Characterization and prognostic impact of ACTBL2-positive tumor-infiltrating leukocytes in epithelial ovarian cancer.

Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p < 0.001; HR = 0.058, p = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis.

Expression pattern and prognostic potential of histamine receptors in epithelial ovarian cancer.

PURPOSE: Despite recent advances in the treatment of ovarian cancer (OC), long-term remissions remain scarce. For a targeted approach, prognostic markers are indispensable for predicting survival and treatment response. Given their association with multiple hallmarks of cancer, histamine receptors (HR) are emerging as promising candidates. Here, we investigate their expression pattern and prognostic value in OC. METHODS: Specimens of 156 epithelial OC patients were collected during cytoreductive surgery at the Department of Obstetrics and Gynecology, LMU, between 1990 and 2002 and combined in a tissue microarray. Immunohistochemical staining of the HR H1, H2, H3 and H4 was quantified by an immunoreactive score and linked with clinico-pathological data by Spearman's correlation. Via ROC curve analysis, optimal cut-off values for potential prognostic markers were defined. Overall survival (OS) was visualized in Kaplan-Maier curves and significances determined by log-rank testing. A Cox regression model was applied for multivariate analysis. RESULTS: HR H3 and H4 expression was restricted to the cytosol of OC cells, while H1 was also present in the nucleus. A significant association between HR H1, H3 and H4 expression with several clinico-pathological parameters was revealed. In addition, HR H1 and H3 expression correlated positively, HR H4 expression negatively with OS. In addition, HR H3 was identified as independent prognostic marker for OS. HR H2 expression had no prognostic value. CONCLUSIONS: HR H1, H3 and H4 could serve as potential predictors for OS of OC patients. Further research is warranted to elucidate their pathophysiologic role and their predictive and therapeutic potential in OC.

Prevalence of oral HPV infection in cervical HPV positive women and their sexual partners.

PURPOSE: Human papillomavirus (HPV) infection represents the primary cause of anogenital premalignant and malignant disease. Regarding the high prevalence of cervical HPV infection and the increasing incidence of HPV associated oropharyngeal cancer in recent years, a significant viral transmission from the cervical to the oral site, possibly depending on the sexual behavior must be considered. The present study aims to determine the prevalence of oral HPV infection in cervical HPV positive and negative women and their sexual partners. METHODS: Cervical HPV positive and negative women and their sexual partners took part in the study. Cervical smears, oral smears and mouthwashes were taken from women attending gynecological outpatient clinics in two different institutions. Further, oral smears as well as mouthwashes of their sexual partners were obtained whenever possible. HPV genotyping was performed using the Cobas® polymerase chain reaction and nucleic acid hybridization assay for the detection of 14 high-risk HPV types. In addition, all participants were invited to complete a personal questionnaire. RESULTS: 144 HPV positive and 77 HPV negative women and altogether 157 sexual partners took part in the study. Age, sexual behaviour, medication, smoking and alcohol consumption were distributed equally in both groups. Cervical HPV positive women had a significantly higher number of sexual partners. One woman with a HPV positive cervical smear and one partner of a woman with a HPV positive cervical smear showed an oral HPV infection. No oral HPV infections were detected in the HPV negative control group. The overall incidence of oral HPV infection was 0.5%, the incidence of oral HPV infection in women with a positive cervical smear was 0.7%. CONCLUSION: The data demonstrate that the overall risk of an oral HPV infection is low. HPV transmission to the oropharynx by autoinoculation or oral-genital contact constitute a rare and unlikely event.

Author Correction: Yolk sac macrophage progenitors traffic to the embryo during defined stages of development.

This article contains errors in Figs. 5 and 6, for which we apologize. In Fig. 5f, the image 'E12.5 tail' was inadvertently replaced with a duplicate of the image 'E12.5 trunk' from the same panel. In Figure 6d, the image 'E9.5/OH-TAM E8.5, embryo' was inadvertently replaced with a duplicate of the image 'E10.5/ OH-TAM E8.5, embryo' from Fig. 6b. The corrected versions of these figures appear in the Author Correction associated with this Article.

