Article

Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Department of Obstetrics and Gynaecology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
PLoS ONE (Impact Factor: 3.23). 01/2012; 7(1):e30840. DOI: 10.1371/journal.pone.0030840
Source: PubMed

ABSTRACT

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).
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.
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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    • "Previously, van der Horst et al. [2] showed that both the presence of TILs and positive progesterone receptor were correlated with better prognosis. These results imply that progesterone might have a potential role in attracting TILs in endometrial cancer [2]. "
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    ABSTRACT: Objective The aim of this study was to determine the distribution of T-lymphocytes and their relationship with clinicopathologic factors in endometrial carcinoma. Methods Samples were collected from 89 patients with endometrial endometrioid adenocarcinoma treated in Pusan National University Hospital from 2004 to 2011. Normal endometrial tissues were obtained from 30 hysterectomized women with benign adnexal masses and served as controls. Paraffin-embedded sections were immunohistochemically stained for CD8 (cytotoxic) and CD4 (helper) T-lymphocytes. The relationship of these cells with stage, histological grade, myometrial invasion, and lymph node metastasis was analyzed. Results The proportion of CD8+ and CD4+ lymphocytes in the endometrial endometrioid adenocarcinoma tissues was 67.4% (60/89) and 44.9% (40/89), respectively, which was significantly higher (P<0.05) than in the control group. The extent of CD8+ lymphocyte expression was negatively correlated with histologic grade, myometrial invasion, and lymph node metastasis. The proportion of infiltration of the CD4+ lymphocytes was negatively correlated with histologic grade and myometrial invasion. Conclusion The high rate of infiltration of T-lymphocytes was negatively correlated with histologic grade, myometrial invasion, and lymph node metastasis. Our findings suggest that tumor-infiltrating T-lymphocytes may be used as pathologic prognostic factors in endometrial carcinoma.
    Full-text · Article · Jul 2014
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    • "However, recurrent or metastatic endometrial cancers still have a poor prognosis. The improvement of clinical outcomes will require a much better understanding of the processes that inhibit and stimulate cancer progression [2]. "
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    Full-text · Article · May 2014
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    • "In addition, the expression of EFEMP also influences epithelial mesenchymal transition (EMT). During this process, endometrial epithelial cells acquire phenotypes of motile fibroblasts, which have been demonstrated in endometrial carcinoma [38]. In our study, to model cancer cell metastasis, we cultured anchorage-independent cells spheroids following trypsinization. "
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