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Sample records for human endometrial carcinoma

  1. Expression of epidermal growth factor receptors in human endometrial carcinoma

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Ottesen, B

    1993-01-01

    Little data exist on the expression of epidermal growth factor receptors (EGF-Rs) in human endometrial cancer. EGF-R status was studied in 65 patients with endometrial carcinomas and in 26 women with nonmalignant postmenopausal endometria, either inactive/atrophic endometrium or adenomatous...

  2. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

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    Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

    2012-01-01

    Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

  3. Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma.

    Science.gov (United States)

    Deng, Lu; Gao, Yiping; Li, Xiao; Cai, Mingbo; Wang, Huimin; Zhuang, Huiyu; Tan, Mingzi; Liu, Shuice; Hao, Yingying; Lin, Bei

    2015-09-11

    It is well-known that the treatment and monitoring methods are limited for advanced stage of endometrial carcinoma. Biological molecules with expression changes during tumor progression become potential therapeutic targets for advanced stage endometrial carcinoma. Annexin A2 (ANXA2) has been reported to be overexpressed in recurrent endometrial carcinoma, and the expression of human epididymis protein 4 (HE4) is upregulated in endometrial carcinoma. What's more, ANXA2 and HE4 interacted in ovarian cancer and promoted the malignant biological behavior. We speculated that their interaction may exist in endometrial carcinoma as well. We evaluated the expression and the correlation relationship of ANXA2 and HE4 in endometrial carcinoma. The expression of ANXA2 and HE4 protein in 84 endometrial carcinoma, 30 endometrial atypical hyperplasia, and 18 normal endometrial tissue samples were then measured using an immunohistochemical assay in paraffin embedded endometrial tissues. The structural relationship between ANXA2 and HE4 was explored by immunoprecipitation and double immunofluorescent staining. ANXA2 and HE4 co-localized in both endometrial tissues and endometrial carcinoma cells. ANXA2 and HE4 were expressed in 95.2 % and 85.7 % of the the endometrial carcinoma, respectively, which were significantly higher than normal endometrium (55.6 % and 16.7 %, both p endometrial carcinoma (p endometrial carcinoma. Expression levels of ANXA2 and HE4 were closely related to the malignant biological behavior of endometrial carcinoma, and ANXA2 was an independent risk factor for poor prognosis. The expression of ANXA2 and HE4 can affect each other.

  4. Aromatase in human endometrial carcinoma and hyperplasia. Immunohistochemical, in situ hybridization, and biochemical studies.

    OpenAIRE

    Watanabe, K.; Sasano, H.; Harada, N.; Ozaki, M.; Niikura, H.; Sato, S.; Yajima, A.

    1995-01-01

    The expression of P450 aromatase and other steroidogenic enzymes were evaluated in 42 endometrioid endometrial carcinomas, 23 endometrial hyperplasias, and 7 normal endometrial specimens. These findings were correlated with clinicopathological findings to elucidate the possible biological significance of in situ estrogen production in the development of human endometrial carcinoma. Only weak aromatase immunoreactivity was observed in vascular walls and myometrial cells. In contrast, strong ar...

  5. Nucleobindin 2 (NUCB2) in human endometrial carcinoma: a potent prognostic factor associated with cell proliferation and migration.

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    Takagi, Kiyoshi; Miki, Yasuhiro; Tanaka, Sota; Hashimoto, Chiaki; Watanabe, Mika; Sasano, Hironobu; Ito, Kiyoshi; Suzuki, Takashi

    2016-01-01

    Nucleobindin 2 (NUCB2) is a multifunctional protein containing several functional domains, and associated with wide variety of biological process such as food intake and energy homeostasis. Recently, NUCB2 has been implicated in not only normal human tissues but also some kinds of human malignancies. However, its clinical and/or biological significance has largely remained unknown in endometrial carcinomas. We therefore immunolocalized NUCB2 protein in 87 endometrial carcinoma tissues and examined its clinical significance. NUCB2 immunoreactivity was detected in 19 out of 87 (22%) of endometrial carcinoma cases examined, and positively correlated with Ki67 labeling index, while there was no significant correlation between NUCB2 and stage, histological grade, and progesterone receptor status. Furthermore, NUCB2 immunoreactivity was significantly correlated with increased risk of recurrence and worse clinical outcome regardless of stage or histological grade. Subsequent multivariate analyses did reveal that NUCB2 immunoreactivity was an independent prognostic factor for both disease-free survival and endometrial cancer specific survival. In vitro experiments demonstrated that knockdown of NUCB2 using specific siRNA for NUCB2 significantly impaired cell proliferation and migration of the endometrial carcinoma cell lines, Ishikawa and Sawano cells, and that nesfatin-1 treatment significantly promoted cell proliferation and migration in Ishikawa cells. These findings possibly suggested that NUCB2 and/or nesfatin-1 had pivotal roles in the progression of endometrial carcinomas. Immunohistochemical NUCB2 status may therefore serve as a potent biomarker for endometrial carcinomas.

  6. Brain Metastases from Endometrial Carcinoma

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    Piura, Ettie; Piura, Benjamin

    2012-01-01

    This paper will focus on knowledge related to brain metastases from endometrial carcinoma. To date, 115 cases were documented in the literature with an incidence of 0.6% among endometrial carcinoma patients. The endometrial carcinoma was usually an advanced-stage and high-grade tumor. In most patients (~90%), brain metastasis was detected after diagnosis of endometrial carcinoma with a median interval from diagnosis of endometrial carcinoma to diagnosis of brain metastases of 17 months. Brain metastasis from endometrial carcinoma was either an isolated disease limited to the brain only (~50%) or part of a disseminated disease involving also other parts of the body (~50%). Most often, brain metastasis from endometrial carcinoma affected the cerebrum (~75%) and was solitary (~60%). The median survival after diagnosis of brain metastases from endometrial carcinoma was 5 months; however, a significantly better survival was achieved with multimodal therapy including surgical resection or stereotactic radiosurgery followed by whole brain radiotherapy (WBRT) and/or chemotherapy compared to WBRT alone. It is suggested that brain imaging studies should be considered in the routine follow up of patients with endometrial carcinoma and that the search for a primary source in females with brain metastases of unknown primary should include endometrial biopsy. PMID:22523707

  7. Estrogen mediated expression of nucleophosmin 1 in human endometrial carcinoma clinical stages through estrogen receptor-α signaling.

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    Zhou, Yunxiao; Shen, Jie; Xia, Liqun; Wang, Yanli

    2014-01-01

    Endometrial carcinoma is one of the most common gynecologic malignancies. Estrogen plays a critical role in its pathogenesis, but the underlying mechanism is not clear. Nucleophosmin 1 (NPM1), a multifunctional protein involved in many cellular activities, has been implicated in the tumorigenesis processes. However, the role of NPM1 in endometrial carcinogenesis remains to be elucidated. The present study was aimed to elucidate the role of NPM1 in different clinical stages of human endometrial carcinoma and the underlying mechanism of NPM1 action. The distribution and expression of NPM1 in normal endometrium, FIGO stages I to IV endometrial carcinoma tissues was analyzed using immunohistochemistry, RT-qPCR and Western blotting. The association between NPM1 expression and estrogen and estrogen receptor signaling was investigated in primary-cultured FIGO stage I endometrial adenocarcinoma cells. A strong positive correlation between NPM1 level and the clinical stage and histological grade of endometrial carcinomas was observed. Expression of NPM1 was up-regulated by estrogen in primary-cultured human endometrial adenocarcinoma cells. Furthermore, estrogen increased NPM1 level via estrogen receptor-α (ERα) signaling, nor estrogen receptor-β signaling. Expression of NPM1 was gradually increased with the increase of clinical stages of endometrial carcinomas. Overexpression of NPM1 may play a role in the effects of estrogen on the malignant progression of endometrioid adenocarcinoma via ERα signaling. These findings may extend our understanding of the oncogenesis of steroid hormone-related cancers and have significance for the diagnosis and treatment of this carcinoma.

  8. Curcumin promotes the apoptosis of human endometrial carcinoma cells by downregulating the expression of androgen receptor through Wnt signal pathway.

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    Feng, W; Yang, C X; Zhang, L; Fang, Y; Yan, M

    2014-01-01

    The current study aimed to explore the effect ofcurcumin on androgen receptor (AR) expression in endometrial carcinoma cells, as well as the underlying mechanisms. Endometrial carcinoma cells were treated with curcumin (10, 50, and 100 micromol/l) for 12, 24, and 48 hours. Their growth curves were drawn using MTT assays and their apoptotic rates were determined using flow cytometry. The mRNA and protein expression of AR was detected using PCR and that of the Wnt signal related nucleopro- tein beta-cantenin was observed using western blot analysis. The influence of beta-cantenin on the action of curcumin was observed. Curcumin downregulated the proliferation and apoptosis of human endometrial carcinoma cells in concentration and time-dependent manners. It downregulated the expression of AR and beta-cantenin in the cells. rWnt3a partially cancelled the effects of curcumin on the proliferation and apoptosis of human endometrial carcinoma cells as well as the AR expression-downregulating effect of curcumin. Curcumin inhibits the proliferation and apoptosis of human endometrial carcinoma cells by downregulating their AR expression through the Wnt signal pathway.

  9. Progesterone receptor structure and protease activity in primary human endometrial carcinoma.

    Science.gov (United States)

    Feil, P D; Clarke, C L; Satyaswaroop, P G

    1988-03-01

    Monoclonal antibodies were used to investigate progesterone receptor structure (isoforms) in 33 primary human endometrial tumors. The monoclonal antibodies recognized on protein blots two progesterone receptor proteins with molecular weights of 116,000 and 81,000. The Mr 116,000 protein appeared as a triplet, while a single band was found for the Mr 81,000 protein. The triplet/singlet structure was found in all progesterone receptor-positive tumors, regardless of the degree of tumor differentiation. Protease activity, which gave rise to a false-negative pattern on protein blots, was found in approximately one-half of the tumors in which it was investigated. Inclusion of a cocktail of protease inhibitors during sample preparation resulted in the maintenance of the triplet/singlet progesterone receptor structure. Mixing experiments using a progesterone receptor-rich human endometrial carcinoma (EnCa 101), which lacks protease activity, and protease-containing primary tumor homogenates indicated that the protease was leupeptin sensitive. Interestingly, while the proteolytic activity reduced or eliminated the triplet/singlet progesterone receptor structure seen on protein blot analysis, it did not affect progesterone receptor concentration measured by Scatchard analysis. Sample preparation in the presence of protease inhibitors is therefore a requisite for structural analysis of the progesterone receptor in endometrial tumors.

  10. Non-random spatial relationships between mast cells and microvessels in human endometrial carcinoma.

    Science.gov (United States)

    Guidolin, Diego; Marinaccio, Christian; Tortorella, Cinzia; Annese, Tiziana; Ruggieri, Simona; Finato, Nicoletta; Crivellato, Enrico; Ribatti, Domenico

    2017-02-01

    Mast cells (MCs) accumulate in the stroma surrounding tumors, where they secrete angiogenic cytokines and proteases, and an increased number of MCs have been demonstrated in angiogenesis associated with solid and hematological tumors. The aim of this study is to contribute to the knowledge of distribution of MCs in tumors, investigating the pattern of distribution of tryptase-positive MCs around the blood vessels in human endometrial carcinoma samples by introducing a quantitative approach to characterize their spatial distribution. The results have shown that in human endometrial cancer bioptic specimens the spatial distribution of MCs shows significant deviation from randomness as compared with control group in which, instead, the spatial distribution of MCs is consistent with a random distribution. These findings confirm that MCs enhance tumor angiogenesis and their preferential localization along blood vessels and sites of new vessel formation sustaining the suggestion for an association between MCs and angiogenesis. However, this spatial association between vessels and MCs might simply reflect migrating MCs from the blood stream at vessel growing sites.

  11. Prediction of concurrent endometrial carcinoma in women with endometrial hyperplasia.

    Science.gov (United States)

    Matsuo, Koji; Ramzan, Amin A; Gualtieri, Marc R; Mhawech-Fauceglia, Paulette; Machida, Hiroko; Moeini, Aida; Dancz, Christina E; Ueda, Yutaka; Roman, Lynda D

    2015-11-01

    Although a fraction of endometrial hyperplasia cases have concurrent endometrial carcinoma, patient characteristics associated with concurrent malignancy are not well described. The aim of our study was to identify predictive clinico-pathologic factors for concurrent endometrial carcinoma among patients with endometrial hyperplasia. A case-control study was conducted to compare endometrial hyperplasia in both preoperative endometrial biopsy and hysterectomy specimens (n=168) and endometrial carcinoma in hysterectomy specimen but endometrial hyperplasia in preoperative endometrial biopsy (n=43). Clinico-pathologic factors were examined to identify independent risk factors of concurrent endometrial carcinoma in a multivariate logistic regression model. The most common histologic subtype in preoperative endometrial biopsy was complex hyperplasia with atypia [CAH] (n=129) followed by complex hyperplasia without atypia (n=58) and simple hyperplasia with or without atypia (n=24). The majority of endometrial carcinomas were grade 1 (86.0%) and stage I (83.7%). In multivariate analysis, age 40-59 (odds ratio [OR] 3.07, p=0.021), age≥60 (OR 6.65, p=0.005), BMI≥35kg/m(2) (OR 2.32, p=0.029), diabetes mellitus (OR 2.51, p=0.019), and CAH (OR 9.01, p=0.042) were independent predictors of concurrent endometrial carcinoma. The risk of concurrent endometrial carcinoma rose dramatically with increasing number of risk factors identified in multivariate model (none 0%, 1 risk factor 7.0%, 2 risk factors 17.6%, 3 risk factors 35.8%, and 4 risk factors 45.5%, pendometrial cancer in those with ≥3 risk factors. Older age, obesity, diabetes mellitus, and CAH are predictive of concurrent endometrial carcinoma in endometrial hyperplasia patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Morules in endometrial carcinoma and benign endometrial lesions differ from squamous differentiation tissue and are not infected with human papillomavirus

    OpenAIRE

    Chinen, K; Kamiyama, K; Kinjo, T; Arasaki, A; Ihama, Y; Hamada, T; Iwamasa, T

    2004-01-01

    Background: Squamous differentiation/squamous metaplasia is often associated with endometrial adenocarcinoma and benign lesions, such as endometrial hyperplasia and chronic endometritis. Morules have distinct histological characteristics, and are referred to as squamous metaplasia or squamoid metaplasia.

  13. Concurrent Endometrial Carcinoma in Patients with a Curettage Diagnosis of Endometrial Hyperplasia

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    Chen, Yu-Li; Cheng, Wen-Fang; Lin, Ming-Chieh; Huang, Chia-Yen; Hsieh, Chang-Yao; Chen, Chi-An

    2009-01-01

    Endometrial hyperplasia is considered a precursor of endometrial carcinoma, but concurrent endometrial carcinoma in patients with endometrial hyperplasia is seen frequently. Our aim was to examine the risk factors for coexisting endometrial carcinoma in patients with endometrial hyperplasia. Methods: Between January 1996 and September 2006, 77 patients who underwent hysterectomy for endometrial hyperplasia were enrolled retrospectively. We divided the patients into non-endometrial carcinom...

  14. High Nuclear Expression of HDGF Correlates with Disease Progression and Poor Prognosis in Human Endometrial Carcinoma

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    Lijing Wang

    2014-01-01

    Full Text Available Aims. This study examined the correlation between high nuclear expression of hepatoma-derived growth factor (HDGF and clinicopathologic data in endometrial carcinoma (EC, including patient survival. Methods. One hundred and twenty-two endometrial carcinoma (EC patients from 2002 to 2008 were reviewed in the study. HDGF expression in tumor tissues was examined using immunohistochemistry (IHC, and its association with clinicopathological parameters was evaluated. Tumors with 80% or more nuclei staining were regarded as high expression and tumors with less than 80% nuclei staining considered as low expression. Results and Conclusions. Immunohistochemical analysis revealed that HDGF was expressed in both the nucleus and cytoplasm. High nuclear expression of HDGF was positively correlated with FIGO stage (P=0.032, but not associated with other clinical features, such as histological grading or lymph node status. Patients with high expression of HDGF had poorer overall survival rates than those with low expression of HDGF (P=0.001. However, multivariate analyses showed that high nuclear expression of HDGF protein was not an independent predictor of prognosis for EC patients (P=0.111. Our results suggest that high nuclear expression of HDGF is a potential unfavorable factor for the progression and prognosis of EC.

  15. Examestane in advanced or recurrent endometrial carcinoma

    DEFF Research Database (Denmark)

    Lindemann, Kristina; Malander, Susanne; Christensen, René dePont

    2014-01-01

    We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma.......We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma....

  16. Microarray expression profile of lncRNAs and the upregulated ASLNC04080 lncRNA in human endometrial carcinoma.

    Science.gov (United States)

    Zhai, Wen; Li, Xu; Wu, Shouzhen; Zhang, Yan; Pang, Huan; Chen, Wei

    2015-05-01

    Long non-coding RNAs (lncRNAs) have been recognized as a regulator of gene expression, and the deregulation of lncRNAs have been reported to be correlated with carcinogenesis and cancer progression. To explore the function of lncRNA in endometrial carcinoma, we analyzed the expression profiles of lncRNAs and coding genes in 3 paired endometrial carcinoma and adjacent non-tumor tissues, using a microarray. The results of microarray analysis indicated a significant difference in lncRNA and coding gene expression between endometrial carcinoma and their paired adjacent non-tumor tissues. A total of 53 lncRNAs (fold change >2.0, p-value endometrial carcinoma compared to the normal controls. Among these ASLNC04080 was the most significantly upregulated lncRNA in microarray data, highly expressed in 22 out of 24 endometrial carcinoma tissues and HEC-1-B cell line. ASLNC04080 is 1867nt in length, consist of 6 exons, and locates at 1 p35.3(chr1: -28905061 - -28909492). In addition, 46 coding gene transcripts were differentially expressed (fold change >2.0, p-value endometrial carcinoma and adjacent non-tumor tissues. Pathway and gene ontology analysis demonstrated that these deregulated transcripts were involved in multiple signal pathways, biological processes, cellular components and molecular functions. Moreover, the ASLNC04080 lncRNA expression was correlated with 19 coding genes, and may contribute to endometrial carcinoma genesis and progression by co-regulating with coding gene. Expression inhibition of lncRNA ASLNC04080 in HEC-1-B cells caused repression of cell proliferation, increased cell apoptosis, and G1 phase arrest. These results suggested a potential function of ASLNC04080 in endometrial carcinoma genesis and progression.

  17. Endometrial carcinoma; Endometriumkarzinom

    Energy Technology Data Exchange (ETDEWEB)

    Engelhard, K. [Krankenhaus Martha-Maria, Nuernberg (Germany)

    2011-07-15

    Magnetic resonance imaging (MRI) is the method of choice in staging endometrial cancer. Using MRI early tumor invasion (stage IA) can be differentiated from a deep tumor growth (stage IB) of the myometrium with reported sensitivities of 85-95%.Tumor invasion of the uterine cervix can be depicted with a sensitivity of 80% and specificity of 96%. In demonstrating lymph node metastases MRI shows a sensitivity of 50%, a specificity of 95% and and accuracy of 90%. These diagnostic criteria are decisive for the choice of therapy procedures. So a simple hysterectomy will be performed in early stage IA disease while an extended surgical procedure with pelvic lymphadenectomy and radiotherapy will be considered in advanced stages IB and II disease. Vaginal ultrasound shows lower values in tumor staging with accuracies of 73-95%. Staging accuracies of computed tomography also show lower results with 61-76%. For planning radiotherapy and detection of cancer recurrence MRI is the most valuable tool. (orig.) [German] Fuer die Stadieneinteilung des Endometriumkarzinoms ist die Magnetresonanztomographie Methode der Wahl. Die Sensitivitaeten zur Differenzierung einer oberflaechlichen (Stadium IA) von einer tiefen myometrialen Invasion des Tumors (Stadium IB) liegen bei 85-95%, bei Spezifitaeten von 80-85%. Eine Infiltration der Zervix (Stadium II) kann mit Sensitivitaeten von 80% und Spezifitaeten von 96% nachgewiesen werden. Bei der Detektion von Lymphknotenmetastasen liegen die Sensitivitaeten der MRT bei 50%, bei Spezifitaeten von 95% und Treffsicherheiten von 90%. Die genannten diagnostischen Kriterien bestimmen das therapeutische Vorgehen. Werden fruehe Stadien mit einfacher Hysterektomie behandelt, erfordern die Stadien IB und II kombinierte erweiterte chirurgische Techniken und eine Radiotherapie. Die Treffsicherheiten des vaginalen Ultraschalls (73-93%) und der Computertomographie (61-76%) fuer die Stadieneinteilung des Tumors liegen deutlich niedriger als die Werte fuer

  18. Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Nicholls Peter K

    2010-06-01

    Full Text Available Abstract Background Interleukin (IL 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines. Methods IL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R α, phosphorylated (p STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot. Results IL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p Conclusions The present study suggests that IL11 in uterine washings may be useful as a diagnostic marker for early stage endometrial cancer. It indicates that IL11, along with its specific receptor, IL11Rα, and downstream signalling molecules, STAT3 and SOCS3, are likely to play a role in the progression of endometrial carcinoma. The precise role of IL11 in endometrial cancer remains to be elucidated.