Yolk sac macrophage progenitors traffic to the embryo during defined stages of development.

Tissue macrophages in many adult organs originate from yolk sac (YS) progenitors, which invade the developing embryo and persist by means of local self-renewal. However, the route and characteristics of YS macrophage trafficking during embryogenesis are incompletely understood. Here we show the early migration dynamics of YS-derived macrophage progenitors in vivo using fate mapping and intravital microscopy. From embryonic day 8.5 (E8.5) CX3CR1+ pre-macrophages are present in the mouse YS where they rapidly proliferate and gain access to the bloodstream to migrate towards the embryo. Trafficking of pre-macrophages and their progenitors from the YS to tissues peaks around E10.5, dramatically decreases towards E12.5 and is no longer evident from E14.5 onwards. Thus, YS progenitors use the vascular system during a restricted time window of embryogenesis to invade the growing fetus. These findings close an important gap in our understanding of the development of the innate immune system.

Disseminated and circulating tumor cells in bone marrow and blood of breast cancer patients: properties, enrichment, and potential targets.

INTRODUCTION: From the early days of pathology back in the nineteenth century until now, there has been an ongoing search for the missing link between solid tumors such as breast cancer and distant metastases, which sometimes occur many years after removal of the primary tumor. The "seed and soil" theory hypothesizes the early dissemination of occult tumor cells into blood or bone marrow, which can persist in a dormant state for a long time and then become precursors of metastases in distant organs which offer appropriate conditions. METHOD: Advances in immunocytochemical methods have enabled the enrichment and visualization of those disseminated tumor cells in bone marrow (DTC-BM) or circulating tumor cells (CTC) in blood. Many studies could demonstrate prognostic significance of the detection of DTC-BM or CTC in different stages of breast cancer. CONCLUSION: Further characterization of those cells by immunocytochemical stainings, fluorescence in situ hybridizations, or PCR-based molecular methods will help to understand the biology of tumor cell dissemination and metastasis formation, as well as to define potential drug targets.

RXRα is upregulated in first trimester endometrial glands of spontaneous abortions unlike LXR and PPARγ.

Nuclear receptors are necessary for uterine invasion of the trophoblast and therefore important for maintaining a viable pregnancy. The aim of this study was to investigate the expression pattern and frequency of LXR, PPARγ and RXRα under physiological circumstances and in spontaneous abortions in endometrial glands and decidual tissue cells. A total of 28 (14 physiologic pregnancies/14 spontaneous abortion) human pregnancies in first trimester were analysed for expression of the nuclear receptors LXR, RXRα and PPARγ. Expression changes were evaluated by immunohistochemistry in decidual tissue and endometrial glands of the decidua. RXRα expression was up-regulated in the endometrial glands of spontaneous abortion (P<0.015). Similar up regulation of RXRα was found in decidual tissue (P<0.05). LXR and PPARγ expression was unchanged in spontaneous abortion. Via Correlation analysis we found a trend to positive correlation of LXR and PPARγ (Spearman correlation coefficient r=0.56 P=0.07) in endometrial glands. In decidual tissue, we found significant negative correlation in the control group, for the combination of RXRα and PPARγ (Spearman correlation coefficient r=0.913, P=0.03). Our data show that RXRα expression is increased in miscarriage in endometrial glands and correlation analysis showed that negative correlation between RXRα and PPARγ disappears in miscarriage. This shift is supposable responsible for the loss of regular function in trophoblast and embryonic tissue.

Galectin 2 (gal-2) expression is downregulated on protein and mRNA level in placentas of preeclamptic (PE) patients.

