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The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten
Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Pten(f/f)Pgr(Cre/+)) results in rapid development of endometrial carcinoma (EMC) with full penetration. We al...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126871/ https://www.ncbi.nlm.nih.gov/pubmed/30142194 http://dx.doi.org/10.1371/journal.pgen.1007630 |
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author | Liang, Xiaohuan Daikoku, Takiko Terakawa, Jumpei Ogawa, Yuya Joshi, Ayesha R. Ellenson, Lora H. Sun, Xiaofei Dey, Sudhansu K. |
author_facet | Liang, Xiaohuan Daikoku, Takiko Terakawa, Jumpei Ogawa, Yuya Joshi, Ayesha R. Ellenson, Lora H. Sun, Xiaofei Dey, Sudhansu K. |
author_sort | Liang, Xiaohuan |
collection | PubMed |
description | Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Pten(f/f)Pgr(Cre/+)) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Pten(f/f)Pgr(Cre/+) uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver (Pten(f/f)/Ltf(Cre/+)) develop uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Pten(f/f)Pgr(Cre/+) uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Pten(f/f)Ltf(Cre/+) hyperplastic epithelia do not undergo stratification, but extensive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten, highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma. |
format | Online Article Text |
id | pubmed-6126871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61268712018-09-17 The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten Liang, Xiaohuan Daikoku, Takiko Terakawa, Jumpei Ogawa, Yuya Joshi, Ayesha R. Ellenson, Lora H. Sun, Xiaofei Dey, Sudhansu K. PLoS Genet Research Article Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Pten(f/f)Pgr(Cre/+)) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Pten(f/f)Pgr(Cre/+) uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver (Pten(f/f)/Ltf(Cre/+)) develop uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Pten(f/f)Pgr(Cre/+) uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Pten(f/f)Ltf(Cre/+) hyperplastic epithelia do not undergo stratification, but extensive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten, highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma. Public Library of Science 2018-08-24 /pmc/articles/PMC6126871/ /pubmed/30142194 http://dx.doi.org/10.1371/journal.pgen.1007630 Text en © 2018 Liang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Liang, Xiaohuan Daikoku, Takiko Terakawa, Jumpei Ogawa, Yuya Joshi, Ayesha R. Ellenson, Lora H. Sun, Xiaofei Dey, Sudhansu K. The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten |
title | The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten |
title_full | The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten |
title_fullStr | The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten |
title_full_unstemmed | The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten |
title_short | The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten |
title_sort | uterine epithelial loss of pten is inefficient to induce endometrial cancer with intact stromal pten |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126871/ https://www.ncbi.nlm.nih.gov/pubmed/30142194 http://dx.doi.org/10.1371/journal.pgen.1007630 |
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