  19. Thalidomide in Treating Patients With Recurrent or Persistent Endometrial Cancer

    Science.gov (United States)

    2013-01-23

    Endometrial Adenoacanthoma; Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma

  20. Pesquisa da prevalência do papilomavírus humano em amostras de tecido endometrial normal e com carcinoma pela técnica de PCR Search for human papillomavirus in samples of normal endometrial tissue and tissue with carcinoma by the PCR technique

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    Edison Natal Fedrizzi

    2004-05-01

    Full Text Available OBJETIVO: comparar a prevalência da presença do DNA do papilomavírus humano (HPV pela técnica de PCR em amostras de tecido endometrial normal e com carcinoma endometrial de mulheres submetidas a tratamento cirúrgico (histerectomia ou carcinoma endometrial e doença benigna. MÉTODOS: trata-se de um estudo observacional do tipo caso-controle onde foram avaliadas 100 mulheres (50 com endométrio normal e 50 com carcinoma endometrial quanto a presença do DNA do HPV em amostra tecidual conservada em blocos de parafina, pelo método de PCR. Foram excluídos os casos de carcinoma endometrial cujo sítio primário da lesão era duvidoso ou com história prévia ou atual de lesões pré-neoplásicas ou carcinoma do trato genital inferior. Variáveis como idade, tabagismo, trofismo endometrial, diferenciação escamosa e grau de diferenciação tumoral foram também avaliadas. RESULTADOS: o risco relativo estimado da presença do HPV foi o mesmo nas mulheres com e sem carcinoma endometrial. O HPV foi detectado em 8% dos casos de carcinoma e 10% no endométrio normal. Apesar de o HPV ter sido detectado 3,5 vezes mais em mulheres fumantes no grupo sem carcinoma, não houve diferença estatística. A presença do HPV também não esteve correlacionada com a idade das mulheres, trofismo endometrial, diferenciação escamosa e grau de diferenciação tumoral. Os HPV 16 e 18 (5 dos casos com o tipo 16 e 4 com o tipo 18 foram os vírus mais freqüentemente encontrados, tanto no tecido endometrial normal, quanto no carcinomatoso. Nenhum vírus de baixo risco oncogênico foi detectado nas amostras. CONCLUSÃO: o HPV está presente no tecido endometrial de mulheres com carcinoma endometrial na mesma proporção que nas com tecido endometrial normal, não se demonstrando a possível associação deste vírus no desenvolvimento do carcinoma endometrial.OBJECTIVE: to compare the prevalence of DNA of human papillomavirus (HPV, in samples of normal endometrial

  1. Isolated Abdominal Wall Metastasis of Endometrial Carcinoma

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    Rita Luz

    2014-01-01

    Full Text Available A woman in her mid-60s presented with a bulky mass on the anterior abdominal wall. She had a previous incidental diagnosis of endometrial adenocarcinoma FIGO stage IB following a vaginal hysterectomy. Physical exam and imaging revealed a well circumscribed bulging tumour at the umbilical region, measuring 10 × 9 × 9 cm, with overlying intact skin and subcutaneous tissue. Surgical resection was undertaken, and histological examination showed features of endometrial carcinoma. She began chemotherapy and is alive with no signs of recurrent disease one year after surgery. This case brings up to light an atypical location of a solitary metastasis of endometrial carcinoma.

  2. Differential Expression and Clinical Significance of DNA Methyltransferase 3B (DNMT3B), Phosphatase and Tensin Homolog (PTEN) and Human MutL Homologs 1 (hMLH1) in Endometrial Carcinomas.

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    Li, Wenting; Wang, Ying; Fang, Xinzhi; Zhou, Mei; Li, Yiqun; Dong, Ying; Wang, Ruozheng

    2017-02-21

    BACKGROUND The aim of this study was to investigate the expression and the clinicopathologic significance of DNA methyltransferase 3B (DNMT3B), phosphatase and tensin homolog (PTEN) and human MutL homologs 1 (hMLH1) in endometrial carcinomas between Han and Uygur women in Xinjiang. MATERIAL AND METHODS The expression of DNMT3B, PTEN, and hMLH1 in endometrial carcinomas were assessed by immunohistochemistry, followed by an analysis of their relationship to clinical-pathological features and prognosis. RESULTS There were a 61.7% (95/154) overexpression of DNMT3B, 50.0% (77/154) loss of PTEN expression and 18.2% (28/154) loss of hMLH1 expression. The expression of DNMT3B and PTEN in endometrial carcinomas was statistically significantly different between Uygur women and Han women (p=0.001, p=0.010, respectively). DNMT3B expression was statistically significant based on the grade of endometrial carcinomas (p=0.031). PTEN loss was statistically significant between endometrioid carcinomas (ECs) and non endometrioid carcinomas (NECs) (p=0.040). DNMT3B expression was statistically significant in different myometrial invasion groups in Uygur women (p=0.010). Furthermore, the correlation of DNMT3B and PTEN expression was significant in endometrial carcinomas (p=0.021). PTEN expression was statistically significant in the overall survival (OS) rate of women with endometrial cancers (p=0.041). CONCLUSIONS Our findings suggest that PTEN and DNMT3B possess common regulation features as well as certain ethnic differences in expression between Han women and Uygur women. An interaction may exist in the pathogenesis of endometrial carcinoma. DNMT3B was expressed differently in cases of myometrial invasion and PTEN was associated with OS, which suggested that these molecular markers may be useful in the evaluation of the biological behavior of endometrial carcinomas and may be useful indicators of prognosis in women with endometrial carcinomas.

  3. The role of 5α-reductase type 1 associated with intratumoral dihydrotestosterone concentrations in human endometrial carcinoma.

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    Tanaka, Sota; Miki, Yasuhiro; Hashimoto, Chiaki; Takagi, Kiyoshi; Doe, Zhulanqiqige; Li, Bin; Yaegashi, Nobuo; Suzuki, Takashi; Ito, Kiyoshi

    2015-02-05

    Endometrial carcinoma, especially endometrioid endometrial adenocarcinoma, is an estrogen-dependent tumor that is similar to breast cancer. Androgen is closely associated with other steroid hormones, but its correlation with endometrioid endometrial adenocarcinoma remains largely unclear. We previously demonstrated the expression of the androgen receptor, 5α-reductase type 1, and 5α-reductase type 2 in endometrioid endometrial adenocarcinoma tissue, but androgen action and its correlation with prognosis are unknown. In this study, we measured the tissue and serum concentrations of androgen and performed immunohistochemical analyses of androgen-associated factors in 41 patients. In 86 additional patients, we performed the same immunohistochemical analyses to identify correlations associated with prognosis. We found that 5α-reductase type 1 was associated with intratumoral dihydrotestosterone concentrations, and it was an independent prognostic factor in endometrioid endometrial adenocarcinoma. The poor prognosis of patients negative for both androgen receptor and 5α-reductase type 1 suggests that androgens have inhibitory effects on tumor growth. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Bisphenol A-induced epithelial to mesenchymal transition is mediated by cyclooxygenase-2 up-regulation in human endometrial carcinoma cells.

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    Wang, Kai-Hung; Kao, An-Pei; Chang, Chia-Cheng; Lin, Ta-Chin; Kuo, Tsung-Cheng

    2015-12-01

    Many studies have highlighted the correlation between the increase of bisphenol A (BPA) level in the environment and the incidence of tumor in humans. In human carcinogenesis, the overexpression of cyclooxygenase-2 (COX-2) and epithelial-mesenchymal transition (EMT) are closely related with tumor development. In this study, human endometrial carcinoma cells line (RL95-2) was used to investigate whether BPA can induce EMT and COX-2 expression. The results show that BPA increased growth rate and colony-forming efficiency in a dose-dependent manner, induced EMT and COX-2 gene expression and promoted the migration and invasion ability of RL95-2 cells. Furthermore, our study showed that the expression of COX-2 was essential for BPA-induced cell migration and invasion. The results of this study provide new insights into the mechanism of endometrial cancer cell growth and invasion and potential therapeutic strategy. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Concurrent Endometrial Carcinoma in Patients with a Curettage Diagnosis of Endometrial Hyperplasia

    Directory of Open Access Journals (Sweden)

    Yu-Li Chen

    2009-06-01

    Conclusion: When patients are diagnosed with endometrial hyperplasia, surgical intervention should be performed in those with cytological atypia and higher BMI because of the possibility of coexisting endometrial carcinoma.

  6. Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: Emergence of new molecular targets.

    Science.gov (United States)

    Strissel, Pamela L; Ruebner, Matthias; Thiel, Falk; Wachter, David; Ekici, Arif B; Wolf, Friedericke; Thieme, Franziska; Ruprecht, Klemens; Beckmann, Matthias W; Strick, Reiner

    2012-10-01

    Endometrial carcinoma (EnCa) is the most common invasive gynaecologic carcinoma. Over 85% of EnCa are classified as endometrioid, expressing steroid hormone receptors and mostly involving pathological prestages. Human endogenous retroviruses (ERV) are chromosomally integrated genes, account for about 8% of the human genome and are implicated in the etiology of carcinomas. The majority of ERV envelope (env) coding genes are either not present or not consistently represented between common gene expression microarrays. The aim of this study was to analyse the absolute gene expression of all known 21 ERV env genes including 19 codogenic and two env genes with premature stop codons in EnCa, endometrium as well as in hyperplasia and polyps. For EnCa seven env genes had high expression with >200 mol/ng cDNA (e.g. envH1-3, Syncytin-1, envT), two middle >50 mol/ng cDNA (envFc2, erv-3) and 12 low less than 50 mol/ng cDNA (e.g. Syncytin-2, envV2). Regarding tumor parameters, Syncytin-1 and Syncytin-2 were significantly over-expressed in advanced stage pT2 compared to pT1b. In less differentiated EnCa Syncytin-1, erv-3, envT and envFc2 were significantly over-expressed. Syncytin-1, Syncytin-2 and erv-3 were specific to glandular epithelial cells of polyps, hyperplasia and EnCa using immunohistochemistry. An analysis of 10 patient-matched EnCa with endometrium revealed that the ERV-W 5' long terminal repeat regulating Syncytin-1 was hypomethylated, including the ERE and CRE overlapping MeCP2 sites. Functional analyses showed that 10 env genes were regulated by methylation in EnCa using the RL95-2 cell line. In conclusion, over-expressed env genes could serve as indicators for pathological pre-stages and EnCa.

  7. Pure compared with mixed serous endometrial carcinoma: two different entities?

    NARCIS (Netherlands)

    Roelofsen, T.; Ham, M.A. van; Wiersma van Tilburg, J.M.; Zomer, S.F.; Bol, M.; Massuger, L.F.A.G.; Bulten, J.

    2012-01-01

    OBJECTIVE: : To analyze whether mixed compared with pure uterine papillary serous carcinoma histology affects clinical outcome, and to assess uterine papillary serous carcinoma for its association with the precursor lesion endometrial intraepithelial carcinoma. METHODS: : A multi-institution

  8. Immunohistochemical Study of ER, PR, Ki67 and p53 in Endometrial Hyperplasias and Endometrial Carcinomas.

    Science.gov (United States)

    Masjeed, Nayar Musfera Abdul; Khandeparkar, Siddhi Gaurish Sinai; Joshi, Avinash R; Kulkarni, Maithili Mandar; Pandya, Nidhi

    2017-08-01

    Endometrial carcinoma is the second most common gynecologic malignancy in the developing countries. Endometrial Hyperplasia (EH) is a precursor to Endometrioid Adenocarcinoma (EMAC). A 23% of Atypical Hyperplasias (AEH) progress to EMAC. This study was undertaken to analyse ER, PR, p53 and Ki67 in EH and endometrial carcinomas and attempt correlation with clinical and histopathological findings. The present study was conducted over a period of seven years. A manual tissue array technique was employed for cases subjected to IHC. Analysis of the expression of IHC markers (ER, PR, p53, Ki67) in EH and endometrial carcinoma was attempted. Results were subjected to statistical analysis. The results were considered to be significant when the p-value endometrial carcinoma were included in the study. EH (75.22%) was more common than endometrial carcinoma (24.78%). Among 28 cases of endometrial carcinomas, EMAC was most common (78.57%) followed by Clear Cell Carcinoma (CCC) (14.28%), and Uterine Serous Carcinoma (USC) (7.14%). ER and PR expression decreased as lesion progressed from EH to EMAC. ER and PR expression was negative in USC and CCC. The p53 expression and mean Ki67 labelling index increased as the severity of lesion increased from EH to endometrial carcinoma. The ER, PR, p53, Ki67 IHC markers may be included in every case of endometrial carcinoma to understand the tumour biological behavior which in turn could help individual treatment strategies.

  9. Hysteroscopic findings of endometrial carcinoma. Evaluation of 104 cases.

    Science.gov (United States)

    Triolo, O; Antico, F; Palmara, V; Benedetto, V; Panama, S; Nicotina, P A

    2005-01-01

    Retrospective evaluation of hysteroscopic findings in the accurate diagnosis of endometrial carcinoma. A retrospective monocentric study from January 1995 to December 2004. One hundred and four patients with hysteroscopic aspects evocative of endometrial carcinoma confirmed by endometrial biopsy during diagnostic hysteroscopy, by surgical hysteroscopic resection pieces or by hysterectomy specimen were included. Among the 104 patients, diagnostic hysteroscopy pointed out endometrial features suggestive of endometrial carcinoma in 102 cases. In two women diagnostic hysteroscopy failed to diagnose endometrial malignancy which was identified on pieces of polyps by surgical hysteroscopic resection. Polypoid proliferations cerebroid in appearance, with ulceration and necrosis, friable and with irregular vessels, represent endometrial findings highly indicative of malignancy. The diagnosis may be missed in cases of focal neoplasias, within endometrial polyps or in conditions of unsatisfactory endouterine visualization.

  10. Cytokine stimulation of MUC4 expression in human female reproductive tissue carcinoma cell lines and endometrial cancer.

    Science.gov (United States)

    Chapela, Patricia J; Broaddus, Russell R; Hawkins, Shannon M; Lessey, Bruce A; Carson, Daniel D

    2015-11-01

    MUC4, a transmembrane glycoprotein, interferes with cell adhesion, and promotes EGFR signaling in cancer. Studies in rat models have demonstrated steroid hormonal regulation of endometrial MUC4 expression. In this study, qRT-PCR screening of mouse tissues determined that Muc4 mRNA also was robustly expressed in mouse uteri. Previous studies from our labs have demonstrated MUC4 mRNA was expressed at levels human endometrium and endometriotic tissue. Multiple human endometrial adenocarcinoma cell lines were assayed for MUC4 mRNA expression revealing extremely low basal expression in the Ishikawa, RL-95-2, AN3CA, and KLE lines. Moderate to high expression was observed in HEC50 and HEC-1A cells. MUC4 mRNA expression was not affected by progesterone and/or estrogen treatment, but was greatly stimulated at both mRNA and protein levels by proinflammatory cytokines (IFN-γ and TNF-α), particularly when used in combination. In endometrial tissue, MUC4 mRNA levels did not change significantly between normal or cancerous samples; although, a subset of patients with grade 1 and 2 tumors displayed substantially higher expression. Likewise, immunostaining of human endometrial adenocarcinoma tissues revealed little to no staining in many patients (low MUC4), but strong staining in some patients (high MUC4) independent of cancer grade. In cases where staining was observed, it was heterogeneous with some cells displaying robust MUC4 expression and others displaying little or no staining. Collectively, these observations demonstrate that while MUC4 is highly expressed in the mouse uterus, it is not a major mucin in normal human endometrium. Rather, MUC4 is a potential marker of endometrial adenocarcinoma in a subset of patients. © 2015 Wiley Periodicals, Inc.

  11. Trans-vaginal sono-elastography in the differentiation of endometrial hyperplasia and endometrial carcinoma

    OpenAIRE

    Mahmoud Abdel Latif; Magda Shady; Hanan Nabil; Yasser Mesbah

    2016-01-01

    Aim: To evaluate efficiency of sono-elastography in differentiation of endometrial hyperplasia and endometrial carcinoma. Patients and methods: Between January 2014 and January 2015, 45 perimenopausal female patients with endometrial thickness more than 6 mm were examined by TV sono-elastography procedure. Results of ultrasound and elastography were compared with pathological data (reference standard). Strain ratios were compared between typical, atypical endometrial hyperplasia and endome...

  12. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma

    NARCIS (Netherlands)

    Dove-Edwin, Isis; Boks, Dominique; Goff, Sheila; Kenter, Gemma G.; Carpenter, Robert; Vasen, Hans F. A.; Thomas, Huw J. W.

    2002-01-01

    BACKGROUND: Endometrial carcinoma is the most common extracolonic malignancy associated with hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC). The risk of endometrial carcinoma in HNPCC mutation carriers is approximately ten times that of the general population, and endometrial

  13. Endometrial carcinoma occuring from polycystic ovary disease : A case report

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Su Ok; Jeon, Woo Ki [Inje Univ. College of Medicine, Seoul (Korea, Republic of)

    1996-12-01

    Endometrial carcinoma usually occurs in postmenopausal women ; less than 5% occurs in women under the age of 40. Up to one quarter of endometrial carcinoma patients below this age have PCO(polycystic ovary disease, Stein-Leventhal syndrome). The increased incidence of endometrial carcinoma in patients with PCO is related to chronic estrogenic stimulation. We report MR imaging in one case of endometrial carcinoma occuring in a 23 year old woman with PCO and had complained of hypermenorrhea for about three years. On T2-weighted MR image the endometrial cavity was seen to be distended with protruded endometrial masses of intermediate signal intensity, and the junctional zone was disrupted beneath the masses. Both ovaries were best seen on T2-weighted MR imaging and showed multiple small peripheral cysts and low signal-intensity central stroma.

  14. Controversies in the Management of Endometrial Carcinoma: An Update

    Directory of Open Access Journals (Sweden)

    Mohamed K. Mehasseb

    2012-01-01

    Full Text Available Endometrial carcinoma is the commonest type of female genital tract malignancy in the developed countries. Endometrial carcinoma is usually confined to the uterus at the time of diagnosis and as such usually carries an excellent prognosis with high curability. Our understanding and management of endometrial cancer have continuously developed. Current controversies focus on screening and early detection, the extent of nodal surgery, and the changing roles of radiation therapy and chemotherapy and will be discussed in this paper.

  15. Antitumor Effects and Biological Mechanism of Action of the Aqueous Extract of the Camptotheca acuminata Fruit in Human Endometrial Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Chi-Shian Lin

    2014-01-01

    Full Text Available The aqueous extracts of the leaves and fruit of Camptotheca acuminata have long been used in traditional Chinese medicine (TCM for treating cancer patients. The chemotherapeutic drug, camptothecin (CPT, and related analogs were first isolated from C. acuminata in the 1970s. Although the antitumor effects of CPT have been characterized in recent years, the antitumor effects of aqueous extracts of C. acuminata have not been clarified. The aims of our current study were to determine the tumor-suppression efficiency of an aqueous extract of the fruit of C. acuminata (AE-CA in the human endometrial carcinoma cell lines, HEC-1A, HEC-1B, and KLE, and compare its antitumor effects with those of CPT. Cell viability assays indicated that a dosage of AE-CA containing 0.28 mg/mL of CPT demonstrated enhanced cytotoxicity, compared with CPT treatment. The effects of AE-CA on the induction of cell cycle arrest, the accumulation of cyclin-A2 and -B1, and the activation of caspase-3 and caspase-7 were similar to those of CPT. Furthermore, AE-CA exhibited a synergistic effect on the cytotoxicity of cisplatin in HEC-1A and HEC-1B cells. These results indicated that AE-CA is a potent antitumor agent and can be combined with cisplatin for the treatment of human endometrial cancer.