INTRODUCTION: Galectin 2 (gal-2) belongs to the proto type group and consists of two homologous carbohydrate recognition domains (CRDs) resulting in multiple sugar binding sites. The expression of gal-2 has been shown to be involved in processes of angiogenesis and inflammation but was not analyzed before in preeclamptic (PE) placentas. Therefore the aim of this study was an analysis of expression and localization of gal-2 in placentas from patients suffering from PE. METHODS: Placental tissues were obtained from 14 women following a normal course of pregnancy and 13 women with PE. Expression of gal-2 was evaluated with immunohistochemistry and a semi quantitative score. Gal-2 mRNA expression was quantified in placental tissue using real time TaqMan PCR. Identification of gal-2 expressing cells in the decidua was achieved by double immunofluorescence microscopy. RESULTS: Expression of gal-2 is downregulated in the syncytiotrophoblast of preeclamptic placentas. Downregulation of gal-2 could also be identified in the decidua of PE patients. These findings on protein level could be supported by the results of TaqMan PCR. Gal-2 is downregulated in PE placentas on mRNA level. Finally, gal-2 expressing cells could be identified as extravillous trophoblast cells in both normal pregnancy and PE. DISCUSSION: Gal-2 was identified as an inhibitor of arteriogenesis in a murine model supposedly via modulation of the monocyte/macrophage population. In PE, both the formation of spiral arteries as well as influx of macrophages are dramatically changed. Therefore we might speculate that disturbed transformation of spiral arteries in PE might correlate with the downregulated gal-2 expression by the trophoblast.

Galectin-13/PP-13 expression in term placentas of gestational diabetes mellitus pregnancies.

INTRODUCTION: Gestational diabetes mellitus (GDM) is an increasing harm in pregnancy. Inflammatory processes in the placenta seem to have an influence on pathogenesis besides known factors like maternal BMI. Galectin-13 (gal-13) is an immunoregulatory protein, which is suspected to play a role in development of GDM in the placenta. METHODS: A total of 40 placentas were obtained from women treated for gestational diabetes mellitus. Placental tissue for control group was obtained from 40 women with normal pregnancy. We investigated the protein expression of gal-13 in term placentas with immunohistochemistry and immunofluorescence. Immunohistochemical staining was analyzed with the semi-quantified IRS score. Gal-13 serum levels were performed with ELISA on a total of 20 probes from women with GDM and healthy control pregnancies in the third trimester. RESULTS: Gal-13 was found in syncytiotrophoblast, in nuclei of syncytiotrophoblast and trophoblast cells as well in extravillous trophoblast cells of normal placentas. In GDM placentas, gal-13 expression was significantly decreased in all of these examined cell types (syncytiotrophoblast p = 0.003, nuclei of syncytiotrophoblast p = 0.007; extravillous trophoblast cells p = 0.001). The ELISA showed a significant lower gal-13 serum level in blood from pregnant women with GDM in comparison to healthy controls. DISCUSSION: As gal-13 with its anti-inflammatory functions plays a role in regulation of maternal immune system, a lack of gal-13 may contribute to an imbalance in inflammation processes in the placenta during pregnancy and therefore influences development of GDM.

Detection and characterisation of disseminated tumour cells in bone marrow of breast cancer patients by immunostaining of Her-2 and MUC-1 in combination with Thomsen-Friedenreich (CD176).

Disseminated tumour cells (DTCs) in the bone marrow derive from many primary tumours, such as breast cancer. Their mere existence hints to present or future metastasis and implicates a worse prognosis for the patient. DTCs may possess different characteristics in comparison to the primary tumour due to events like Epithelial-Mesenchymal-Transition. Therefore, these cells might be able to survive chemotherapy and cause relapses of the disease at a later point. We aimed to detect and further characterise DTCs by an immunostaining approach with three different antigen markers (Her-2, MUC-1 and TF, also known as CD 176). For that reason, bone marrow of 41 breast cancer patients was obtained during surgery; DTCs were enriched by density gradient centrifugation and cytospins were prepared. After fixation, immunofluorescent double-stainings were carried out with antibodies against CD176 in combination with HER-2 or MUC-1. Cells co-expressing two antigens were found in all staining combinations (Her-2 and CD176: 46.14%; MUC-1 and CD176: 18.15% of all cases). Cells that stained for a single antigen only were also found (Her-2: 36.86%; MUC-1: 34.45%; CD176: 29.65% of all cases). Significant correlations between the stainings of all markers could be shown (p<0,001). In conclusion, Thomsen-Friedenreich Antigen (TF, CD176) is a promising marker in combination with the established marker Her-2 and other markers like MUC-1. These results may serve as a basis for future DTC detection routines and help to individualize medical treatment, reducing side effects and increasing the efficiency of the therapy.

