-cadherin), PAX8, and hormone receptors. In contrast, none of the endometrioid and serous endometrial carcinomas expressed ZEB1, while 6% and 36% of endometrioid and 11% and 25% of serous carcinomas focally expressed ZEB2 and TWIST1, respectively. Although morphologically different, EMT appears to be implicated in the dedifferentiation in both CSs and UEC/DEC. Indeed, we speculate that the occurrence of EMT in a well differentiated endometrioid carcinoma may consecutively lead to a dedifferentiated and undifferentiated carcinoma, while in a type II carcinoma, it may result in a CS.

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Author information

Affiliations

Authors

Contributions

Tatiana Franceschi: writing of the article and immunohistochemical analyses.

Emeline Durieux: immunohistochemical analyses and selection of the cases and of the paraffin blocks.

Anne Pierre Morel: choosing and providing antibodies for the study and critical review of the manuscript.

Pierre de Saint Hilaire: selection of the patients and surgery and providing surgical tumor material for the study.

Isabelle Ray-Coquard: selection of the patients,

Alain Puisieux: designing the study, critical review of the article.

Mojgan Devouassoux-Shisheboran: designing the study and writing of the article.

Corresponding author

Correspondence to Mojgan Devouassoux-Shisheboran.

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The study was approved by the Ethics Committee of the Medical Board (CHU Lyon). This study was conducted in accordance with the Declaration of Helsinki.

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The authors declare that they have no conflict of interest.

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Franceschi, T., Durieux, E., Morel, A.P. et al. Role of epithelial–mesenchymal transition factors in the histogenesis of uterine carcinomas. Virchows Arch 475, 85–94 (2019). https://doi.org/10.1007/s00428-019-02532-w

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Keywords

  • Epithelial mesenchymal transition
  • ZEB1
  • ZEB2
  • TWIST
  • Endometrial carcinoma
  • Dedifferentiated
  • Undifferentiated