  16. Role of pelvic lymphadenectomy in stage 1A endometrial carcinoma ...

    African Journals Online (AJOL)

    Hossam Hassan Aly Hassan El Sokkary

    2013-10-31

    Oct 31, 2013 ... 1A endometrial carcinoma diagnosed preoperatively by pelvic ultrasonography and ... Endogenous risk factors include obesity, early menarche, ..... node resection in endometrioid corpus cancer: a study of 12,333 · patients.

  17. Prevalence of Co-existing Endometrial Carcinoma in Patients with Preoperative Diagnosis of Endometrial Hyperplasia

    Science.gov (United States)

    Kadirogullari, Pinar; Atalay, Cemal Resat; Sari, Mustafa Erkan

    2015-01-01

    Introduction Endometrial hyperplasia has been associated with the presence of concomitant endometrial carcinoma. In this study, patients who were diagnosed with endometrial hyperplasia and had hysterectomy, determination of the incidence of endometrial cancer accompanying postoperatively and clinical parameters associated with cancer are aimed. Materials and Methods Endometrial biopsies were taken from patients for various reasons and among them 158 patients diagnosed with endometrial hyperplasia from pathologic examination results were retrospectively evaluated. All of the patient’s age, parity, weight, transvaginal ultrasound measured by endometrial thickness, concomitant systemic disease (diabetes, hypertension, hypothyroidism), tamoxifen use, hormone use and whether in reproductive age or menopause were all questioned. Patients who applied with endometrial cancer, their cervical stromal involvement, lymph node involvement, cytology positivity and omental metastases were examined. Patients were classified according to their stage and grade. Patients who had intraoperative frozen were re-evaluated. Results Fifteen cases with preoperative endometrial hyperplasia diagnosed with endometrial cancer postoperatively, 2 cases had complex hyperplasia without atypia and 13 cases had complex atypical hyperplasia. The rate of preoperative hyperplasia with postoperative endometrial cancer was found to be 10.8% where by 15 cases of patients diagnosed with endometrial cancer postoperatively 11 cases were in postmenopausal period. In patients diagnosed with endometrial cancer according to their histologic types 14 cases had endometrioid adenocarcinoma while one patient with preoperative complex hyperplasia without atypia was diagnosed with serous papillary carcinoma postoperatively. Evaluation of stages in patients diagnosed with cancer, 7 cases of patients had stage IA, 7 cases of patients had stage IB, and 7 cases cases of patients with serous papillary carcinoma were

  18. PTEN Sequence Analysis in Endometrial Hyperplasia and Endometrial Carcinoma in Slovak Women

    Directory of Open Access Journals (Sweden)

    H. Gbelcová

    2015-01-01

    Full Text Available Phosphatase and tensin homolog (PTEN is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa. ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3, complex hyperplasia (5, atypical complex hyperplasia (7, endometrioid carcinomas G1 (20 and G3 (5, and serous carcinoma (5 were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

  19. Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells.

    Science.gov (United States)

    Gu, Yuting; Zhang, Jing; Guan, Huai

    2017-12-01

    Expression of enhancer of zeste homolog 2 (EZH2) has been implicated in cancer pathology, but research on its mechanistic activity is limited. The present study sought to assess the levels expression of EZH2 in patients with endometrial carcinoma (EC) and to explore the effects of EZH2 downregulation on the biological behavior of endometrial carcinoma RL-952 cells. Samples were obtained from a total of 104 patients with EC and an immunohistochemical assay was used to detect the expression of EZH2 in cancer and adjacent tissues. The relationship between the expression of EZH2 and the clinicopathological features was analyzed. Endometrial carcinoma RL-952 cells were transfected with chemically synthesized siRNA to conduct targeting inhibition of EZH2 expression. The expression levels of EZH2 protein were detected by immunoblotting. MTT and Transwell assays were used to detect the changes of cell proliferation and invasion after EZH2 downregulation. Of the 104 cases of endometrial carcinoma samples, 71 cases showed positive expression of EZH2, with an expression rate of 68.27%. In 104 cases of adjacent tissue samples, 25 cases showed positive expression of EZH2, with an expression rate of 24.03%. The expression of EZH2 in endometrial carcinoma tissue was significantly higher than that in adjacent tissue (Pendometrial carcinoma tissue was not correlated with the menopausal status and age of patients (P>0.05), but was correlated with the histological grade, depth of tumor invasion, lymph node metastasis and TNM stage (Pendometrial carcinoma and can enhance the proliferative activity of endometrial carcinoma RL-952 cells and promote cell invasion.

  20. Tubal Pregnancy Associated with Endometrial Carcinoma after In Vitro Fertilization Attempts

    Directory of Open Access Journals (Sweden)

    Yesim Bayoglu Tekin

    2014-01-01

    Full Text Available Endometrial carcinoma is rarely seen during reproductive ages and commonly related to infertility, polycystic ovarian syndrome (PCOS, and obesity. Pregnancy associated endometrial carcinoma is even rarer and this is the second case reported in the literature concerning tubal pregnancy associated endometrial carcinoma. We present a case of a 36-year-old woman with a history of PCOS, infertility, and several attempts of ovulation induction and in vitro fertilization, who was diagnosed with tubal pregnancy and a well differentiated endometrial carcinoma. We also review the literature about pregnancy associated endometrial carcinoma in the first trimester.

  1. Endometrial carcinoma: MR staging and causes of error.

    Science.gov (United States)

    Foti, P V; Farina, R; Coronella, M; Ruggeri, C; Palmucci, S; Montana, A; Milone, P; Zarbo, G; Caltabiano, R; Lanzafame, S; Politi, G; Ettorre, G C

    2013-04-01

    This study was undertaken to prospectively determine the diagnostic capabilities of magnetic resonance (MR) imaging in detecting myometrial and cervical invasion and lymph node involvement in endometrial carcinoma and to identify the causes of errors in staging endometrial carcinoma. Twenty consecutive patients with a histological diagnosis of endometrial carcinoma underwent preoperative MR imaging. MR findings were compared with surgical staging, considered as the standard of reference. In assessing myometrial invasion, MR imaging showed 70% accuracy, 80% sensitivity, 40% specificity, 80% positive predictive value (PPV), and 40% negative predictive value (NPV). In detecting cervical invasion, MR imaging had 95% accuracy, 100% sensitivity, 94.4% specificity, 66.7% PPV, and 100% NPV. In evaluating lymph node involvement, MR imaging showed 100% accuracy, sensitivity, specificity, PPV and NPV. Errors in evaluating myometrial invasion were caused by polypoid tumour, adenomyosis and leiomyomas, whereas those in evaluating cervical invasion were caused by dilatation and curettage. MR imaging is a reliable technique for preoperative evaluation of endometrial carcinoma. Its main limitation is differentiating between stage IA and IB carcinomas, which is not highly important for surgical planning. Cooperation between the gynaecologist and radiologist is mandatory to avoid staging errors.

  2. Mutations of the KRAS oncogene in endometrial hyperplasia and carcinoma.

    Directory of Open Access Journals (Sweden)

    Wiesława Niklińska

    2009-05-01

    Full Text Available The aim of this study was to examine the prevalence and clinicopathological significance of KRAS point mutation in endometrial hyperplasia and carcinoma. We analysed KRAS in 11 cases of complex atypical hyperplasia and in 49 endometrial carcinomas using polymerase chain reaction associated with restriction fragment length polymorphism (PCR-RFPL. Point mutations at codon 12 of KRAS oncogene were identified in 7 of 49 (14,3% tumor specimens and in 2 of 11 (18,2% hyperplasias. No correlation was found between KRAS gene mutation and age at onset, histology, grade of differentiation and clinical stage. We conclude that KRAS mutation is a relatively common event in endometrial carcinogenesis, but with no prognostic value.

  3. Role of pelvic lymphadenectomy in stage 1A endometrial carcinoma ...

    African Journals Online (AJOL)

    Hossam Hassan Aly Hassan El Sokkary

    2013-10-31

    Oct 31, 2013 ... late menopause, low parity, polycystic ovary syndrome, estro- gen secreting tumors, and family history, ... ation therapy.4 The median age for diagnosis of endometrial carcinoma is about 60 years. Abnormal ... IIIC Metastasis to pelvic or paraaortic lymph nodes. IVA Tumor invasion of the bladder and/or ...

  4. Reproducibility of measurement of myometrial invasion in endometrial carcinoma

    NARCIS (Netherlands)

    Putten, L.J.M. van der; Vijver, K. van der; Bartosch, C.; Davidson, B.; Gatius, S.; Matias-Guiu, X.; McCluggage, W.G.; Toledo, G.; Wurff, A.A. van der; Pijnenborg, J.M.A.; Massuger, L.F.A.G.; Bulten, J.

    2017-01-01

    Myometrial invasion (MI) as a percentage (%MI), categorized into <50 or >/=50 %, is an important predictor of prognosis in endometrial carcinoma. Recent studies suggest that tumor-free distance (TFD) to serosa and the absolute depth of invasion (DOI) might be stronger predictors of prognosis.

  5. Nintedanib in Treating Patients With Recurrent or Persistent Endometrial Cancer

    Science.gov (United States)

    2017-09-08

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Malignant Uterine Corpus Mixed Epithelial and Mesenchymal Neoplasm; Recurrent Uterine Corpus Carcinoma

  6. {sup 18}F-FDG-PET/CT in Endometrial Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, Tae Joo [Pochon CHA University College of Medicine, Sungnam (Korea, Republic of)

    2008-12-15

    Endometrial carcinoma is one of the most common gynecologic malignancies and which is predominant in postmenopausal women. Clinically many patients are hospitalized in early stage due to clinical sign and symptom such as vaginal bleeding and in this case, patient's prognosis is known to be good. However, considerable number of patients with advanced and relapsed disease reveal poor prognosis. Therefore, exact staging work up is essential for proper treatment as is primary lesion detection. {sup 18}F-FDG-PET has been widely used for the evaluation of gynecologic malignancies such as cervical carcinoma and ovarian cancer. In contrast, FDG PET application to endometrial carcinoma is limited until now and there is no sufficient data to validate the usefulness of FDG PET for this disease yet. However, several studies showed promising results that FDG PET is sensitive and specific in detection of recurrent or metastatic lesions. Therefore further active investigation in this field can facilitate the use of FDG PET for endometrial carcinoma.

  7. PTEN expression in benign human endometrial tissue and cancer in relation to endometrial cancer risk factors.

    Science.gov (United States)

    Yang, Hannah P; Meeker, Alan; Guido, Richard; Gunter, Marc J; Huang, Gloria S; Luhn, Patricia; d'Ambrosio, Lori; Wentzensen, Nicolas; Sherman, Mark E

    2015-12-01

    Clonal loss of PTEN expression occurs frequently in endometrial carcinoma and endometrial hyperplasia. Limited data from immunohistochemical studies suggest that PTEN-null appearing endometrial glands are detectable in women without pathologic abnormalities, but the relationship of PTEN expression to endometrial cancer risk factors has not been extensively explored. We evaluated relationships between endometrial cancer risk factors and loss of PTEN expression in a set of benign endometrial samples prospectively collected from women undergoing hysterectomy and in endometrial cancer tissues from a population-based case-control study. We used a validated PTEN immunohistochemical assay to assess expression in epidemiological studies designed to assess benign endometrium [Benign Reproductive Tissue Evaluation Study (n = 73); Einstein Endometrium Study (n = 19)], and endometrial cancer [Polish Endometrial Cancer Study (n = 148)] tissues. Associations between endometrial cancer risk factors (collected via study-specific risk factor questionnaires) and PTEN expression in endometrial tissues were determined using Fisher's exact tests. PTEN loss was detected in 19% of benign endometrial tissues versus 55% in endometrial cancers. NSAID use was statistically significantly associated with PTEN loss in the benign endometrium (p = 0.02). Our data demonstrate that PTEN loss is detectable in endometrial tissues that are benign and malignant, with substantially more frequent loss in endometrial cancer compared with benign endometrium. However, alterations in expression were unrelated to most risk factors in this analysis, except for the association with NSAID use, which may represent a chance finding or reverse causality among patients with endometriosis who may have PTEN pathway abnormalities in eutopic endometrium. Further evaluation of factors associated with PTEN loss and long-term follow-up of women with PTEN-null endometrial glands may be useful in understanding early events

  8. The genetic landscape of endometrial clear cell carcinomas.

    Science.gov (United States)

    DeLair, Deborah F; Burke, Kathleen A; Selenica, Pier; Lim, Raymond S; Scott, Sasinya N; Middha, Sumit; Mohanty, Abhinita S; Cheng, Donavan T; Berger, Michael F; Soslow, Robert A; Weigelt, Britta

    2017-10-01

    Clear cell carcinoma of the endometrium is a rare type of endometrial cancer that is generally associated with an aggressive clinical behaviour. Here, we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs), and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs showed abnormal expression patterns for p53, ARID1A, and at least one DNA mismatch repair (MMR) protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, and these revealed that two ECCs (7%) were ultramutated and harboured mutations affecting the exonuclease domain of POLE. In POLE wild-type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations; 18% and 11% harboured CCNE1 and ERBB2 amplifications, respectively, and 11% showed DAXX homozygous deletions. ECCs less frequently harboured mutations affecting CTNNB1 and PTEN but more frequently harboured PPP2R1A and TP53 mutations than non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA). Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harboured TP53 mutations. When a surrogate model for the molecular-based TCGA classification was used, all molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR-deficient, copy-number high (serous-like)/p53 abnormal, and copy-number low (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs constitute a histologically and

  9. Dedifferentiated endometrial carcinoma: A report of three cases and review of the literature.

    Science.gov (United States)

    Yokomizo, Ryo; Yamada, Kyosuke; Iida, Yasushi; Kiyokawa, Takako; Ueda, Kazu; Saito, Motoaki; Yanaihara, Nozomu; Nakamura, Mayo; Okamoto, Aikou

    2017-12-01

    Dedifferentiated endometrial carcinoma, which is defined microscopically as the co-existence of undifferentiated carcinoma and grade 1 or 2 endometrioid adenocarcinoma, is an aggressive type of cancer regardless of the percentage of undifferentiated components. It is reported that undifferentiated carcinoma comprises 9% of endometrial carcinoma. The percentage of dedifferentiated endometrial carcinoma has been hypothesized to be 40% of undifferentiated carcinoma. A precise pathological diagnosis is essential for defining the appropriate therapeutic approach and prognosis. Furthermore, since there is an association between dedifferentiated endometrial carcinoma and Lynch syndrome, it is important to identify the patient's genetic background. The current case report presents three cases of dedifferentiated endometrial carcinoma treated in our hospital. In immunohistochemical staining for DNA mismatch-repair (MMR) proteins in dedifferentiated endometrial carcinoma, the components of undifferentiated carcinoma demonstrated a loss of MMR protein expression, and it is suspected that there may be a germline mutation in these cases. Therefore, Lynch syndrome should be suspected and the appropriate genetic approaches in cases of dedifferentiated endometrial carcinoma should be considered.

  10. Adult granulosa cell tumor associated with endometrial carcinoma: a case report

    National Research Council Canada - National Science Library

    Ukah, Cornelius O; Ikpeze, Okechukwu C; Eleje, George U; Eke, Ahizechukwu C

    2011-01-01

    If strict criteria for the diagnosis of carcinoma are used and all patients with granulosa cell tumors are considered, the best estimate of the incidence of associated endometrial carcinomas is under 5...

  11. Role of MicroRNA in Endometrial Carcinoma

    Directory of Open Access Journals (Sweden)

    Zeeshan Javed

    2016-11-01

    Full Text Available Endometrial carcinoma (EC is a hall mark of gynecological malignancies that usually affects women above the age 50. It is one of the major causes of mortality in females with ever increasing prevalence and the mortality rate is 1.7 to 2.4 per 100000 and each year 10000 death occur due to ECs. MiRNAs regulate the expression of different proto-oncogenes and signaling pathways that are directly or indirectly involved in the development of cancer. Different miRNAs i.e. (miRNA-449, miRNA 370, miRNA-424, and miRNA-152 which gets up or down regulated during endometrial cancer are the potential biomarkers for early diagnosis of EC. Targeting this relationship between the miRNA and signaling pathways may help in the development of new treatment in endometrial cancer. In current study, we reviewed literature from PubMed using miRNA and endometrial cancer as keywords and outlined the synthesis of potent miRNA and role of different miRNAs involved in ECs. The study revealed different sub types of miRNA played crucial role in the development of cancer by up and down regulation of different metabolic pathways. Many evidences have supported that miRNAs play role in control and regulation of different pathways leading to cancer and targeting these pathways may bring changes in the diagnosis as well as in treatment of EC.

  12. Adult granulosa cell tumor associated with endometrial carcinoma: a case report

    OpenAIRE

    Eke Ahizechukwu C; Eleje George U; Ikpeze Okechukwu C; Ukah Cornelius O

    2011-01-01

    Abstract Introduction If strict criteria for the diagnosis of carcinoma are used and all patients with granulosa cell tumors are considered, the best estimate of the incidence of associated endometrial carcinomas is under 5%. In patients with granulosa cell tumors, estrogen-dependent endometrial cancers are rarely found, and most of these endometrial cancers are well-differentiated endometrioid adenocarcinomas that carry a good prognosis when detected early. Case presentation We report the ca...

  13. Treatment results in women with clinical stage I and pathologic stage II endometrial carcinoma

    NARCIS (Netherlands)

    Jobsen, J.J.; Schutter, E.M.J.; Meerwaldt, J.H.; van der Palen, Jacobus Adrianus Maria; van der Sijde, R.; Naudin ten Cate, L.

    2001-01-01

    The aim of this study is to report survival and results of therapy and possible prognostic factors in women with pathologic stage II endometrial carcinoma. Forty-two patients with pathologic stage II endometrial carcinoma were treated at the department of Radiation Oncology of the Medisch Spectrum

  14. Prevalence of Human Papillomavirus in endometrial cancer

    DEFF Research Database (Denmark)

    Olesen, Tina Bech; Svahn, Malene Frøsig; Faber, Mette Tuxen

    2014-01-01

    HPV is a common sexually transmitted infection and is considered to be a necessary cause of cervical cancer. The anatomical proximity to the cervix has led researchers to investigate whether Human Papillomavirus (HPV) has a role in the etiology of endometrial cancer.......HPV is a common sexually transmitted infection and is considered to be a necessary cause of cervical cancer. The anatomical proximity to the cervix has led researchers to investigate whether Human Papillomavirus (HPV) has a role in the etiology of endometrial cancer....

  15. Xanthogranulomatous Endometritis: A Challenging Imitator of Endometrial Carcinoma

    Directory of Open Access Journals (Sweden)

    A. Işın Doğan-Ekici

    2007-01-01

    Full Text Available Xanthogranulomatous inflammation is a distinguished histopathological entity affecting several organs, predominantly the kidney and gallbladder. So far, only a small number of cases of xanthogranulomatous inflammation occurring in female genital tract have been described, most frequently affecting the endometrium and histologically characterized by replacement of endometrium by xanthogranulomatous inflammation composed of abundant foamy histiocytes, siderophages, giant cells, fibrosis, calcification and accompanying polymorphonuclear leucocytes, plasma cells and lymphocytes of polyclonal origin. We present a case of a 69-year-old female complained of post menopausal bleeding and weight loss. Clinical preliminary diagnoses were endometrial carcinoma or hyperplasia and ultrasound was supposed to be endometrial malignancy, hyperplasia or pyometra by radiologist. Histopathological examination of uterus revealed xanthogranulomatous endometritis. Since xanthogranulomatous endometritis may mimic endometrial malignancy clinically and pathologically as a result of the replacement of the endometrium and occasionally invasion of the myometrium by friable yellowish tissue composed of histiocytes, knowledge of this unusual inflammatory disease is needed for both clinicians and pathologists.