Expression and function of galectins in the endometrium and at the human feto-maternal interface.

Galectins are classified as lectins that share structural similarities and bind ß-galactosides via a conserved carbohydrate recognition domain. So far 16 out of 19 identified galectins were shown to be present in humans and numerous studies revealed galectins as pivotal modulators of cell death, differentiation and growth. Galectins were highlighted to interact with both the adaptive and innate immune response. In the field of reproductive medicine and placenta research different roles for galectins have been proposed. Several galectins, being abundantly present at the human feto-maternal interphase and endometrium, were hypothesized to significantly contribute to endometrial receptivity and pregnancy physiology. Hence, this review outlines selected aspects of galectin action within endometrial function and at the feto-maternal interphase. Further current knowledge on galectins in reproductive and pregnancy disorders like endometriosis, abortion or preeclampsia is summarized.

Nuclear hormone receptors and female reproduction.

BACKGROUND: Nuclear Hormone Receptors (NHR) are, as the name implies, receptors located in the cell nucleus that have transcription modulating characteristics. Activated non-steroidal lipophilic ligands bind these receptors resulting in dimerisation of the ligands, DNA-binding and transcriptional regulation of target proteins that influence especially cell differentiation, metabolic homeostasis and embryogenesis. METHODS: This review is based on publications derived from PubMed based pursuit of scientific literature in conjunction with the authors' experience. RESULTS: Here, a summary of NHR family members (RXR, PPAR, VDR, TR) first in respect to known general aspects such as ligands, binding domains, signalling mechanism and second focussing especially their influence on female reproduction is offered. Furthermore, crosstalk with other prominent signalling proteins important to trophoblast function [signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB), Akt/ phosphaidyl-3-kinase (PI3K), and Wnt, are described. CONCLUSION: Considering their attributes, it is not surprising that NHR family members play a central role in female reproduction by targeting cell differentiation, metabolic homeostasis and embryogenesis. However, it seems that crosstalk depends on stage of trophoblast differentiation.

IFPA Meeting 2012 Workshop Report I: comparative placentation and animal models, advanced techniques in placental histopathology, human pluripotent stem cells as a model for trophoblast differentiation.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2012 there were twelve themed workshops, three of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of models and technical issues involved in placenta research: 1) comparative placentation and animal models; 2) advanced techniques in placental histopathology; 3) human pluripotent stem cells as a model for trophoblast differentiation.

Aberrant expression of corticotropin-releasing hormone in pre-eclampsia induces expression of FasL in maternal macrophages and extravillous trophoblast apoptosis.

Corticotropin-releasing hormone (CRH) and its receptors are expressed in human placenta. Recently, the impaired function of this system has been associated with a number of complications of pregnancy, including pre-eclampsia. The aim of the study was to test the hypothesis that CRH participates in the pathophysiology of pre-eclampsia through the induction of macrophage-mediated apoptosis of extravillous trophoblasts (EVTs). We found that the expression of CRH was increased in the EVT of the placental bed biopsy specimens from pre-eclamptic pregnancies (1.8-fold increase; P < 0.05). In addition, significantly larger numbers of apoptotic EVT were detected in pre-eclamptic placentas compared with normal ones (P < 0.05), and only in pre-eclamptic placentas, decidual macrophages were found to be Fas ligand (FasL)-positive. In vitro studies on the effect of CRH on human macrophages suggested that CRH induced the expression of the FasL protein in human macrophages and potentiated their ability to induce the apoptosis of a Fas-expressing EVT-based hybridoma cell line in co-cultures. These findings demonstrate a possible mechanism by which the aberrant expression of CRH in pre-eclampsia may activate the FasL-positive decidual macrophages, impair the physiological turnover of EVT and eventually disturb placentation.

Expression of the tumor markers sialyl Lewis A, sialyl Lewis X, Lewis Y, Thomsen-Friedenreich antigen, galectin-1 and galectin-3 in human osteoblasts in vitro.

