Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.

<h4>Background</h4>Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This stud...

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Autores principales:	Paul H van der Horst, Yongyi Wang, Ingrid Vandenput, Liesbeth C Kühne, Patricia C Ewing, Wilfred F J van Ijcken, Marten van der Zee, Frederic Amant, Curt W Burger, Leen J Blok
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c2b97bfee31c43be916121a5f545b551
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spelling	oai:doaj.org-article:c2b97bfee31c43be916121a5f545b5512021-11-18T07:29:19ZProgesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.1932-620310.1371/journal.pone.0030840https://doaj.org/article/c2b97bfee31c43be916121a5f545b5512012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22295114/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).<h4>Methodology and principal findings</h4>Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.<h4>Conclusion</h4>Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.Paul H van der HorstYongyi WangIngrid VandenputLiesbeth C KühnePatricia C EwingWilfred F J van IjckenMarten van der ZeeFrederic AmantCurt W BurgerLeen J BlokPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30840 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paul H van der Horst Yongyi Wang Ingrid Vandenput Liesbeth C Kühne Patricia C Ewing Wilfred F J van Ijcken Marten van der Zee Frederic Amant Curt W Burger Leen J Blok Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
description	<h4>Background</h4>Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).<h4>Methodology and principal findings</h4>Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.<h4>Conclusion</h4>Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.
format	article
author	Paul H van der Horst Yongyi Wang Ingrid Vandenput Liesbeth C Kühne Patricia C Ewing Wilfred F J van Ijcken Marten van der Zee Frederic Amant Curt W Burger Leen J Blok
author_facet	Paul H van der Horst Yongyi Wang Ingrid Vandenput Liesbeth C Kühne Patricia C Ewing Wilfred F J van Ijcken Marten van der Zee Frederic Amant Curt W Burger Leen J Blok
author_sort	Paul H van der Horst
title	Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
title_short	Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
title_full	Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
title_fullStr	Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
title_full_unstemmed	Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
title_sort	progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/c2b97bfee31c43be916121a5f545b551
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Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.

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