  16. Endometrial carcinoma clinical management: results of a regional survey.

    Science.gov (United States)

    Carlomagno, G

    2009-01-01

    In Southern regions of Italy, many women affected by oncologic pathology go to larger towns to referral hospitals to be treated. However there is the impression that this does not apply to endometrial cancer, which affects older women less prone to seek care far from home. To verify this premise and to ascertain the quality of treatment these patients received, and the degree of compliance of their treatment with the International Federation of Gynecology and Obstetrics (FIGO) recommendations, a database was created collecting information concerning the clinical management of endometrial cancer in 13 different gynecological units in the Campania region. We confirmed that endometrial carcinoma, the most frequent oncologic pathology in all participating units, was treated independently from the dimensions of all of these units. The adopted diagnostic and therapeutic procedures seemed to be largely compliant with FIGO guidelines. Limited dishomogeneity only regarded the smallest units. Overall, a good quality of treatment seemed to be given to women affected by this pathology who wanted to be treated in, or close to, their town of residence.

  17. [Histological and molecular classification of endometrial carcinoma and therapeutical implications].

    Science.gov (United States)

    Genestie, Catherine; Leary, Alexandra; Devouassoux, Mojgan; Auguste, Aurélie

    2017-12-01

    Endometrial cancer is the fourth cause of cancer in women in France and is the second most common cancer of the gynecologic cancer after breast cancer with 7275 new cases in 2012. The incidence of this neoplasm tends to increase with population aging, diabetes and obesity's augmentation. In rare cases, a hereditary factor has been described: Lynch's syndrome. The therapeutic management of the patient depends on the endometrial biopsy which specifies the histological type and the histo-prognostic grade as well as the MRI which allow the tumor staging. Within the last decade, improvement in technologies such as genomic, transcriptomic and histological analyses, allowed the establishment of new and finer classifications of endometrial carcinomas. The latest classification proposed by The Cancer Genomic Atlas (TCGA), has been made routinely applicable through the international consortium TransPORTEC. It consists of 4 groups listed from good to poor prognosis: (1) ultra-mutated "POLE"; (2) hyper-mutated "MSI"; (3) low copy number "NSMP" and (4) high number of copies "TP53 mutated" (serous-like). This integrated characterization combined with mutational data opens new opportunities for therapeutic strategies. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  18. [The Role of 5-Aza-CdR on Methylation of Promoter in RASSF1A Gene in Endometrial Carcinoma].

    Science.gov (United States)

    Huang, Li-ping; Chen, Chen; Wang, Xue-ping; Liu, Hui

    2015-05-01

    To explore the effect of demethylating drug 5-Aza-2'-deoxycytidine (5-Aza-CdR) on methtylation status of the Ras-association domain familylA gene (RASSF1A) in human endometrial carcinoma. Randomly'assign the human endometrial carcinoma cell line HEC-1-B into groups and use demethylating drug 5-Aza-CdR of different concentration to treat them. Then Methylation-specific polymerase chain reaction (MSP), real-time PCR, Western blot, TUNEL technology were used to analyze methylation status of RASSF1A promoter CpG islands, RASSF1A mRNA expression, RASSF1A protein expression and apoptosis of HEC-1-B cell. High DNA methylation in RASSF1A gene promoter region, low RASSF1A mRNA level and protein expression and out of control of human endometrial carcinoma cell HEC-1-B apoptosis were observed. 5-Aza-CdR of different concentration could reverse RASSF1A gene's methylation status, recover the expression of mRNA and protein, and control the growth of HEC-1-B by inducing apoptosis. Aberrant methylation of RASSF1A in endometrial cancer as a therapeutic target, demethylating agent 5-Aza-CdR could be an effective way of gene therapy.

  19. Association of the apolipoprotein E 2 allele with concurrent occurrence of endometrial hyperplasia and endometrial carcinoma.

    Science.gov (United States)

    Ivanova, Tatiana I; Krikunova, Ludmila I; Ryabchenko, Nikolay I; Mkrtchyan, Liana S; Khorokhorina, Vera A; Salnikova, Lyubov E

    2015-01-01

    Genes encoding proteins with antioxidant properties may influence susceptibility to endometrial hyperplasia (EH) and endometrial carcinoma (ECa). Patients with EH (n = 89), EH concurrent with ECa (n = 76), ECa (n = 186), and healthy controls (n = 1110) were genotyped for five polymorphic variants in the genes involved in metabolism of lipoproteins (APOE Cys112Arg and Arg158Cys), iron (HFE Cys282Tyr and His63Asp), and catecholamines (COMT Val158Met). Patients and controls were matched by ethnicity (all Caucasians), age, body mass index (BMI), and incidence of hypertension and diabetes. The frequency of the APOE E 2 allele (158Cys) was higher in patients with EH + ECa than in controls (P = 0.0012, P(Bonferroni) = 0.018, OR = 2.58, 95% CI 1.49-4.45). The APOE E 4 allele (112Arg) was more frequently found in patients with EH than in controls and HFE minor allele G (63Asp) had a protective effect in the ECa group, though these results appeared to be nonsignificant after correction for multiple comparisons. The results of the study indicate that E 2 allele might be associated with concurrent occurrence of EH and ECa.

  20. Association of the Apolipoprotein E 2 Allele with Concurrent Occurrence of Endometrial Hyperplasia and Endometrial Carcinoma

    Directory of Open Access Journals (Sweden)

    Tatiana I. Ivanova

    2015-01-01

    Full Text Available Genes encoding proteins with antioxidant properties may influence susceptibility to endometrial hyperplasia (EH and endometrial carcinoma (ECa. Patients with EH (n = 89, EH concurrent with ECa (n = 76, ECa (n = 186, and healthy controls (n = 1110 were genotyped for five polymorphic variants in the genes involved in metabolism of lipoproteins (APOE Cys112Arg and Arg158Cys, iron (HFE Cys282Tyr and His63Asp, and catecholamines (COMT Val158Met. Patients and controls were matched by ethnicity (all Caucasians, age, body mass index (BMI, and incidence of hypertension and diabetes. The frequency of the APOE E 2 allele (158Cys was higher in patients with EH + ECa than in controls (P = 0.0012, PBonferroni = 0.018, OR = 2.58, 95% CI 1.49–4.45. The APOE E 4 allele (112Arg was more frequently found in patients with EH than in controls and HFE minor allele G (63Asp had a protective effect in the ECa group, though these results appeared to be nonsignificant after correction for multiple comparisons. The results of the study indicate that E 2 allele might be associated with concurrent occurrence of EH and ECa.

  1. Endometrial metaplasia: correlation of histological and cytological specimens obtained from 103 cases undergoing hysterectomy for endometrial carcinoma.

    Science.gov (United States)

    Toomine, Y; Watanabe, S; Ohishi, Y; Tamiya, S; Sugishima, S; Kobayashi, H; Oda, Y; Kaku, T

    2014-04-01

    To assess the frequency of endometrial metaplasia in histological and cytological specimens from the same cases, and to determine the relationship between various types of metaplasia and clinicopathological findings. We reviewed 103 histological specimens diagnosed as endometrioid adenocarcinoma, in which endometrial smears had been obtained before surgery. We examined the correlation between the frequency of endometrial metaplasia occurring in association with carcinoma in both histological and cytological specimens. The categories of metaplasia were eosinophilic metaplasia, squamous metaplasia, mucinous metaplasia, ciliated cell metaplasia and others. We compared the incidence of endometrial metaplasia with the clinicopathological findings for each case. Endometrial metaplasia was recognized in 90 (87.4%) of the histological and 80 (77.7%) of the cytological specimens of 103 specimens, with the respective frequency of subtypes as follows: eosinophilic metaplasia (36.0% and 43.7%), squamous metaplasia (70.9% and 68.0%), mucinous metaplasia (38.8% and 19.4%), ciliated cell metaplasia (22.3% and 2.9%) and others (11.7% and 0%). Mixed subtypes were seen in 58.3% and 41.7% of histological and cytological specimens, respectively. In histology, mucinous metaplasia was significantly more frequent in G1-G2 than G3 carcinomas (P = 0.0089). Ciliated cell metaplasia was significantly related to endometrial hyperplasia (P = 0.0068). In cytology, eosinophilic and mucinous metaplasia were significantly associated with G1-G2 cases (P = 0.0061 and P = 0.0385). Endometrial metaplasia was seen in 87.4% of the histological and 77.7% of the cytological specimens. Where routine endometrial cytopathology is practiced, it is important to understand the detailed histological and cytological features of these changes. © 2013 John Wiley & Sons Ltd.

  2. Estrogen and progesterone receptors in endometrial carcinoma: comparison of immunohistochemical and biochemical analysis

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

    1993-01-01

    In 159 endometrial carcinomas, estrogen (ER) and progesterone receptors (PR) were determined biochemically by dextran-coated charcoal (DCC) assay and immunohistochemically (ICA) on frozen sections. ICA receptor content was estimated by a total histologic score (HSCORE), including all tissue...

  3. Human Endometrial Transcriptomics: Implications for Embryonic Implantation

    Science.gov (United States)

    Gómez, Eva; Ruíz-Alonso, Maria; Miravet, Jose; Simón, Carlos

    2015-01-01

    Human endometrium has been extensively investigated in the search for markers capable of predicting its receptive status. The completion of the Human Genome Project has triggered a rapid development of new fields in molecular biology, the “transcriptomics” being a major turning point in the knowledge acquisition of endometrial receptivity. Based on this, a customized Endometrial Receptivity Array (ERA) has been developed, which is capable of identifying the genomic signature of receptivity. This diagnostic tool showed that the window of implantation (WOI) is displaced in one out of four patients with implantation failure, allowing the identification of their personalized WOI. This strategy allows performing a personalized embryo transfer (pET) on the day in which the endometrium is receptive. The combination of a systems biology approach and next-generation sequencing will overcome the limitations of microarrays, and will, in the future, allow elucidation of the mechanisms involved in embryo implantation. PMID:25818663

  4. Estrogen receptor determination in endometrial carcinoma: ligand binding assay versus enzyme immunoassay

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

    1995-01-01

    We compared concentrations of cytosolic estrogen receptors (ERc) measured in 35 postmenopausal endometrial carcinomas by ligand binding method (LBA) (dextran-coated charcoal assay) and enzyme immunoassay (EIA). Correlations between ERc, nuclear estrogen receptors (ERn) determined by EIA, and cyto......We compared concentrations of cytosolic estrogen receptors (ERc) measured in 35 postmenopausal endometrial carcinomas by ligand binding method (LBA) (dextran-coated charcoal assay) and enzyme immunoassay (EIA). Correlations between ERc, nuclear estrogen receptors (ERn) determined by EIA...

  5. Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Bignotti Eliana

    2012-11-01

    Full Text Available Abstract Background Endometrial cancer is the most common gynecologic malignancy in developed countries. Trop-2 is a glycoprotein involved in cellular signal transduction and is differentially overexpressed relative to normal tissue in a variety of human adenocarcinomas, including endometrioid endometrial carcinomas (EEC. Trop-2 overexpression has been proposed as a marker for biologically aggressive tumor phenotypes. Methods Trop-2 protein expression was quantified using tissue microarrays consisting of formalin-fixed paraffin-embedded specimens from 118 patients who underwent surgical staging from 2001–9 by laparotomy for EEC. Clinicopathologic characteristics including age, stage, grade, lymphovascular space invasion, and medical comorbidities were correlated with immunostaining score. Univariate and multivariate analyses were performed for overall survival, disease-free survival, and progression-free survival in relation to clinical parameters and Trop-2 protein expression. Results Clinical outcome data were available for 103 patients. Strong Trop-2 immunostaining was significantly associated with higher tumor grade (p=0.02 and cervical involvement (p Conclusions Trop-2 protein overexpression is significantly associated with higher tumor grade and serves as an independent prognostic factor for DFS in endometrioid endometrial cancer.

  6. Xenografted tissue models for the study of human endometrial biology.

    Science.gov (United States)

    Kuokkanen, Satu; Zhu, Liyin; Pollard, Jeffrey W

    The human endometrium undergoes extensive morphological, biochemical and molecular changes under the influence of female sex steroid hormones. Besides the fact that estrogen stimulates endometrial cell proliferation and progesterone inhibits this proliferation and induces differentiation, there is limited knowledge about precise molecular mechanisms underlying human endometrial biology. The importance of paracrine signaling in endometrial physiology explains why in vitro culture of endometrial cells has been challenging. Researchers, therefore, have developed alternative experimental in vivo models for the study of endometrial biology. The objective of this review is to summarize the recent developments and work on these in vivo endometrial research models. The in vivo recombinant tissue models in which wild-type endometrial cells are combined with endometrial cells from a gene-targeted mouse strain followed by xenografting to host mice have been critical in confirming the significance of paracrine signaling between the epithelium and stroma in the growth regulation of the endometrium. Additionally, these studies have uncovered differences between the mouse and human, emphasizing the need for the development of experimental models specifically of the human endometrium. Recently, xenotransplants of human endometrial fragments into the subcutaneous space of host mice and endometrial xenografts of dissociated and recombined epithelial and stromal cells beneath the kidney capsule of immunodeficient host mice have proven to be highly promising tools for in vivo research of endometrial functions. For the first time, the latter approach provides an immense opportunity for the application of genome engineering, such as targeted ablation of endometrial genes for example by using CRISPR/CAS9 system. This research will begin to elucidate the functional role of specific genes in this complex tissue. Another advantage of xenotransplantation and xenograft models of the human

  7. Osteopontin Promotes Invasion, Migration and Epithelial-Mesenchymal Transition of Human Endometrial Carcinoma Cell HEC-1A Through AKT and ERK1/2 Signaling

    Directory of Open Access Journals (Sweden)

    Yinghua Li

    2015-10-01

    Full Text Available Background/Aims: Osteopontin (OPN is an Extracellular Matrix (ECM molecule and is involved in many physiologic and pathologic processes, including cell adhesion, angiogenesis and tumor metastasis. OPN is a well-known multifunctional factor involved in various aspects of cancer progression, including endometrial cancer. In this study, we examined the significance of OPN in endometrial cancer. Methods: The proliferation, migration and invasion ability of HEC-1A cells were detected by Cell Counting Kit-8 (CCK-8, Wound scratch assay and transwell. Western blots were employed to detect the expression of Matrix metalloproteinase-2 (MMP-2 and epithelial-mesenchymal transition (EMT-related factors in HEC-1A cells treated with rhOPN. Results: rhOPN promotes cell proliferation, migration and invasion in HEC-1A cells. rhOPN influenced EMT-related factors and MMP-2 expression in HEC-1A cells. rhOPN promoted HEC-1A cells migration, invasion and EMT through protein kinase B (PKB/AKT and Extracellular regulated protein kinases (ERK1/2 signaling pathway. Conclusions: These results may open up a novel therapeutic strategy for endometrial cancer: namely, rhOPN have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.

  8. Liquid-based endometrial cytology associated with curettage in the investigation of endometrial carcinoma in a population of 1987 women.

    Science.gov (United States)

    Yang, Xi; Ma, Ke; Chen, Rui; Zhao, Jian; Wu, Cheng; Zhang, Naiyi; Ma, Xiuhua; Dong, Ying; Zhu, Sainan; Liao, Qinping

    2017-07-01

    The aim of this study was to investigate the diagnostic accuracy of liquid-based endometrial cytology, in comparison with histology. 1987 patients scheduled for hysteroscopy were enrolled in this study. All patients proceeded sequentially through endometrial cytology, hysteroscopy and then dilatation and curettage (D&C). Cytology sampling was performed by brushing the uterus cavity using SAP-1 and the sample was prepared to liquid-based smear using SurePath technology. The slides were stained by Papanicolaou method. All cytological diagnosis was correlated with the D&C histological diagnosis. Cyto-histological correlations were possible in 1672 (89.3%) patients: in 254 (12.8%) patients the D&C was inadequate, in 75 (3.8%) patients the cytology was inadequate, and in 14 (0.7%) patients both were inadequate. In postmenopausal women, 758 of 790 cytologies (96.0%) were adequate, while 586 of 790 histologies (74.2%) were adequate. SAP-1 provided more sufficient materials for cytology than D&C for histology (P endometrial cytology was 86.1%, sensitivity was estimated at 70.3%, specificity at 88.5%, positive predictive value at 48.0% and negative predictive value at 95.2%. Taking endometrial carcinoma as a positive result, the diagnostic accuracy of liquid-based endometrial cytology was 94.4%; sensitivity was estimated at 53.2%, specificity at 98.6%, positive predictive value at 79.8% and negative predictive value at 95.3%. Liquid-based endometrial cytology can be considered a useful method for detecting of endometrial pathology as a first-line approach.

  9. Long-Term Outcome and Quality of Life of Patients With Endometrial Carcinoma Treated With or Without Pelvic Radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) Trial

    NARCIS (Netherlands)

    Nout, Remi A.; van de Poll-Franse, Lonneke V.; Lybeert, Marnix L. M.; Warlam-Rodenhuis, Carla C.; Jobsen, Jan J.; Mens, Jan Willem M.; Lutgens, Ludy C. H. W.; Pras, Betty; van Putten, Wim L. J.; Creutzberg, Carien L.

    2011-01-01

    Purpose To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial. Patients and Methods Between 1990 and

  10. KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation.

    Science.gov (United States)

    Ikenberg, Kristian; Valtcheva, Nadejda; Brandt, Simone; Zhong, Qing; Wong, Christine E; Noske, Aurelia; Rechsteiner, Markus; Rueschoff, Jan H; Caduff, Rosmarie; Dellas, Athanassios; Obermann, Ellen; Fink, Daniel; Fuchs, Thomas; Krek, Wilhelm; Moch, Holger; Frew, Ian J; Wild, Peter J

    2014-10-01

    Endometrial cancer is the most frequently occurring malignancy of the female genital tract in Western countries. Although in many cases surgically curable, about 30% of the tumours represent an aggressive and untreatable disease. In an attempt to establish a reliable prognostic marker for endometrial carcinomas disregarding their histological diversity, we investigated the expression of KPNA2, a mediator of nucleocytoplasmic transport, and other cell proliferation-associated proteins and their correlation with cancer progression. We analysed patient tissue microarrays (TMAs) assembled from 527 endometrial cancer tissue specimens and uterus samples from a Trp53 knockout mouse model of endometrial cancer. Our data show that KPNA2 expression was significantly up-regulated in human endometrial carcinomas and associated with higher tumour grade (p = 0.026), higher FIGO stage (p = 0.027), p53 overexpression (p endometrial cancer subtype was detected. In the mouse model, KPNA2 showed increased expression levels from precancerous (EmgD, EIC) to far-advanced invasive lesions. We further investigated the cell proliferation capacity after siRNA-mediated KPNA2 knockdown in the human endometrial cancer cell line MFE-296. KPNA2 silencing led to decreased proliferation of the cancer cells, suggesting interplay of the protein with the cell cycle. Taken together, increased expression of KPNA2 is an independent prognostic marker for poor survival. The mechanism of enhanced nucleocytoplasmic transport by KPNA2 overexpression seems a common event in aggressive cancers since we have shown a significant correlation of KPNA2 expression and tumour aggressiveness in a large variety of other solid tumour entities. Introducing KPNA2 immunohistochemistry in routine diagnostics may allow for the identification of patients who need more aggressive treatment regimens. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  11. Human Endometrial CD98 Is Essential for Blastocyst Adhesion

    Science.gov (United States)

    Domínguez, Francisco; Simón, Carlos; Quiñonero, Alicia; Ramírez, Miguel Ángel; González-Muñoz, Elena; Burghardt, Hans; Cervero, Ana; Martínez, Sebastián; Pellicer, Antonio; Palacín, Manuel; Sánchez-Madrid, Francisco; Yáñez-Mó, María

    2010-01-01

    Background Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. Methods and Principal Findings Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. Conclusions These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window. PMID:20976164

  12. Human endometrial CD98 is essential for blastocyst adhesion.

    Directory of Open Access Journals (Sweden)

    Francisco Domínguez

    Full Text Available BACKGROUND: Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. METHODS AND PRINCIPAL FINDINGS: Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. CONCLUSIONS: These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window.

  13. Human papillomavirus effect on the development of endometrial polyps.

    Science.gov (United States)

    Korucuoglu, U; Guler, I; Dogan, H; Biri, A

    2015-01-01

    Although the association of human papillomavirus (HPV) with warts arising in different parts of the human body has been well-demonstrated, the association of HPV with endometrial polyps has never been studied in the literature up to now. Detection of the HPV DNA was carried out by using 13 high-risk HPV real-time PCR Kit and five low-risk HPV real-time PCR Kit. Among 50 endometrial polyp samples, one endometrial polyp sample revealed a positive result for the presence of HPV type 18. This first study in the medical literature investigating the possible effect of HPV on the development of endometrial polyps has demonstrated that HPV might have a role in the development of some of the endometrial polyps. If the present authors' hypothesis that endometrial polyps caused by carcinogenic HPV types are prone to proceed to endometrial cancer if left untreated is correct, HPV vaccine has a potential to prevent development of at least some of the endometrial polyps and endometrial cancers.