AIM: Lewis antigens and the Thomsen-Friedenreich (TF) antigen are complex glycan structures that modulate processes such as cell adhesion and proliferation and tumor metastasis. The aim of our study was to analyze the expression of sialyl Lewis A (sLeA), sialyl Lewis X (sLeX), Lewis Y (LeY), TF, galectin-1 (Gal-1) and galectin-3 (Gal-3) in human osteoblasts in vitro. MATERIALS AND METHODS: The expression of the tumor markers sLeA, sLeX, LeY, TF, Gal-1 and Gal-3 was studied by means of immunohistochemistry on cells grown on chamber slides (2D) and on paraffin sections three-dimensional scaffold-free cultures (3D). The results of the stainings were evaluated semiquantitatively with the immunoreactive scoring system (IRS). RESULTS: Analysis of sLeA expression in both types of culture, 2D and 3D showed no detectable staining. After 5 days, in the 2D culture, expression of sLeX was weak, but the 3D culture (after 56 weeks) displayed a strong expression. LeY was expressed very slightly in the 2D culture, however LeY was not detectable in the 3D culture. The TF epitope was identified in the 2D cell culture model. In the 3D model, however, TF was completely lacking. Gal-1 was expressed very strongly in 2D culture, but in the 3D culture was not detectable. In contrast, Gal-3 was expressed in 3D culture but not in 2D. CONCLUSION: Within this study, we present a systematic analysis of the expression of sLeA, sLeX, LeY, TF, Gal-1 and Gal-3 in human osteoblasts grown in 2D and in 3D scaffold-free cultures. Summarizing the results of our study, we suggest that Lewis antigens and Gal-1 and -3 might play an important role in cell-cell and cell-matrix interactions of osteoblastic cells.

Expression of the carbohydrate tumour marker Sialyl Lewis A, Sialyl Lewis X, Lewis Y and Thomsen-Friedenreich antigen in normal squamous epithelium of the uterine cervix, cervical dysplasia and cervical cancer.

The carbohydrate molecules Sialyl Lewis X (SLeX), Sialyl Lewis A (SLeA), Lewis Y (LeY) and Thomsen-Friedenreich antigen (TF) are known to mediate the adhesion between tumor cells and endothelium. They are used as serum markers in diagnosis and treatment in a broad spectrum of human carcinomas, but their expression profile and role in the development of cervical cancer remains unclear. The aim of this study was to investigate the expression of SLeX, SLeA, LeY and TF in normal cervical squamous epithelium, cervical dysplasia and cervical cancer. Slides of paraffin-embedded tissue were fixed and incubated with monoclonal antibodies against SLeX, SLeA, LeY and TF. Immunohistochemical staining was evaluated by using a semi-quantitative score (IRS Score). We found a significant difference of SLeA expression in invasive cervical cancer compared to normal epithelium (p=0.006) and all grades of dysplasia (p=0.002). The expression of SLeX in normal epithelium was less intense than in carcinoma in situ (p=0.036). Staining for LeY showed the weakest results of the investigated markers. Significant differences were found when normal epithelium was compared to CIN I (p=0.011), to CIN II (p=0.013) and to invasive cervical cancer (p=0.005). For TF, significant differences were found in normal epithelium compared to CIN I (p=0.011), CIN II (p=0.013) and compared to invasive cervical cancer (p=0.005). This is the first study on the expression of SLeA, SLeX, LeY and TF in normal cervical endothelium, cervical dysplasia, carcinoma in situ and invasive cervical cancer. Further studies and higher numbers are desirable.

Expression of cathepsin-D in primary breast cancer and corresponding local recurrence or metastasis: an immunohistochemical study.

