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P.H. van der Horst (Paul), Y. Wang (Yue), I. van den Put (Ingrid), L.C. Kühne (Liesbeth), P.C. Ewing (Patricia), W.F.J. van IJcken (Wilfred), M. van der Zee (Marten), F. Amant (Frédéric), C.W. Burger (Curt) and L.J. Blok (Leen)

2012-01-25

Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer

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Publication

PLoS ONE , Volume 7 - Issue 1

Background: 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). Methodology and Principal Findings: 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. Conclusion: 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.

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Keywords CD4+ T lymphocyte, CD8+ T lymphocyte, CXCL14 gene, DKK1 gene, DKK4 gene, PEG10 gene, T lymphocyte subpopulation, WIF1 gene, Wnt signaling pathway, adult, aged, article, beta catenin gene, cancer cell culture, cancer growth, cancer invasion, cancer localization, cell assay, cell loss, cell motion, controlled study, disease association, disease course, down regulation, drug effect, endometrium cancer, endometrium tumor, epithelial mesenchymal transition, female, genetic analysis, genetic association, genetics, genomics, hormone action, human, human cell, human tissue, immunology, immunosurveillance, interleukin 6 gene, lymphocyte activation, lymphocytic infiltration, metabolism, metastasis, middle aged, migration inhibition, oncogene, pathology, protein expression, recurrent cancer, regulator gene, retrospective study, reverse transcription polymerase chain reaction, tissue characterization, transforming growth factor beta gene, tumor cell line, upregulation
Persistent URL doi.org/10.1371/journal.pone.0030840, hdl.handle.net/1765/38315
Journal PLoS ONE
Organisation Erasmus MC: University Medical Center Rotterdam
Citation
van der Horst, P., Wang, Y., van den Put, I., Kühne, L., Ewing, P., van IJcken, W., … Blok, L. (2012). Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer. PLoS ONE, 7(1). doi:10.1371/journal.pone.0030840
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