  14. Gene expression changes after ionizing radiation in endothelial cells derived from human endometrial cancer-preliminary outcomes.

    Science.gov (United States)

    Liu, Ting; Du, Xuelian; Sheng, Xiugui

    2014-06-01

    Accumulating evidence has demonstrated that death of microvascular endothelial cells plays a decisive role in the tumor response against radiotherapy. Nevertheless, radiation-induced gene alterations on cancer-associated endothelial cells of human endometrial carcinoma remain poorly understood. The purpose of this study was to elucidate the gene expression changes after X-ray radiation in human endometrial carcinoma vascular endothelial cells and to provide new targets for combined treatment of radiation and anti-angiogenesis in human endometrial carcinoma. Endometrial cancer-derived endothelial cells, which obtained before and 4 h after 400 cGy X-ray radiation from four endometrial carcinomas, were analyzed by gene expression profile. The selected meaningful genes from gene microarray experiments were validated by real-time quantitative PCR. Microarray analyses showed 49 significantly changed genes which were common to all the microarray experiments. There into, 14 genes were found to be in persistent up-regulation and 14 in persistent down-regulation 4 h after X-ray radiation when compared with the control group. These genes were involved in cell cycle and growth regulation, cell-apoptosis, chemokine, cell signaling, cellular stress response, angiogenesis, DNA synthesis and repair and cell adhesion. Eight randomly selected genes were validated by real-time PCR. The genes of cancer-derived endothelial cells regulated by X-ray radiation as well as their related signal pathways, which obtained from gene expression profiling data, were relevant to radiosensitivity of endometrial cancer. This study shows that the identified genes and their related signaling pathways are candidated biomarkers for radiation and anti-angiogenesis of human endometrial carcinoma.

  15. The evolution of endometrial carcinoma classification through application of immunohistochemistry and molecular diagnostics: past, present and future.

    Science.gov (United States)

    Goebel, Emily A; Vidal, August; Matias-Guiu, Xavier; Blake Gilks, C

    2017-12-12

    Uterine cancer was first subclassified based on anatomic site, separating those tumours arising from the endometrium from cervical cancers. There was then further subclassification of endometrial cancers based on cell type, and this correlated with the Type I and Type II categories identified through the epidemiological studies of Bokhman, with endometrioid carcinoma corresponding (approximately) to Type I and serous carcinoma to Type II. These histotypes are not clearly separable in practice, however, with considerable interobserver variability in histotype diagnosis, especially for high-grade tumours. There followed studies of immunomarkers and then mutational studies of single genes, in attempts to improve subclassification. While these have revealed significant differences in protein expression and mutation profiles between endometrioid and serous carcinomas, there is also considerable overlap, so that there remain challenges in subclassification of endometrial carcinoma. Gene panel testing, using next-generation sequencing, was applied to endometrial cancers and highlighted that there are tumours that show genetic alterations intermediate between classic Type I/endometrioid and Type II/serous carcinomas. The Cancer Genome Atlas studies of endometrioid and serous carcinoma offered revolutionary insight into the subclassification of endometrial carcinoma, i.e. that there are four distinct categories of endometrial carcinoma, rather than two, based on genomic architecture. In this review, we provide an overview of immunohistochemical and molecular markers in endometrial carcinoma and comment on the important future directions in endometrial carcinoma subclassification arising from The Cancer Genome Atlas results.

  16. Endometrioid Endometrial Carcinoma Indirectly Caused by Pituitary Prolactinoma:A Case Report

    Directory of Open Access Journals (Sweden)

    Kimihiro Nishino

    2013-01-01

    Full Text Available We present the case of a 44-year-old nulliparous woman who experienced irregular menstrual cycles for about 10 years and developed both pituitary prolactinoma and endometrioid endometrial carcinoma. In premenopausal women, hyperprolactinemia causes hypogonadism by inhibiting secretion of gonadotropin-releasing hormone and thus suppressing luteinizing hormone levels, which can cause menstrual disorders ranging from amenorrhea, oligomenorrhea and chronic anovulatory cycle to short luteal phase of the menstrual cycle. A chronic anovulatory menstrual cycle is the most common cause of long-term exposure of the endometrium to endogenous estrogen without adequate opposition from progestins, which can lead to endometrioid endometrial carcinoma. In this case, pituitary prolactinoma may have caused the chronic anovulatory cycle and indirectly led to the endometrioid endometrial carcinoma. In patients for whom the cause of irregular menstruation and chronic anovulatory cycle is suspected to be hyperprolactinemia, explorations of both the hypophysis and endometrium are essential.

  17. Adult granulosa cell tumor associated with endometrial carcinoma: a case report

    Directory of Open Access Journals (Sweden)

    Eke Ahizechukwu C

    2011-08-01

    Full Text Available Abstract Introduction If strict criteria for the diagnosis of carcinoma are used and all patients with granulosa cell tumors are considered, the best estimate of the incidence of associated endometrial carcinomas is under 5%. In patients with granulosa cell tumors, estrogen-dependent endometrial cancers are rarely found, and most of these endometrial cancers are well-differentiated endometrioid adenocarcinomas that carry a good prognosis when detected early. Case presentation We report the case of a 65-year-old post-menopausal Nigerian woman of the Igbo tribe with an adult granulosa cell tumor that was initially treated as endometrial carcinoma. She underwent a total abdominal hysterectomy and a bilateral salpingo-oophorectomy after histopathologic confirmation of a well-differentiated granulosa cell tumor of the ovary and a nuclear grade 1 adenocarcinoma of the endometrium (International Federation of Obstetricians and Gynecologists stage 1B. She had a good post-operative recovery and was discharged 10 days after treatment. Conclusion The association between adult granulosa cell tumors of the ovary and endometrial carcinomas is rare. A high index of suspicion as well as good imaging and histopathologic analyses are important in making this diagnosis.

  18. Adult granulosa cell tumor associated with endometrial carcinoma: a case report.

    Science.gov (United States)

    Ukah, Cornelius O; Ikpeze, Okechukwu C; Eleje, George U; Eke, Ahizechukwu C

    2011-08-02

    If strict criteria for the diagnosis of carcinoma are used and all patients with granulosa cell tumors are considered, the best estimate of the incidence of associated endometrial carcinomas is under 5%. In patients with granulosa cell tumors, estrogen-dependent endometrial cancers are rarely found, and most of these endometrial cancers are well-differentiated endometrioid adenocarcinomas that carry a good prognosis when detected early. We report the case of a 65-year-old post-menopausal Nigerian woman of the Igbo tribe with an adult granulosa cell tumor that was initially treated as endometrial carcinoma. She underwent a total abdominal hysterectomy and a bilateral salpingo-oophorectomy after histopathologic confirmation of a well-differentiated granulosa cell tumor of the ovary and a nuclear grade 1 adenocarcinoma of the endometrium (International Federation of Obstetricians and Gynecologists stage 1B). She had a good post-operative recovery and was discharged 10 days after treatment. The association between adult granulosa cell tumors of the ovary and endometrial carcinomas is rare. A high index of suspicion as well as good imaging and histopathologic analyses are important in making this diagnosis.

  19. Benzotriazole Enhances Cell Invasive Potency in Endometrial Carcinoma Through CTBP1-Mediated Epithelial-Mesenchymal Transition

    Directory of Open Access Journals (Sweden)

    Yiquan Wang

    2017-12-01

    Full Text Available Background/Aims: Benzotriazole (BTR and its derivatives, such as intermediates and UV stabilizers, are important man-made organic chemicals found in everyday life that have been recently identified as environmental toxins and a threat to female reproductive health. Previous studies have shown that BTR could act as a carcinogen by mimicking estrogen. Environmental estrogen mimics could promote the initiation and development of female cancers, such as endometrial carcinoma, a type of estrogenic-sensitive malignancy. However, there is little information on the relationship between BTR and endometrial carcinoma. In this study, we aimed to demonstrate the biological function of BTR in endometrial carcinoma and explored the underlying mechanism. Methods: The CCK-8 assay was performed to detect cell viability; transwell-filter assay was used to assess cell invasion; gene microarray analysis was employed to determine gene expression patterns in response to BTR treatment; western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR were carried out to detect the expression levels of BTR-related genes. Results: Our data showed that BTR could induce the invasion and migration of endometrial carcinoma cells (Ishikawa and HEC-1-B. In addition, BTR increased the expression level of CTBP1, which could enhance the epithelial-mesenchymal transition (EMT in cancer cells. Moreover, CTBP1 silencing reversed the effect of BTR on EMT progression in endometrial carcinoma cells. Conclusion: This study indicates that BTR could act as a carcinogen to promote the development of endometrial carcinoma mainly through CTBP1-mediated EMT, which deserves more attention.

  20. Endometrial carcinoma located in the right septate uterus cavity: a ...

    African Journals Online (AJOL)

    Endometrial cancer in patients with uterine congenital malformations is exceptional and there are only a few rare cases published in the literature. We report the case of a 67 years-old patient with an endometrial cancer located in the right cavity of a complete septate uterus. Pan African Medical Journal 2015; 22 ...

  1. Concurrent Endometrial Carcinosarcoma and Thyroid Papillary Carcinoma: PET CT Imaging Findings

    Directory of Open Access Journals (Sweden)

    Mine Genc

    2015-06-01

    Full Text Available The aim of this study is to report a patient who was diagnosed with a concurrent primary tumor by 18-fluoro-2-deoxy-glucose positron emission tomography (FDG PET imaging performed for staging of an endometrial cancer. FDG uptake was detected in the uterus, where the primary cancer was located, and in the left lobe of the thyroid gland. The biopsy sample from the hypermetabolic nodular lesion in thyroid gland revealed intermediate cytology according to Bethesda Classification. The patient underwent hysterectomy and thyroidectomy. An endometrial carcinoma in the uterus and a multicentric thyroid papillary carcinoma in the thyroid gland were diagnosed.

  2. Cyclin D1 is significantly associated with stage of tumor and predicts poor survival in endometrial carcinoma patients.

    Science.gov (United States)

    Khabaz, Mohamad Nidal; Abdelrahman, Amer Shafie; Butt, Nadeem Shafique; Al-Maghrabi, Basim; Al-Maghrabi, Jaudah

    2017-10-01

    Cyclin D1 overexpression has been described to have oncogenic role and association with diagnosis, prognosis and survival in various tumors. This study will describe the immunohistochemical phenotype of cyclin D1, and investigate the correlation between these patterns of expression and clinicopathological parameters of endometrial carcinomas, to conclude the clinical relevance of cyclin D1 expression in the evolution of endometrial neoplasms. This study employed 101 endometrial tissue samples which include 71 endometrial carcinomas and thirty normal and benign endometrium cases. All these tissue samples were used in the assembly of tissue microarrays which have been utilized afterward in immunohistochemistry staining to detect cyclin D1 expression. Forty (56.3%) cases of endometrial carcinomas showed brown nuclear expression of cyclin D1 including 36 (61%) cases of endometrioid carcinomas, and 3 (33.3%) cases of serous carcinomas. Twenty three (76.6%) cases of control group demonstrated nuclear expression. High score cyclin D1 immunohistochemical staining has been significantly linked with patient age (P=0.0001). Large proportion of high score cyclin D1 immunohistochemical staining was observed in females who are endometrial tissues in comparison with carcinomas. The distribution pattern of cyclin D1 immunoexpression suggests poor prognoses in endometrial carcinoma patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Benign Endometrial Polyp and Primary Endometrial Small Cell Neuroendocrine Carcinoma Confined to the Polyp: A Rare Association

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    Pembe Oltulu

    2016-03-01

    Full Text Available Neuroendocrine tumors (NETs are a heterogeneous group of tumoral lesions originating from diffuse endo­crine system cells. They occur mostly in the gastrointes­tinal system and the lung. Primary NETs of the female reproductive tract are rare. In a widely used classification, primary small cell neuroendocrine carcinomas (SCNECs and large cell neuroendocrine carcinomas (LCNECs of the endometrium were included in a subgroup of poorly differentiated neuroendocrine carcinomas. SCNECs of the endometrium are very rare and they are often com­bined with other epithelial neoplasms. Their myometrial and extrauterine invasions are common during the initial diagnosis due to their aggressive behaviors. In this ar­ticle, we present a rare case of primary endometrial SC­NEC detected within the benign endometrial polyp and without invasion of myometrium and extrauterine tissues in a 70-year-old female patient presenting with post­menopausal bleeding. Histopathologically, the tumor cells showed positive staining with Synaptophysin, the Ki-67 labeling index was 80-90%, the mitotic index was 15/10 per HPF and there was no necrosis and lymphovascular invasion. J Clin Exp Invest 2016; 7 (1: 107-110

  4. Identification of HSPA8 as a candidate biomarker for endometrial carcinoma by using iTRAQ-based proteomic analysis

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    Shan N

    2016-04-01

    Full Text Available Nianchun Shan,1 Wei Zhou,2 Shufen Zhang,1 Yu Zhang1 1Department of Obstetric and Gynecology, 2Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China Abstract: Although there are advances in diagnostic, predictive, and therapeutic strategies, discovering protein biomarker for early detection is required for improving the survival rate of the patients with endometrial carcinoma. In this study, we identify proteins that are differentially expressed between the Stage I endometrial carcinoma and the normal pericarcinous tissues by using isobaric tags for relative and absolute quantitation (iTRAQ-based proteomic analysis. Totally, we screened 1,266 proteins. Among them, 103 proteins were significantly overexpressed, and 30 were significantly downexpressed in endometrial carcinoma. Using the bioinformatics analysis, we identified a list of proteins that might be closely associated with endometrial carcinoma, including CCT7, HSPA8, PCBP2, LONP1, PFN1, and EEF2. We validated the gene overexpression of these molecules in the endometrial carcinoma tissues and found that HSPA8 was most significantly upregulated. We further validated the overexpression of HSPA8 by using immunoblot analysis. Then, HSPA8 siRNA was transferred into the endometrial cancer cells RL-95-2 and HEC-1B. The depletion of HSPA8 siRNAs significantly reduced cell proliferation, promoted cell apoptosis, and suppressed cell growth in both cell lines. Taken together, HSPA8 plays a vital role in the development of endometrial carcinoma. HSPA8 is a candidate biomarker for early diagnosis and therapy of Stage I endometrial carcinoma. Keywords: iTRAQ, HSPA8, endometrial carcinoma, RL-95-2 cells

  5. Expressions and clinical significance of COX-2, VEGF-C, and EFGR in endometrial carcinoma.

    Science.gov (United States)

    Cai, Shengnan; Zhang, Yue-Xiang; Han, Ke; Ding, Yi-Qian

    2017-07-01

    The article is to study the expressions of COX-2, VEGF-C, and EGFR in endometrial carcinoma as well as its clinical significances. Clinical data of 183 patients with endometrial carcinoma who received surgery as initial treatment in the Nanjing Drum Tower Hospital Affiliated to the Nanjing University Medical School and the Nantong Maternal and Child Health Hospital Affiliated to the Nantong University from January 2005 to December 2010 were retrospectively investigated; 152 out of the 183 patients were closely followed up. Expressions of COX-2, VEGF-C, and EGFR proteins in 152 endometrial carcinoma samples were detected by immunohistochemical S-P assay. A 5-year survival rate of 152 patients was 81.56% (124/152). Positive COX-2 expression rate was 67.76% (103/152), and its positive expression was related to FIGO stage, differentiation degree, and myometrial invasion depth of patients (P  0.05). Positive expression rates of VEGF-C and EGFR were 64.47% (98/152) and 82.24% (125/152), respectively, and their positive expression was associated with FIGO stage, differentiation degree, myometrial invasion depth, and lymphatic metastasis (P  0). Patient prognosis was associated with the FIGO stage, differentiation degree, and myometrial invasion depth of tumors, as well as the presence or absence of lymph node metastasis (P  0.05). COX-2, VEGF-C, and EGFR are of significance for determining the FIGO stage, differentiation degree, and myometrial invasion depth of endometrial carcinoma, of which VEGF-C and EGFR are important in determining whether tumors metastasize to lymph nodes. Combined detection of COX-2, EGFR, and VEGF-C can be used as the indices for early diagnosis, recurrence prediction, and outcome evaluation for patients with endometrial carcinoma.

  6. Fertility preservation in young women with endometrial carcinoma; report of three cases

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    Mousavi A.S

    2007-06-01

    Full Text Available Background: Although endometrial cancer is primarily a disease of the postmenopausal female, 25% of patients are premenopausal, with 3-5% in women 40 years old or younger. The younger group of women with endometrial carcinoma are frequently nulligravid with a history of infertility, and a strong desire to preserve fertility. This may pose a therapeutic dilemma for both patients and treating physician. Case report: We reported 3 young patients with atypical; complex hyperplasia or early stage endometrial cancer that treated with conservative hormonal therapy. Conclusion: Medical treatment of young patients with endometrial carcinoma and complex atypical hyperplasia who wish to preserve fertility is a reasonable and appealing option. A comprehensive evaluation prior to counseling the patient should include A complete history and physical examination. A formal D&C with review of history with an experienced gyn-onc pathologist. Evaluation of the pelvic and abdomen preferably with contrast-enhanced MRI or transvaginal ultrasound. In patients found to have a clinical stage I grade I tumor and who want to preserve fertility , thorough counseling include risks and benefits, and explanation that the data is partial and incomplete due to the lack of appropriate controlled studies is mandatory. In patients considered for medical treatment, a high dose progestin regimen should be started with endometrial sampling every 3 months until complete regression of the tumor is documented. Although most responses are long standing, there is a small risk of progression during or after cessation of progestin therapy.

  7. Fractal Dimension as a Diagnostic Tool of Complex Endometrial Hyperplasia and Well-differentiated Endometrioid Carcinoma.

    Science.gov (United States)

    Bikou, Olga; Delides, Alexander; Drougou, Aggeliki; Nonni, Afroditi; Patsouris, Efstratios; Pavlakis, Kitty

    Fractal dimension (FD) is widely used in medicine and biology as a tool for defining features of structure. This study aimed to compare pathological endometrium (simple-complex hyperplasia and endometrial carcinoma), as well as the endometrial changes, during the phases of the menstrual cycle. The main goal was the objective measurement of fractal dimension and to refrain from subjective evaluation. Two thousand cases of endometrial tissue from patients who underwent dilatation and curettage (D&C) were reviewed. Out of these, 137 cases were eligible for the study. In each case, immunohistochemistry with cytokeratin Ae1/AE3 was performed in order to simplify the evaluation of the FD. Endometria with carcinoma, simple or complex hyperplasia showed significant differences only in the immunohistochemically stained fractal dimensions. As expected, significant differences were also found between atrophic and secretory endometrium and carcinoma. FD is an objective, rapid and simple procedure for the differential diagnosis between complex hyperplasia and endometrial adenocarcinoma. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  8. Synchronous Endometrial and Ovarian Carcinoma: A Case Series

    Science.gov (United States)

    Makris, Georgios-Marios; Manousopoulou, Georgia; Battista, Marco-Johannes; Salloum, Ioannis; Chrelias, Georgios; Chrelias, Charalampos

    2017-01-01

    Synchronous ovarian and endometrial cancer (SEOC) is a rare instance but it accounts for 50–70% of all synchronous female genital tract tumors. We report three cases of women who were diagnosed with SEOC and underwent surgical staging. All cases were of the endometrioid subtype, grade 1, both in the ovarian and endometrial component. Two of them were stage Ia/Ia, and the third was stage Ib/Ib. More than 2 years after the diagnosis, all patients were alive and recurrence-free. The present report critically discusses the main characteristics, risk factors, and management of patients with SEOCs. PMID:28878658

  9. Synchronous Endometrial and Ovarian Carcinoma: A Case Series

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    Georgios-Marios Makris

    2017-08-01

    Full Text Available Synchronous ovarian and endometrial cancer (SEOC is a rare instance but it accounts for 50–70% of all synchronous female genital tract tumors. We report three cases of women who were diagnosed with SEOC and underwent surgical staging. All cases were of the endometrioid subtype, grade 1, both in the ovarian and endometrial component. Two of them were stage Ia/Ia, and the third was stage Ib/Ib. More than 2 years after the diagnosis, all patients were alive and recurrence-free. The present report critically discusses the main characteristics, risk factors, and management of patients with SEOCs.