BACKGROUND/AIM: The role of cathepsin-D is well established in breast cancer progression, being correlated with worse clinical outcomes. However, to our knowledge, no study has been performed investigating its expression in primary breast cancer tumors and their corresponding recurrences or metastasis. MATERIALS AND METHODS: Tissue sections from ten breast cancer cases and their corresponding local recurrences and six breast cancer cases and their corresponding metastases were immunohistochemically assessed for cathepsin-D reactivity. Cases diagnosed as either ductal carcinoma in situ (n=7), or breast carcinoma with no evidence of local recurrence or metastasis during follow-up (n=8) served as controls. RESULTS: Cathepsin-D was significantly up-regulated in all the study groups compared to controls. No difference was found between primary tumors and their corresponding recurrences or metastases. CONCLUSION: Cathepsin-D-expressing breast cancer cells seem to be involved in local recurrence or metastasis formation. Large series are needed to further verify this result with the aim of possible future molecular intervention.

Retinoid X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) expression in breast cancer: an immunohistochemical study.

BACKGROUND/AIM: The role of retinoid X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) in breast cancer has been well studied in vitro. The aim of the study was to assess the presence of these molecules in human breast cancer specimens and correlate them with major clinicopathological features. PATIENTS AND METHODS: Tissue sections from 82 breast cancer cases clustered according to histological grade, lymph node (LN) and hormone receptor (HR) status were assessed by immunohistochemistry for RXRα and PPARγ. RESULTS: RXRα was found to be strongly and moderately expressed in 11 (14.10%) and 33 (42.31%) cases, respectively. PPARγ was found to be strongly and moderately expressed in 33 (41.25%) and 25 (31.25%) cases, respectively. Only RXRα expression was inversely correlated with histological grade. Surprisingly, significantly elevated PPARγ expression was found in cases with positive LN status. Survival analysis did not yield significant results. CONCLUSION: Our data support the current thesis of RXRα being a potential target for feature molecular interventions.

Effects of phytoestrogen extracts isolated from flax on hormone production of trophoblast tumour cells Jeg 3 and BeWo.

UNLABELLED: AIM AND SETTING: To test the effects of crude extracts from flax (Linum usitatissimum) on progesterone and estradiol and ERα and ß/PR production in choriocarcinoma cell lines Jeg 3 and BeWo. Tumor trophoblast cells (Jeg 3 and BeWo) were incubated in the presence of different concentrations of the flax crude extracts. Estradiol and progesterone production was measured. Estrogen receptor α and ß as well as progesterone receptor expressions were also assessed. RESULTS: In Jeg 3 cells, progesterone production was downregulated by flax root and leaves extract, while in BeWo cells only flax root extract did manage to downregulate progesterone production. ERß expression was significantly downregulated by flax root and flax leaves extract in both cell lines; on the contrary, ERα expression was increased by flax leaves extract in BeWo cells. PR expression was downregulated by flax leaves extract in Jeg 3 and by flax root extract in BeWo cells. CONCLUSION: Flax extracts derived from leaves and especially from roots can modify progesterone and possibly estradiol production, while at the same time they seem to alter ERß expression. Further studies on animal models and adequately designed retrospective epidemiological studies are imperative to clarify this role upon progesterone.

Retinoid X receptor α and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages.

The retinoid X receptor α (RXRα) is a nuclear hormone receptor that is able to bind other nuclear receptors in a heterodimeric complex, thereby activating gene transcription. Recently, we identified enhanced expression of RXRα in extravillous trophoblasts (EVT) and villous trophoblasts (VT) of miscarried placentas. In addition, an increased number of apoptotic EVT was present in miscarried placentas. In this study, on the basis of immunocytochemical analysis, western blots, and quantitative real-time reverse transcription PCR, we could demonstrate a reduced expression of RXRα in choriocarcinoma cell lines and in human VTs after stimulation with the retinoids 9-cis-retinoic acid and all-trans-retinoic acid and the prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2). Furthermore, a simultaneous expression of RXRα and the apoptotic marker M30 CytoDEATH in EVT of miscarried placentas from the first trimester was shown. In EVT of control placentas from legal termination of pregnancies, no co-expression of RXRα and M30 could be detected. A likely conclusion is that RXRα plays an important role in the induction of apoptosis. Downregulation of RXRα, as observed in the tested choriocarcinoma cells and trophoblasts, might serve as a protection against apoptosis and miscarriage. In conclusion, RXRα represents a potential target in the treatment of recurrent miscarriages.