  10. Sensitivity of endometrial cancer cells from primary human tumor samples to new potential anticancer peptide lactaptin.

    Science.gov (United States)

    Koval, Olga A; Sakaeva, Galiya R; Fomin, Alexander S; Nushtaeva, Anna A; Semenov, Dmitry V; Kuligina, Elena V; Gulyaeva, Ludmila F; Gerasimov, Alexey V; Richter, Vladimir A

    2015-01-01

    Endometrial carcinoma is the most common gynecologic malignancy which is associated with a poor prognosis when diagnosed at an advanced stage; therefore, the discovery of efficacious new drugs is required to reinforce conventional chemotherapy. Short-term cultures of primary cells from endometrial tumors could be used for testing new anticancer therapeutics as well as for the development of personalized cancer therapy strategy. Here, the antitumor effect of a recombinant analogue of lactaptin (RL2), a new potential anticancer molecule, was examined against primary human endometrial cancer cells. Primary cell cultures of malignant and normal human endometrium were performed by enzymatic digestion of endometrial tissue from biopsy material. Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the messenger ribonucleic acid (mRNA) state of estrogen (ERs) and progesterone (PRs) hormone receptors and aromatase (Cyp 19) in cell cultures. Dynamic monitoring of cell adhesion and proliferation was made using the iCELLigence system (ASEA Biosciences). The sensitivity of cell cultures to conventional anticancer drugs and the lactaptin analog was estimated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, flow cytometry, and the iCELLligence system. Established short-term primary cultures of endometrial cancer cells were ERα/ERβ/PR-positive and sensitive for RL2. The IC 50 values of doxorubicin and cisplatin were determined for all of the primary cultures designed. KE normal cells displaying low Cyp19 mRNA levels and high ERβ and PR mRNA levels were more resistant to RL2 treatment as well as to cisplatin and doxorubicin. Our results indicate that the recombinant analog of lactaptin, RL2, exerts cytotoxic effects against primary hormone-dependent endometrial tumor cells in vitro with features of apoptosis.

  11. The role of human epididymis secretory protein E4 in patients with endometrial cancer and premalignant endometrial lesions.

    Science.gov (United States)

    Yılmaz, Setenay Arzu; Altınkaya, Sündüz Özlem; Kerimoglu, Özlem Seçilmiş; Tazegül Pekin, Aybike; Akyürek, Fikret; Ilhan, Tolgay Tuyan; Benzer, Nilgün; Unlu, Ali; Yuksel, Hasan; Celik, Cetin

    2017-01-01

    We evaluated the concentrations of human epididymis secretory protein E4 (HE4) and Ca-125 in relation to clinicopathologic features in patients with endometrial cancer and premalignant endometrial lesions. Women with abnormal uterine bleeding (n = 167) who underwent endometrial sampling were divided into four groups. Group 1: endometrial cancer (n = 68), group 2: atypical endometrial hyperplasia (n = 12), group 3: endometrial hyperplasia without atypia (n = 39) and group 4: controls (n = 48). Women with endometrial cancer exhibited higher concentrations of HE4 levels than controls (91.4 pmol/L vs. 46.2 pmol/L, p endometrial cancer were 72.7%, 84.4%, 80% and 78.4%, respectively. Preoperative HE4 levels are more elevated in women with endometrial cancer than those with benign endometrium as well as in women with prognostic high-risk factors with endometrial cancer. HE4 may be used as an additional marker in combination with other clinicopathologic features for planning the treatment.

  12. Effective Selection of a Well-Differentiated Type of Human Uterine Endometrial Carcinoma Cells by Transfection of the Sulfotransferase Gene and Possible Association of Sulfoglycolipids With Well-Differentiated Phenotypes.

    Science.gov (United States)

    Tanaka, Kyoko; Ishiwata, Isamu; Kubushiro, Kaneyuki; Mikami, Mikio; Aoki, Daisuke; Kiguchi, Kazushige; Iwamori, Masao

    2017-02-01

    Sulfatide has been shown to be characteristically increased on the apical surface of the normal endometrium at the secretory phase, and to be related with the formation of the glandular structure and the secretion of mucin from glands for the implantation of a fertilized egg. Additionally, sulfatides are expressed in the well-differentiated type, but not in the poorly differentiated type, of endometrial carcinomas. This suggests that sulfatides are a molecular marker of differentiated phenotypes. To further elucidate the biological significance of sulfoglycolipids, we transfected the sulfotransferase gene into endometrial carcinoma-derived cells without sulfoglycolipids and compared their glycolipid compositions and phenotypes with those of the original cells. The glycolipid sulfotransferase gene was transfected into endometrial carcinoma-derived SNG-II cells, the resultant transfected cells being found to frequently form a domelike structure, and some of them were selected as SNG-II-GST cells. We compared the glycolipid compositions and phenotypes of SNG-II and SNG-II-GST cells. Although the original SNG-II cells grew in a paving stone pattern, SNG-II-GST cells formed a domelike structure. SNG-II-GST cells exhibited high GST activity and contained sulfoglycolipids, IISO3-LacCer and IISO3-Gg3Cer, which were not found in SNG-II cells. The amounts of sulfoglycolipids in SNG-II-GST cells were 1.5 times higher than those of gangliosides, and the proportions of LacCer and GM3 in SNG-II-GST cells were greatly different from those in SNG-II cells. SNG-II and SNG-II GST cells exhibited poorly differentiated and well-differentiated phenotypes on histochemical examination of cancerous nodules in nude mice. However, by means of an oxygen electrode, SNG-II-GST cells were found to be more resistant to anticancer drugs than SNG-II cells. Enhanced expression of sulfoglycolipids in poorly differentiated cells is a feasible means of selecting well-differentiated ones, and

  13. Progestogenic effects of tibolone on human endometrial cancer cells

    OpenAIRE

    Blok, Leen; Ruiter, Petra; Kuhne, E.C.; Hanekamp, Eline; Grootegoed, Anton; Smid-Koopman, Ellen; Gielen, Susanne; Gooyer, M.E.; Kloosterboer, Helenius; Burger, Curt

    2003-01-01

    textabstractTibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a Delta(4) isomer (exerting progestogenic and androgenic effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3 alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In the present study an endometrial carcinoma cell line (Ishikawa PRAB-36) was used to investigate the progestogenic properties of tibolone a...

  14. ASPECTS OF SURGERY IN OVARIAN AND ENDOMETRIAL CARCINOMA

    NARCIS (Netherlands)

    AALDERS, JG; NEIJT, JP

    1993-01-01

    In ovarian cancer and endometrial cancer the surgeon plays an important role in both the staging procedure and in the removal of as much of the tumour as possible. Although uniform treatment policies have not been developed, a better understanding of the pattern of spread in both tumours allows for

  15. A case of endometrial carcinoma with age related hyperkyphosis treated with definitive radiotherapy

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    Arvind S Murthy

    2015-03-01

    Full Text Available This report describes a simple brachytherapy procedure in a patient with endometrial cancer with age related hyperkyphosis.  Sixty-eight year-old postmenopausal woman with age related hyperkyphosis presented with endometrial carcinoma, and the patient was not operated on due to associated pelvic deformity. The patient received whole pelvic radiation followed by uterovaginal brachytherapy. Patient was supported with soft pillows to support her exaggerated anterior concavity during brachytherapy procedure and execution. The brachytherapy dose was 6 Gy per fraction per week for 3 weeks using image guidance. This is probably the first reported case of endometrial cancer with age related hyperkyphosis. In spite of the associated skeletal problems, a simple brachytherapy procedure is possible and provides good result. 

  16. Controversies in the Treatment of Early Stage Endometrial Carcinoma

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    Joshua Z. Press

    2012-01-01

    Full Text Available Despite the publication of numerous studies, including some multicentered randomized controlled trials, there continues to be vigorous debate regarding the optimal management of early stage endometrial cancer, including the extent of surgery and the role of adjuvant chemotherapy and radiation. Resolving these questions has become increasingly important in view of the increase of endometrial cancer, related to the aging population and the alarming incidence of obesity. Furthermore, there are more surgical challenges encountered when operating on elderly patients or on patients with increased BMI and the associated comorbidities, such as diabetes, hypertension, heart disease, and pulmonary dysfunction. This paper will focus on the advantages of minimally invasive surgery, the value of lymphadenectomy including sentinel lymph node mapping, and some of the current controversies surrounding adjuvant chemotherapy and radiation.

  17. Surgery for early stage endometrial carcinoma in the obese patient

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    E Leblanc

    2016-01-01

    Full Text Available Obese patients have increased risk of developing endometrial cancer proportional to the excess in body mass index. In this review, we explored the latest information on surgical management and its adaptation to the obese condition. Mini-invasive treatments (laparoscopic, robotic, vaginal, or combinations should be systematically considered. Prevention and active treatment of obesity seem an interesting approach to reduce incidence and severity of the disease.

  18. The relationship of cerb B 2 expression with estrogen receptor and progesterone receptor and prognostic parameters in endometrial carcinomas

    Directory of Open Access Journals (Sweden)

    Kandemir Nilufer

    2010-02-01

    Full Text Available Abstract Background Endometrial carcinoma (EC is the most common malignancy of the female genital tract. Gene alterations and overexpression of various oncogenes are important in tumor development. The human HER 2 neu (c-erbB-2 gene product is a transmembrane receptor with an intracellular tyrosine kinase that plays an important role in coordinating the endometrial growth factor receptor signaling network. The aim of this study was to investigate the expression of c-erbB-2 in endometrial cancer, to study its correlation to established prognostic parameters and estrogen receptor (ER and progesterone receptor (PR status. Methods Immunohistochemical (IHC analyses of ER, PR and c-erbB-2 were performed in 72 EC cases. Results We detected a positive staining with c erbB 2 in 18.1% of the cases and determined a statistically significant relation between c-erbB-2 and PR. We could not find a statistically significant relation between c-erbB-2 staining and ER. There was not a statistically significant difference between c-erbB-2 and histological grade. The highest level of c-erbB-2 was found in grade 2 cases. There was not any statistically significant relation between c-erbB-2 and menstrual status, myometrial invasion, lymph node status, stage and survival. Conclusions Although our study provides additional evidence of the potential prognostic role of c-erbB-2, further prospective and controlled studies are required to validate their clinical usefulness.

  19. Human Endometrial Adenocarcinoma Transplanted into Nude Mice: Growth Regulation by Estradiol

    Science.gov (United States)

    Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R.

    1983-01-01

    A model for studying the growth of primary tumors of human endometrium and its regulation by 17β -estradiol has been developed in which ovariectomized nude mice are used as recipients. The receptors for sex steroids are maintained during serial transplantation of the tumor in this system. Although the rate of growth of receptor-negative endometrial tumors transplanted into ovariectomized nude mice is unaffected by the sustained presence or absence of estradiol, the growth of receptor-positive tumors is significantly increased by estradiol. Receptor-positive tumors treated with estradiol produced elevated concentrations of progesterone receptor. That the progesterone receptor is functional in this tumor is evident from the induction of estradiol 17β -dehydrogenase activity upon progestin administration. These findings are consistent with receptor-mediated regulation of growth of endometrial carcinoma.

  20. Disseminated tumor cells are not associated with established risk factors, L1CAM immunoreactivity and outcome in endometrial carcinoma.

    Science.gov (United States)

    Kommoss, Stefan; Hartkopf, Andreas D; Krämer, Bernhard; Bunz, Anne-Kathrin; Grevenkamp, Friederike; Kommoss, Felix; Pasternak, Jana; Arbabi, Sabine M; Wallwiener, Markus; Staebler, Annette; Lax, Sigurd F; Brucker, Sara Y; Taran, Florin-Andrei

    2017-11-01

    The presence of disseminated tumor cells (DTC) in the bone marrow of endometrial carcinoma patients has been demonstrated previously. In contrast to breast cancer, no prognostic significance or association with clinicopathological features was revealed for endometrial carcinoma so far. The aim of this study was to investigate DTC in a large patient cohort with in-depth pathology review data available and to study DTC occurrence in the context of L1CAM and long-term disease specific follow-up. Patients treated for endometrial carcinoma at the Tuebingen University Women's hospital between 2003 and 2013 were identified. Cases with previous expert central pathology review including L1CAM immunohistochemistry and bone marrow aspirates available were selected. The presence of DTC and L1CAM expression was studied immunohistochemically. In 395 cases with a confirmed diagnosis of endometrial carcinoma, bone marrow aspirates were available. DTC were detected in 17.2%. The presence of DTC was independent from tumor histology, grade, lymphovascular space involvement (LVSI), FIGO stage, myoinvasion, L1CAM immunoreactivity, and nodal metastasis. DTC occurred less frequently in cases with a microcystic elongated and fragmented (MELF) pattern of invasion (2.2 vs. 21.8%, p = 0.0003). Disease progression was distributed equally among patients with and without DTC present. We were able to confirm previous findings of DTC presence in a large well-characterized cohort of endometrial carcinoma patients. DTC are detectable in almost one-fifth of endometrial carcinoma and occur less frequently with a MELF pattern of invasion. Further studies investigating the role of DTC in endometrial carcinoma are warranted.

  1. Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.

    Science.gov (United States)

    McCampbell, A S; Mittelstadt, M L; Dere, R; Kim, S; Zhou, L; Djordjevic, B; Soliman, P T; Zhang, Q; Wei, C; Hursting, S D; Lu, K H; Broaddus, R R; Walker, C L

    2016-01-01

    Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.

  2. Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity

    Science.gov (United States)

    McCampbell, Adrienne S.; Mittelstadt, Megan L.; Dere, Ruhee; Kim, Sunam; Zhou, Lijun; Djordjevic, Bojana; Soliman, Pamela T.; Zhang, Qian; Wei, Caimiao; Hursting, Stephen D.; Lu, Karen H.; Broaddus, Russell R.; Walker, Cheryl Lyn

    2017-01-01

    Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In “at risk” obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both “normal” endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2–4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity. PMID:26917264

  3. Downregulation of tyrosine threonine kinase inhibits tumor growth via G2/M arrest in human endometrioid endometrial adenocarcinoma.

    Science.gov (United States)

    Zhang, Jiamiao; Jiang, Yan; Zhao, Yu; Wang, Wanxue; Xie, Yiran; Wang, Huating; Yang, Yihua

    2017-07-01

    Endometrial cancer is the most common gynecologic malignancy, about 80% of which is endometrial endometrioid carcinoma. Dysregulation of spindle assembly checkpoint plays a vital role in endometrial endometrioid carcinoma tumorigenesis and progression. The purpose of this study was to explore how tyrosine threonine kinase, a spindle assembly checkpoint-related protein, promotes the endometrial endometrioid carcinoma progression. We found that both messenger RNA and protein levels of tyrosine threonine kinase in endometrial endometrioid carcinoma tissues are higher than those in normal endometrial tissues, and its expression is associated with tumor stages. Genetic depletion of tyrosine threonine kinase by RNA interference in two endometrial endometrioid carcinoma cell lines significantly inhibits cell proliferation and induces apoptosis. Mechanistically, depletion of tyrosine threonine kinase induces G2/M cell cycle arrest and triggers caspase-dependent cell apoptosis. Collectively, tyrosine threonine kinase is significantly upregulated in endometrial endometrioid carcinoma, and downregulation of tyrosine threonine kinase can suppress endometrial endometrioid carcinoma cell proliferation and promote apoptosis via G2/M cell cycle arrest. Our study demonstrates that tyrosine threonine kinase can be a potential therapeutic target for endometrial endometrioid carcinoma treatment.

  4. Human embryo-conditioned medium stimulates in vitro endometrial angiogenesis

    NARCIS (Netherlands)

    Kapiteijn, K.; Koolwijk, P.; Weiden, R.M.F. van der; Nieuw Amerongen, G. van; Plaisier, M.; Hinsbergh, V.W.M. van; Helmerhorst, F.M.

    2006-01-01

    Objective: Successful implantation and placentation depend on the interaction between the endometrium and the embryo. Angiogenesis is crucial at this time. In this article we investigate the direct influence of the human embryo on in vitro endometrial angiogenesis. Design: In vitro study. Setting:

  5. L1CAM expression in endometrial carcinomas is regulated by usage of two different promoter regions

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    Pfeifer Marco

    2010-08-01

    Full Text Available Abstract Background The L1 cell adhesion molecule (L1CAM was originally identified as a neural adhesion molecule involved in axon guidance. In many human epithelial carcinomas L1CAM is overexpressed and thereby augments cell motility, invasion and metastasis formation. L1CAM positive carcinomas are associated with bad prognosis. Recent data point out that L1CAM is regulated in a fashion similar to epithelial-mesenchymal transition (EMT. Previous studies have implied the transcription factors Slug and/or β-catenin in L1CAM transcriptional regulation. However, the regulation of human L1CAM expression at the transcriptional level is not well understood. Results To better understand the molecular basis of L1CAM transcriptional regulation, we carried out a detailed characterization of the human L1CAM promoter. We identified two transcription start sites, the first in front of a non-translated exon 0 (promoter 1 and the other next to the first protein-coding exon 1 (promoter 2. Both sites could be verified in endometrial carcinoma (EC cell lines and appear to be used in a cell-type specific manner. The two identified promoter regions showed activity in luciferase reporter assays. Chromatin-IP analyses confirmed the in silico predicted E-boxes, binding sites for transcription factors Snail and Slug, as well as Lef-1 sites, which are related to β-catenin-mediated transcriptional regulation, in both promoters. Overexpression of β-catenin exclusively augmented activity of promoter 1 whereas Slug enhanced promoter 1 and 2 activity suggesting that both promoters can be active. Overexpression of β-catenin or Slug could upregulate L1CAM expression in a cell-type specific manner. Conclusions Our results, for the first time, provide evidence that the L1CAM gene has two functionally active promoter sites that are used in a cell-type specific manner. Slug and β-catenin are involved L1CAM transcriptional regulation. Nevertheless, Slug rather than

  6. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling.

    Science.gov (United States)

    Zhao, Yan; Sun, Hongli; Feng, Minjuan; Zhao, Jinyan; Zhao, Xiaogui; Wan, Qiuyuan; Cai, Dongge

    2017-11-28

    Metformin recently gained traction as potential anti-endometrial cancer agent for its new applications. However, the underlying mechanisms of the anti-cancer effect of metformin in the endometrial cancer have not yet been fully elucidated. Sixty-five patients diagnosed as endometrial carcinoma were grouped into (n = 33) and non-treatment mixed (n = 32) for analysis. Thirty healthy donors were recruited as controls. We attempt to investigate the effect of metformin on Ki-67, PI3K, p-AKT, p-S6K1, and p-4EBP1 staining in human endometrial cancer by immunohistochemical staining. We found that increased Ki-67 expression in women with endometrial cancer, which were reversed by conventional anti-diabetic doses of metformin in present work. In parallel, the reduced PI3K, p-AKT, p-S6K1, and p-4EBP1 staining induced by metformin appeared to play an important role for the anti-proliferative effects of metformin in endometrial cancer patients. Metformin significantly decreased proliferation in human endometrial cancer may by inhibiting PI3K/AKT/mTOR signaling. Our present results add to the growing body of evidence supporting metformin as a potential anti-cancer agent in endometrial cancer.

  7. Association of endothelial nitric oxide synthase gene polymorphisms with endometrial carcinoma: a preliminary study.

    Science.gov (United States)

    Oztürk, Ebru; Dikensoy, Ebru; Balat, Ozcan; Uğur, Mete Gürol; Balcı, Sibel Oğuzkan; Aydın, Abdullah; Kazancı, Ulkü; Pehlivan, Sacide

    2011-01-01

    To investigate the relationship between specific endothelial nitric oxide synthase (eNOS) gene polymorphisms and endometrial cancer (ECa). The study group consisted of 89 patients histologically diagnosed with the endometrioid type of endometrial carcinoma. The control group consisted of 60 randomly selected individuals who had undergone total hysterectomy. Genomic DNA was isolated from paraffin-embedded endometrial tissues. We investigated the G894T polymorphisms (G894T) and variable number tandem repeats polymorphisms in intron 4 (VNTR intron 4) in the eNOS gene by using polymerase chain reaction (PCR) and/or restriction fragment length polymorphism (RFLP). The genotype distributions and allele frequencies of the two groups were compared. Analysis of the VNTR intron 4 polymorphisms in eNOS gene revealed that the frequency of the AA genotype was significantly higher in the control group, whereas the frequency of the BB genotype was significantly higher in the ECa group. Analysis of the G894T polymorphisms in eNOS gene revealed a significantly higher frequency of the GG genotype in the control group but a significantly higher frequency of the TT genotype in the endometrial cancer group. The G894T and VNTR intron 4 polymorphisms in eNOS gene could be an intriguing susceptibility factor that modulates an individual's risk of ECa in the Turkish population.

  8. Preoperative high dose rate brachytherapy for clinical stage II endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Alexander Olawaiye

    2011-07-01

    Full Text Available Purpose: We sought to evaluate pathological response, tolerance, and outcome after preoperative (neoadjuvant high dose rate brachytherapy in a small series of patients with clinical stage II endometrial carcinoma, and to evaluate a dose and fractionation protocol for this treatment. Material and methods: Twelve women diagnosed with clinical stage II endometrial carcinoma from 1999-2010 were treated with preoperative radiation therapy. Their medical charts were retrospectively analyzed for HDR treatment regimen, pathological response, and longitudinal outcomes. Radiation doses were normalized to a biologically equi­valent dose of 2 Gy per fraction (EQD2. Results: Two patients had complete pathological response to neoadjuvant therapy; five more had only microscopic residual disease at the time of surgery. At a median follow up of 37 months (1-91 months, one patient has developed recurrence at the vaginal apex six months after completing initial therapy, while another developed a lung recurrence at 28 months. Two-year disease-free and cause-specific survivals were 88% and 100%, respectively. Conclusions: Our small study shows that the HDR fractionation schedule, as done in our series for preoperative radiation therapy for clinical stage II endometrial cancer, is well tolerated and would be an option for patients treated with neoadjuvant radiation therapy.

  9. Capacity of endometrial thickness measurement to diagnose endometrial carcinoma in asymptomatic postmenopausal women: a systematic review and meta-analysis

    NARCIS (Netherlands)

    Breijer, M. C.; Peeters, J. A. H.; Opmeer, B. C.; Clark, T. J.; Verheijen, R. H. M.; Mol, B. W. J.; Timmermans, A.

    2012-01-01

    Objectives Measurement of endometrial thickness is an important tool in the assessment of women with postmenopausal bleeding, but the role of endometrial thickness measurement by ultrasound in asymptomatic women is unclear. The aims of this study were to determine: (1) the normal endometrial

  10. Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma.

    Directory of Open Access Journals (Sweden)

    Wei Bao

    Full Text Available Mechanisms governing the metastasis of endometrial carcinoma (EC are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF, are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05 and lymphovascular space involvement (p<0.05 in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT. RNA interference (RNAi-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC.

  11. Deciphering the proteomic signature of human endometrial receptivity.

    Science.gov (United States)

    Garrido-Gómez, Tamara; Quiñonero, Alicia; Antúnez, Oreto; Díaz-Gimeno, Patricia; Bellver, Jose; Simón, Carlos; Domínguez, Francisco

    2014-09-01

    Are there any proteomic differences between receptive (R) and non-receptive (NR) endometrial receptivity array (ERA)-diagnosed endometria obtained on the same day of a hormonal replacement therapy (HRT) treatment cycle? There is a different proteomic signature between R and NR ERA-diagnosed endometrium obtained on the same day of HRT cycles. The human endometrial transcriptome has been extensively investigated in the last decade resulting in the development of a new diagnostic test based on the transcriptomic signature of the window of implantation (WOI). Much less is known about the proteomics derived from the transcripts present during the WOI. This study was a basic proteomic analysis of human endometrial biopsies taken from twelve IVF patients. Human endometrial biopsies were collected during HRT cycles after 5 days of progesterone (P) administration, and diagnosed as receptive (R; n = 6) or non-receptive (NR; n = 6) by the ERA test. Endometrial proteins were extracted, labelled and separated using differential in-gel electrophoresis (DIGE). Proteins were identified using mass spectrometry, followed up by in silico analysis. Validation studies using western blots and immunolocalization were performed for the progesterone receptor membrane component 1 (PGRMC1) and annexin A6 (ANXA6) proteins. DIGE analysis followed by protein identification by MALDI-MS and database searches revealed 24 differentially expressed proteins in R versus NR samples. In silico analysis showed two pathways which were significantly different between R and NR samples. Expression of PGRMC1 and ANXA6 was validated and localized by western blots and immunohistochemistry. These results highlight these proteins as key targets likely to be important in the comprehension of human endometrial receptivity. This was mainly a descriptive study with no functional studies on the proteins found. We also used a low number of human endometrial samples for the DIGE analysis. This study identified the

  12. The antiprogesterone Org 31710 inhibits human blastocyst-endometrial interactions in vitro

    DEFF Research Database (Denmark)

    Petersen, Astrid; Bentin-Ley, Ursula; Ravn, Vibeke

    2005-01-01

    OBJECTIVE: To investigate the effect of the anti-P Org 31710 on human blastocyst attachment to cultured endometrial epithelial cells. DESIGN: Experimental in vitro study. SETTING: University hospital. PATIENT(S): Eleven fertile endometrial donors. INTERVENTION(S): Timed endometrial biopsy for cell......(3) on endometrial epithelial cells examined by immunohistochemistry. Endometrial pinopodes visualized by scanning electron microscopy. RESULT(S): Eleven of 16 human blastocysts attached to control cultures, whereas none of 10 blastocysts attached when Org 31710 was added to the culture medium (P...... statistical significance. The presence of swollen microvilli, precursors of endometrial pinopodes, was significantly reduced on cultures with Org 31710 (P=.03). CONCLUSION(S): The study presents a model for human blastocyst-endometrial interactions responding to an anti-P drug. The exact mechanism...

  13. The antiprogesterone Org 31710 inhibits human blastocyst-endometrial interacttions in vitro

    DEFF Research Database (Denmark)

    Petersen, A; Bentin-Ley, Ursula; Ravn, V

    2005-01-01

    OBJECTIVE: To investigate the effect of the anti-P Org 31710 on human blastocyst attachment to cultured endometrial epithelial cells. DESIGN: Experimental in vitro study. SETTING: University hospital. PATIENT(S): Eleven fertile endometrial donors. INTERVENTION(S): Timed endometrial biopsy for cell......(3) on endometrial epithelial cells examined by immunohistochemistry. Endometrial pinopodes visualized by scanning electron microscopy. RESULT(S): Eleven of 16 human blastocysts attached to control cultures, whereas none of 10 blastocysts attached when Org 31710 was added to the culture medium (P...... statistical significance. The presence of swollen microvilli, precursors of endometrial pinopodes, was significantly reduced on cultures with Org 31710 (P=.03). CONCLUSION(S): The study presents a model for human blastocyst-endometrial interactions responding to an anti-P drug. The exact mechanism...

  14. Predictive factors for prolonged survival in recurrent endometrial carcinoma: Implications for follow-up protocol.

    Science.gov (United States)

    Otsuka, Isao; Uno, Masaya; Wakabayashi, Akira; Kameda, Shogo; Udagawa, Hideo; Kubota, Toshiro

    2010-12-01

    To evaluate the role of follow-up after curative treatment in endometrial carcinoma, we determined predictive factors for prolonged survival after recurrence. We retrospectively studied patients with endometrioid endometrial carcinoma who had a follow-up appointment consisting of pelvic examination, vaginal cytology, imaging and CA-125 measurements and who developed recurrence. Possible prognostic factors were evaluated by univariate and multivariate analyses. Fifty-one patients developed recurrence. The median time from initial treatment to recurrence was 12 months (range, 3-119 months). A total of 25 (49%) and 45 (88%) recurrences were detected within 1 and 3 years of initial treatment, respectively. Twenty (39%) patients were symptomatic, while 31 (61%) were asymptomatic. The median survival time of symptomatic patients was longer than that of asymptomatic patients (27 vs. 12 months); however, the difference was not statistically significant (P = 0.42). No recurrences were detected by vaginal cytology. Of asymptomatic patients with low/intermediate risk (stage I/II), patients with recurrence detected by imaging or CA-125 measurements tended to have shorter survival than patients with recurrence detected by physical examination (7 vs. 31+ months, P = 0.057). Multivariate analysis revealed that site of recurrence (vaginal vs. extravaginal, P 1 year vs. ≤ 1 year, P = 0.01) were significant independent predictors of prolonged survival after recurrence. In endometrial carcinoma, site of and time to recurrence are significant predictive factors of prolonged survival after recurrence, suggesting that early detection of recurrence by imaging studies and CA-125 measurements cannot improve prognosis. Although intensive follow-up using these methods may provide psychological reassurance to some patients, the use of these methods must be balanced against the wise use of limited health care resources. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. ERCC1 and XRCC1 but not XPA single nucleotide polymorphisms correlate with response to chemotherapy in endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Chen L

    2016-11-01

    Full Text Available Liang Chen,1 Mei-Mei Liu,1 Hui Liu,1 Dan Lu,2 Xiao-Dan Zhao,3 Xue-Jing Yang4 1Department of Gynecology and Obstetrics, 2Department of Oncology, 3Department of Clinical Laboratory, The 2nd Affiliated Hospital, Harbin Medical University, 4Nursing Department, Harbin Chest Hospital, Harbin, People’s Republic of China Abstract: Our study aimed to investigate the correlation between single nucleotide polymorphisms of ERCC1/XRCC1/XPA genes and postoperative chemotherapy efficacy and prognosis of endometrial carcinoma. Our study included 108 patients with endometrial carcinoma and 100 healthy participants. ERCC1 rs11615/XRCC1 rs25487/XPA rs1800975 gene polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism. Then the chemotherapy efficacy and toxic effects of the patients were assessed. The genotype and allele frequency of ERCC1 rs11615/XRCC1 rs25487 in the case group were significantly different from that in the control group (all P<0.05. The patients with AA + GA in ERCC1 rs11615 had an increased risk of endometrial carcinoma than those with GG, and the risk of endometrial carcinoma for patients with AA + GA was also higher in comparison with patients with GG genotype in XRCC1 rs25487 (all P<0.05. GG on both ERCC1 rs11615/XRCC1 rs25487 had a higher effective rate of chemotherapy than GA + AA (all P<0.05. ERCC1 rs11615/XRCC1 rs25487 gene polymorphisms were linked with toxic effects in liver, kidney, and nervous system. ERCC1 rs11615/XRCC1 rs25487, muscular invasion, and tumor stage were independent risk factors for the prognosis of endometrial carcinoma (all P<0.05. However, no significant associations were observed between XPA rs1800975 polymorphism and chemotherapy efficacy and prognosis of endometrial carcinoma (all P>0.05. These results indicated that ERCC1 and XRCC1 but not XPA polymorphisms correlate with response to chemotherapy in endometrial carcinoma. Keywords: ERCC1, XRCC1, XPA, single nucleotide

  16. Enhanced cytotoxicity and apoptosis by raloxifene in combination with estrogen and methotrexate in human endometrial stromal cells.

    Science.gov (United States)

    Nikolic, Ivana; Andjelkovic, Marija; Zaric, Milan; Zelen, Ivanka; Milosavljevic, Zoran; Canovic, Petar; Mitrovic, Marina

    2017-11-22

    Endometrial hyperplasia is a condition that may lead to the development of endometrial carcinoma. Initially, changes of the endometrium are caused by the estrogen's hyperstimulation that may lead to the development of an irregular bleeding and the infertility problems. Therapy of endometrial hyperplasia is limited to medical and surgical approaches. During the past decade, the new types of drugs were developed for the treatment of the endometrial hyperplasia. Here, for the first time, we investigated the cytotoxic effects of the various combinations of estrogen, raloxifene, and methotrexate in human ThESC cell line as a possible potential treatment of the endometrial hyperplasia. Our aim was to investigate and to determine the most efficient combination of investigated drugs in ThESC cells during 24-hr period using MTT assay, FACS analysis, and immunofluorescence staining. Our results demonstrated that the combination of raloxifene with methotrexate efficiently induced both the cytotoxicity and apoptosis in ThESC cells when compared to their single effect, as well as to the effect of combined treatment of raloxifene with estrogen. The application of the low doses of methotrexate combined with raloxifene offers all advantages of a potential beneficial antitumor match in cancer chemoprevention and therapy. © 2017 John Wiley & Sons A/S.

  17. MRI for local staging of endometrial carcinoma: Is endovenous contrast medium administration still needed?

    Energy Technology Data Exchange (ETDEWEB)

    Bonatti, Matteo, E-mail: matteobonatti@hotmail.com [Department of Radiology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Stuefer, Josef [Department of Radiology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Oberhofer, Nadia [Department of Physics of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Negri, Giovanni [Department of Pathology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Tagliaferri, Tiziana [Department of Gynecology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Schifferle, Günther [Department of Radiology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Messini, Sergio [Department of Gynecology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy); Manfredi, Riccardo [Department of Radiology of the University of Verona, Piazzale L.A. Scuro 10, 37134 Verona (Italy); Bonatti, Giampietro [Department of Radiology of Bolzano Central Hospital, 5 Böhler St., 39100 Bolzano (Italy)

    2015-02-15

    Highlights: • Intravenous contrast material administration is not routinely indicated for MRI local staging of endometrial carcinoma. • The combination of T2-weighted images with diffusion-weighted images warrants at least the same accuracy as the combination of T2-weighted images with contrast-enhanced T1-weighted images in recognizing deep myometrial invasion and cervical stromal infiltration by endometrial carcinoma. - Abstract: Purpose: To compare the diagnostic performance of T2-weighted images (T2-WI) + contrast-enhanced T1-weighted images (CE T1-WI) with the one of T2-WI + diffusion-weighted images (DWI) in the assessment of myometrial and cervical stromal infiltration by endometrial carcinoma (EC). Materials and methods: Institutional review board approved our retrospective study; requirement for informed consent was waived. 56 patients with histologically proven EC who underwent preoperative MRI and surgery at our Institution over a 34 months period were included. Two radiologists independently evaluated T2-WI + CE T1-WI and T2-WI + DWI of each patient. Confidence in imaging evaluation (0–3), depth of myometrial invasion ( 0.05) whereas both imaging sequences combinations showed the same diagnostic performance in recognizing cervical stromal infiltration (accuracy, sensitivity and specificity of 0.95, 0.98 and 0.80, p > 0.05). Conclusion: T2-WI + DWI can reliably replace the “classical” combination T2-WI + CE T1-WI for local staging of endometrial carcinoma.

  18. The Effect of Copper on Endometrial Receptivity and Induction of Apoptosis on Decidualized Human Endometrial Stromal Cells.

    Science.gov (United States)

    Carrascosa, Jose P; Cotán, David; Jurado, Inmaculada; Oropesa-Ávila, Manuel; Sánchez-Martín, Pascual; Savaris, Ricardo F; Tan, Justin; Sánchez-Alcázar, Jose A; Tan, Seang L; Horcajadas, José Antonio

    2017-01-01

    Intrauterine devices (IUDs) have been widely used to prevent pregnancies with great efficacy during decades. It has been demonstrated that IUD alters the endometrial gene expression, but there is no scientific data about how copper, a metal commonly used in these devices, by itself, is able to influence the processes of endometrial receptivity and apoptosis in decidualized human endometrial stromal cells. Five endometrial samples were obtained from fertile women and processed by a standard protocol to obtain human endometrial stromal cells for in vitro studies. Stromal cells were cultured in vitro and decidualized for 8 days. At day 6, copper was added to the treatment group or camptothecin as positive control for apoptosis until day 8. Five endometrial samples were used in each group. The aim of this study was to analyze the effect of copper in apoptosis and necrosis by flow cytometry, to visualize the apoptotic microtubule network during apoptosis by immunofluorescence, and finally to determine the gene expression profile of a panel of 192 genes related to endometrial receptivity and immune system by quantitative reverse transcription PCR (RT-qPCR). Copper, compared to the decidualized group, induced changes in the gene expression by an order of magnitude in 49 genes (42 up- and 9 downregulated). This alteration in the decidualization gene signature by copper includes 19 genes involved in the endometriosis pathology and others related to other gynecological disorders such as preeclampsia and infertility. Our results indicate that copper does not increase the apoptosis level induced by the decidualization treatment. However, copper alters the gene expression of some biomarkers of endometrial receptivity and immune response.

  19. The genetic regulation of transcription in human endometrial tissue.

    Science.gov (United States)

    Fung, Jenny N; Girling, Jane E; Lukowski, Samuel W; Sapkota, Yadav; Wallace, Leanne; Holdsworth-Carson, Sarah J; Henders, Anjali K; Healey, Martin; Rogers, Peter A W; Powell, Joseph E; Montgomery, Grant W

    2017-04-01

    Do genetic effects regulate gene expression in human endometrium? This study demonstrated strong genetic effects on endometrial gene expression and some evidence for genetic regulation of gene expression in a menstrual cycle stage-specific manner. Genetic effects on expression levels for many genes are tissue specific. Endometrial gene expression varies across menstrual cycle stages and between individuals, but there are limited data on genetic control of expression in endometrium. We analysed genome-wide genotype and gene expression data to map cis expression quantitative trait loci (eQTL) in endometrium. We recruited 123 women of European ancestry. DNA samples from blood were genotyped on Illumina HumanCoreExome chips. Total RNA was extracted from endometrial tissues. Whole-transcriptome profiles were characterized using Illumina Human HT-12 v4.0 Expression Beadchips. We performed eQTL mapping with ~8 000 000 genotyped and imputed single nucleotide polymorphisms (SNPs) and 12 329 genes. We identified a total of 18 595 cis SNP-probe associations at a study-wide level of significance (P endometrial tissue were rs4902335 for CHURC1 (P = 1.05 × 10-32) and rs147253019 for ZP3 (P = 8.22 × 10-30). We further performed a context-specific eQTL analysis to investigate if genetic effects on gene expression regulation act in a menstrual cycle-specific manner. Interestingly, five cis-eQTLs were identified with a significant stage-by-genotype interaction. The strongest stage interaction was the eQTL for C10ORF33 (PYROXD2) with SNP rs2296438 (P = 2.0 × 10-4), where we observe a 2-fold difference in the average expression levels of heterozygous samples depending on the stage of the menstrual cycle. The summary eQTL results are publicly available to browse or download. A limitation of the present study was the relatively modest sample size. It was not powered to identify trans-eQTLs and larger sample sizes will also be needed to provide better power to detect cis-eQTLs and

  20. Clinicopathological comparison of colorectal and endometrial carcinomas in patients with Lynch-like syndrome versus patients with Lynch syndrome.

    Science.gov (United States)

    Mas-Moya, Jenny; Dudley, Beth; Brand, Randall E; Thull, Darcy; Bahary, Nathan; Nikiforova, Marina N; Pai, Reetesh K

    2015-11-01

    Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome-associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome-associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Biological effects of plasma rich in growth factors (PRGF) on human endometrial fibroblasts.

    Science.gov (United States)

    Anitua, Eduardo; de la Fuente, María; Ferrando, Marcos; Quintana, Fernando; Larreategui, Zaloa; Matorras, Roberto; Orive, Gorka

    2016-11-01

    To evaluate the biological outcomes of plasma rich in growth factors (PRGF) on human endometrial fibroblasts in culture. PRGF was obtained from three healthy donors and human endometrial fibroblasts (HEF) were isolated from endometrial specimens from five healthy women. The effects of PRGF on cell proliferation and migration, secretion of vascular endothelial growth factor (VEGF), procollagen type I and hyaluronic acid (HA) and contractility of isolated and cultured human endometrial fibroblasts (HEF) were analyzed. Statistical analysis was performed in order to compare the effects of PRGF with respect to control situation (T-test or Mann-Whitney U-test). We report a significantly elevated human endometrial fibroblast proliferation and migration after treatment with PRGF. In addition, stimulation of HEF with PRGF induced an increased expression of the angiogenic factor VEGF and favored the endometrial matrix remodeling by the secretion of procollagen type I and HA and endometrial regeneration by elevating the contractility of HEF. These results were obtained for all PRGF donors and each endometrial cell line. The myriad of growth factors contained in PRGF promoted HEF proliferation, migration and synthesis of paracrine molecules apart from increasing their contractility potential. These preliminary results suggest that PRGF improves the biological activity of HEF in vitro, enhancing the regulation of several cellular processes implied in endometrial regeneration. This innovative treatment deserves further investigation for its potential in "in vivo" endometrial development and especially in human embryo implantation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Prognostic factors influencing the result of postoperative radiotherapy in endometrial carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ki, Yong Kan; Kwon, Byung Hyun; Kim, Won Taek; Nam, Ji Ho; Yun, Man Su; Kim, Dong Won [Pusan National University School of Medicine, Busan (Korea, Republic of); Lee, Hyung Sik [Dong-A University School of Medicine, Busan (Korea, Republic of)

    2006-06-15

    This study was performed to determine the prognostic factors influencing relapse pattern, overall and disease-free survival in patients treated with postoperative radiotherapy for endometrial carcinoma. The records of 54 patients with endometrial adenocarcinoma treated postoperative radiotherapy at Pusan National University Hospital between April 1992 and May 2003 were reviewed retrospectively. Median age of the patients was 55 (range 35 {approx} 76). The distribution by surgical FIGO stages were 63.0% for 0 Stage I, 14.8% for Stage II, 22.2% for Stage III. All patients received postoperative external radiotherapy up to 41.4 {approx} 54 Gy (median: 50.4 Gy). Additional intravaginal brachytherapy was applied to 20 patients (37.0% of all). Median follow-up time was 35 months (5 {approx} 115 months). Significant factors of this study: histologic grade, lymphovascular space invasion and myometrial invasion depth were scored (GLM sore) and analyzed. Survival analysis was performed using Kaplan-Meier method. The log-rank test was used for univariate analysis and the Cox regression model for multivariate analysis. 5-year overall and disease-free survival rates were 87.7% and 87.1%, respectively. Prognostic factors related with overall and disease-free survival were histologic grade, lymphovascular space invasion and myometrial invasion according to the univariate analysis. According to the multivariate analysis, lymphovascular space invasion was associated with decreased disease-free survival. GLM score was a meaningful factor affecting overall and disease-free survival ({rho} = 0.0090, {rho} = 0.0073, respectively) and distant recurrence ({rho} = 0.0132), which was the sum of points of histologic grade, lymphovascular space invasion and myometrial invasion. Total failure rate was 11% with 6 patients. Relapse sites were 2 para-aortic lymph nodes, 2 lungs, a supraclavicular lymph node and a vagina. The prognosis in patients with endometrial carcinoma treated by

  3. Primary Endometrial Squamous Cell Carcinoma In Situ; Report of a rare disease

    Directory of Open Access Journals (Sweden)

    Sujata Jetley

    2015-11-01

    Full Text Available Squamous cell carcinoma (SCC of the endometrium, whether primary or secondary to cervical cancer, is a rare entity. Primary endometrial squamous cell carcinoma in situ is even more uncommon; it usually occurs in postmenopausal women and has a strong association with pyometra. We report a 60-year-old multiparous postmenopausal woman who presented to the Hakeem Abdul Hameed Centenary Hospital, New Delhi, India, in May 2014 with a lower abdominal swelling corresponding in size to a pregnancy of 26 gestational weeks and vaginal discharge of one year’s duration. A total abdominal hysterectomy with a bilateral salpingooophorectomy was performed, which revealed an enlarged uterus with pyometra. Histopathology showed that the entire endometrial lining had been replaced with malignant squamous cells without invasion of the myometrium. Immunohistochemistry revealed that the tumour cells were positive for p63 with a high Ki-67 labelling index. No adjuvant therapy was required and the patient was disease-free at a seven-month follow-up.

  4. Growth hormone-releasing hormone antagonist inhibits the invasiveness of human endometrial cancer cells by down-regulating twist and N-cadherin expression.

    Science.gov (United States)

    Wu, Hsien-Ming; Huang, Hong-Yuan; Schally, Andrew V; Chao, Angel; Chou, Hung-Hsueh; Leung, Peter C K; Wang, Hsin-Shih

    2017-01-17

    More than 25% of patients diagnosed with endometrial carcinoma have invasive primary cancer accompanied by metastases. Growth hormone-releasing hormone (GHRH) plays an important role in reproduction. Here, we examined the effect of a GHRH antagonist on the motility of endometrial cancer cells and the mechanisms of action of the antagonist in endometrial cancer. Western blotting and immunohistochemistry (IHC) were used to determine the expression of the GHRH receptor protein. The activity of Twist and N-cadherin was determined by Western blotting. Cell motility was assessed by an invasion and migration assay. GHRH receptor siRNA was applied to knockdown the GHRH receptor in endometrial cancer cells. The GHRH antagonist inhibited cell motility in a dose-dependent manner. The GHRH antagonist inhibited cell motility and suppressed the expression of Twist and N-cadherin, and the suppression was abolished by GHRH receptor siRNA pretreatment. Moreover, the inhibition of Twist and N-cadherin with Twist siRNA and N-cadherin siRNA, respectively, suppressed cell motility. Our study indicates that the GHRH antagonist inhibited the cell motility of endometrial cancer cells through the GHRH receptor via the suppression of Twist and N-cadherin. Our findings represent a new concept in the mechanism of GHRH antagonist-suppressed cell motility in endometrial cancer cells and suggest the possibility of exploring GHRH antagonists as potential therapeutics for the treatment of human endometrial cancer.

  5. Inguinal lymph node presenting as the delayed site of metastasis in early stage endometrial carcinoma: Case report

    Directory of Open Access Journals (Sweden)

    Shomaila Amir M. Akbar

    2017-01-01

    Conclusion: Inguinal lymph nodes as delayed site of metastasis in early endometrial carcinoma is extremely rare entity. Incorporation of FDG-PET during the preoperative screening of inguinal nodes may be helpful. The impact of lymph node dissection and adjuvant radiation therapy on survival needs to be established.

  6. Reception of Steroid Hormones, Features of Proliferation and Apoptosis in Endometrial Carcinoma in Patients with Microsatellite Instability Phenomenon

    Directory of Open Access Journals (Sweden)

    S.V. Danyliuk

    2015-06-01

    Full Text Available On the surgical specimen, we have studied the morphological features of endometrial cancer with microsatellite instability. The presence of this phenomenon in patients causes the prevalence of endometrioid forms of carcinomas, positive receptor status, increased proliferative activity of tumor cells, reduced ability to apoptosis.

  7. The number of metastatic sites for stage IIIA endometrial carcinoma, endometrioid cell type, is a strong negative prognostic factor

    NARCIS (Netherlands)

    Jobsen, Jan J.; Naudin ten Cate, Lambert; Lybeert, Marnix L.M.; van der Steen-Banasik, Elzbieta M.; Scholten, A.M.; van der Palen, Jacobus Adrianus Maria; van der Palen, J.; Slot, Annerie; Stenfert Kroese, Marika C.; Schutter, Eltjo M.; Siesling, Sabine

    2010-01-01

    The aim of this study was to look at the impact of the number of sites with tumour involvement on outcome for patients with stage IIIA endometrioid-type endometrial carcinoma. Patients and methods: 141 patients stage IIIA were included. A central histopathological review was performed. Patients

  8. Human Endometrial Exosomes Contain Hormone-Specific Cargo Modulating Trophoblast Adhesive Capacity: Insights into Endometrial-Embryo Interactions.

    Science.gov (United States)

    Greening, David W; Nguyen, Hong P T; Elgass, Kirstin; Simpson, Richard J; Salamonsen, Lois A

    2016-02-01

    Embryo implantation into receptive endometrium requires synergistic endometrial-blastocyst interactions within the uterine cavity and is essential for establishing pregnancy. We demonstrate that exosomes (40-150 nm nanovesicles) released from endometrial epithelial cells are an important component of these interactions. We defined the proteome of purified endometrial epithelial-derived exosomes (Exos) influenced by menstrual cycle hormones estrogen (E; proliferative phase) and estrogen plus progesterone (EP; receptive phase) and examined their potential to modify trophoblast function. E-/EP-Exos were uniquely enriched with 254 and 126 proteins, respectively, with 35% newly identified proteins not previously reported in exosome databases. Importantly, EP-Exos protein cargo was related to fundamental changes in implantation: adhesion, migration, invasion, and extracellular matrix remodeling. These findings from hormonally treated ECC1 endometrial cancer cells were validated in human primary uterine epithelial cell-derived exosomes. Functionally, exosomes were internalized by human trophoblast cells and enhanced their adhesive capacity, a response mediated partially through active focal adhesion kinase (FAK) signaling. Thus, exosomes contribute to the endometrial-embryo interactions within the human uterine microenvironment essential for successful implantation. © 2016 by the Society for the Study of Reproduction, Inc.

  9. Inhibition of CXCR4 and CXCR7 for reduction of cell proliferation and invasion in human endometrial cancer.

    Science.gov (United States)

    Long, Ping; Sun, Fengyi; Ma, Yingying; Huang, Yu

    2016-06-01

    As one of the most common malignant cancers in female reproductive tract, endometrial cancer accounts for 20-30 % of the most frequent gynecological malignancy, which is originated from endometrial epithelial. The molecular mechanisms for the generation of endometrial cancer are up to now unclear, hindering the development of corresponding therapy. CXCR4 and CXCR7 were receptors of CXCL12 chemokine ligand, which could regulate critical procedures of neoplastic transformation, including proliferation, invasion, and apoptosis of the cells. The messenger RNA (mRNA) and protein expression levels of CXCR4 and CXCR7 in human endometrial adenocarcinoma cancer, as well as in Ishikawa and HEC-1-A cell line, were analyzed by using reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting. In order to explore the biological function of CXCR4 and CXCR7 in endometrial tumor, small interference RNAs of CXCR4 and CXCR7 fragments were designed, synthesized, and transfected into Ishikawa and HEC-1-A by using Lipofectamine2000. The influence of RNA interference (RNAi)-mediated silencing CXCR4 and CXCR7 on the cell proliferation was investigated under CCK-8. The invasion assay was performed transwell, and cell apoptosis was tested by FCM. Higher mRNA and protein expression levels of CXCR4 and CXCR7 were investigated in endometrial adenocarcinomas. The expression levels of CXCR4 and CXCR7 could be inhibited by RNA interference, reducing the cell proliferation, invasion in Ishikawa and HEC-1-A cells. In this study, we also observed that treated with CXCR4 and CXCR7 small interfering RNA (siRNA) arrested cells in S phase. CXCL12/CXCR4 and CXCL12/CXCR7 receptor ligand systems affect the invasion of endometrial carcinoma cell line into Ishikawa and HEC-1-A. CXCR4 and CXCR7 were silenced by RNAi, which can inhibit the invasion of Ishikawa and HEC-1-A cell lines. Hence, CXCR4 and CXCR7 are expected to become two target genes for the treatment of endometrial carcinoma.

  10. Vitronectin in human breast carcinomas

    DEFF Research Database (Denmark)

    Aaboe, Mads; Offersen, Birgitte Vrou; Christensen, Anni

    2003-01-01

    We have analysed the occurrence of the extracellular glycoprotein vitronectin in carcinomas and normal tissue of human breast. Immunohistochemical analysis of carcinomas revealed a strong vitronectin accumulation in extracellular matrix (ECM) around some cancer cell clusters and in the subendothe......We have analysed the occurrence of the extracellular glycoprotein vitronectin in carcinomas and normal tissue of human breast. Immunohistochemical analysis of carcinomas revealed a strong vitronectin accumulation in extracellular matrix (ECM) around some cancer cell clusters...... of the role of vitronectin in tumour biology in interaction with the plasminogen activation system and integrins....

  11. [The Expression of Pokemon in Endometrial Carcinoma Tissue and the Correlation with Mutant p53].

    Science.gov (United States)

    Yi, Tian-jin; Wang, Ping

    2016-05-01

    To detect the expression of Pokemon in endometrial carcinoma (EC), to provide preliminary theoretical basis for clarifying pathogenesis and searching for effective targets. Ninety-eight cases of endometrial tissue paraffin specimens form July 2012 to July 2014 in West China Second University Hospital, Sichuan University, were collected, including: EC group, consisting of adenocarcinoma 23 cases, adenosquamous 12 cases, serous 3 cases, mucinous 11 cases and clear cell 9 cases, and control group, consisting of atypical hyperplasia endometrium 20 cases and normal endometrium 20 cases (secretory 10 cases, hyperplasia 10 cases). Immunohistochemistry was used to detect the expression of Pokemonin each section, analyzing the correlation of Pokemon expression with clinicopathologic characteristics and p53 expression. The positive rate of Pokemon in normal endometrium was 25% (5/20), significantly lower than that in atypical hyperplasia endometrium (60.0%, 12/20) and EC (93.1%, 54/58) (P Pokemon in III-IV stage, type II and Ki-67 ≥ 50 EC tissue was much higher (P = 0.012, 0.023, 0.029). In type II EC tissue, the correlation index between Pokemon and p53 is 0.669 (P = 0.000). The over expression of Pokemon upregulates the expression of mutant p53, which may be one of the carcinogenesis modes in type II EC.

  12. Mig-6 Mouse Model of Endometrial Cancer.

    Science.gov (United States)

    Kim, Tae Hoon; Yoo, Jung-Yoon; Jeong, Jae-Wook

    2017-01-01

    Endometrial cancer is a frequently occurring gynecological disorder. Estrogen-dependent endometrioid carcinoma is the most common type of gynecological cancer. One of the major pathologic phenomena of endometrial cancer is the loss of estrogen (E2) and progesterone (P4) control over uterine epithelial cell proliferation. P4 antagonizes the growth-promoting properties of E2 in the uterus. P4 prevents the development of endometrial cancer associated with unopposed E2 by blocking E2 actions. Mitogen inducible gene 6 (Mig-6, Errfi1, RALT, or gene 33) is an immediate early response gene that can be induced by various mitogens and common chronic stress stimuli. Mig-6 has been identified as an important component of P4-mediated inhibition of E2 signaling in the uterus. Decreased expression of MIG-6 is observed in human endometrial carcinomas. Transgenic mice with Mig-6 ablation in the uterus develop endometrial hyperplasia and E2-dependent endometrial cancer. Thus, MIG-6 has a tumor suppressor function in endometrial tumorigenesis. The following discussion summarizes our current knowledge of Mig-6 mouse models and their role in understanding the molecular mechanisms of endometrial tumorigenesis and in the development of therapeutic approaches for endometrial cancer.

  13. The antiprogesterone Org 31710 inhibits human blastocyst-endometrial interacttions in vitro

    DEFF Research Database (Denmark)

    Petersen, A; tin-Ley, U; Ravn, V

    2005-01-01

    OBJECTIVE: To investigate the effect of the anti-P Org 31710 on human blastocyst attachment to cultured endometrial epithelial cells. DESIGN: Experimental in vitro study. SETTING: University hospital. PATIENT(S): Eleven fertile endometrial donors. INTERVENTION(S): Timed endometrial biopsy for cell...... cultures. MAIN OUTCOME MEASURE(S): Blastocyst attachment rate on endometrial cell cultures; secretion of glycodelin and leukemia inhibitory factor into the culture medium measured by RIA and ELISA techniques; and expression of progesterone receptors, interleukin-1 receptor type-1, and integrin subunit beta...

  14. HMGB1 is negatively correlated with the development of endometrial carcinoma and prevents cancer cell invasion and metastasis by inhibiting the process of epithelial-to-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Luan XR

    2017-03-01

    Full Text Available Xiaorong Luan,1,2 Chunjing Ma,2 Ping Wang,2 Fenglan Lou1 1Nursing College, Shandong University, 2Qilu Hospital of Shandong University, Jinan, People’s Republic of China Abstract: High-mobility group box protein 1 (HMGB1, a nuclear protein that plays a significant role in DNA architecture and transcription, was correlated with the progression of some types of cancer. However, the role of HMGB1 in endometrial cancer cell invasion and metastasis remains unexplored. HMGB1 expression was initially assessed by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR in normal endometrial tissue and endometrial carcinoma tissue. High expressions of HMGB1 protein were detected in normal endometrial tissues; however, in endometrial cancer tissues, the expressions of HMGB1 were found to be very weak. Furthermore, HMGB1 expressions were negatively correlated with advanced stage and lymph node metastasis in endometrial cancer. Then by RT-qPCR, Western blot and immunocytochemistry, HMGB1 was also detected in primary cultured endometrial cells and four kinds of endometrial cancer cell lines (Ishikawa, HEC-1A, HEC-1B and KLE. We found that the expression of HMGB1 was much higher in normal endometrial cells than in endometrial cancer cells, and reduced expression levels of HMGB1 were observed especially in the highly metastatic cell lines. Using lentivirus transfection, HMGB1 small hairpin RNA was constructed, and this infected the lowly invasive endometrial cancer cell lines, Ishikawa and HEC-1B. HMGB1 knockdown significantly enhanced the proliferation, invasion and metastasis of endometrial cancer cells and induced the process of epithelial-to-mesenchymal transition. These results can contribute to the development of a new potential therapeutic target for endometrial cancer. Keywords: HMGB1, endometrial cancer, invasion, metastasis, epithelial-to-mesenchymal transition

  15. Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration.

    Science.gov (United States)

    Grewal, Seema; Carver, Janet G; Ridley, Anne J; Mardon, Helen J

    2008-10-21

    Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.

  16. External hemipelvectomy as treatment for solitary coxofemoral metastasis from endometrial carcinoma: case report and review of the literature.

    Science.gov (United States)

    Vizzielli, Giuseppe; Fanfani, Francesco; Costantini, Barbara; Gallotta, Valerio; Scambia, Giovanni; Fagotti, Anna

    2012-05-01

    The best treatment for bone metastasis from endometrial cancer as a presenting feature is unclear. We report the first case in the literature of coxofemoral metastases from endometrial cancer treated by surgical approach. Then, after a careful review of the literature, we discuss the best therapeutic option for this subset of patients. A 62-year-old woman with pain, erythema and swelling of the left leg and no history of postmenopausal bleeding underwent biopsy of the leg, which revealed a moderately differentiated endometrial carcinoma, infiltrating muscle and adipose tissues. There were no other sites of distal spread. A literature review was conducted by searching the items 'endometrial cancer' and 'bone metastasis' in MEDLINE and EnBase up to September 2010. The patient was treated with neoadjuvant chemotherapy, but she did not show a clinical response. By considering her prognosis and quality of life, we decided to perform for the first time a total abdominal hysterectomy with bilateral salpingo-oophorectomy in addition to an external hemipelvectomy with a limb amputation and partial ilium and pubic preservation. Thirty months after the procedure the patient is still alive. No other similar results are present in the literature. Patients in good clinical condition with a single bone metastasis of endometrial cancer should be treated aggressively with surgery, as survival can be extended with an acceptable quality of life. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

  17. Human Papillomavirus in Endometrial Adenocarcinomas: Infectious Agent or a Mere “Passenger”?

    Science.gov (United States)

    Giatromanolaki, A.; Sivridis, E.; Papazoglou, D.; Koukourakis, M. I.; Maltezos, E.

    2007-01-01

    Aims. To investigate the possible association of human papillomavirus (HPV) with endometrial hyperplasias and neoplasia. Does HPV play any role in the initiation or prognosis of endometrial adenocarcinomas? Methods. Twenty-five endometrial adenocarcinomas of the endometrioid cell type, with and without squamous differentiation, and twenty-four endometrial hyperplasias of various forms (simple, complex, and atypical) were analyzed for the presence of type 16 and 18 HPV by the polymerase chain reaction (PCR). The results were related to histopathological features of the tumour, and the patients' age, and prognosis. Results. Six of 25 endometrial adenocarcinomas were HPV 16-positive (24%), and 5 of 25 (20%) were HPV 18-positive. Simple endometrial hyperplasias was associated somewhat more commonly with HPV 16 and 18 (2/8 and 1/8 cases, resp.) than hyperplasias progressing to endometrial adenocarcinomas, namely, atypical endometrial hyperplasia (1/8 and 0/8 cases, resp.). None of the positive cases in the series, whether hyperplastic or neoplastic, demonstrated cytological evidence of HPV infection. There was no relation between HPV-positive cases and squamous differentiation, depth of myometrial invasion, lymphatic involvement, lymphocytic response, patients' age, or prognosis. Conclusion. It appears that the presence of HPV in the endometrium, as detected by PCR, does not play any role in the initiation or prognosis of endometrial adenocarcinoma. PMID:18274613

  18. Does the Loss of ARID1A (BAF-250a Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment

    Directory of Open Access Journals (Sweden)

    Oluwole Fadare, Idris L. Renshaw, Sharon X. Liang

    2012-01-01

    Full Text Available SWI/SNF chromatin-modification complexes use the energy of ATP hydrolysis to remodel nucleosomes and to affect transcription and several cellular processes. Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC. The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications. 34 endometrial carcinomas with a CCC component (including 22 pure CCC, 8 mixed carcinomas with a 10% CCC component, and 4 carcinosarcomas with a CCC epithelial component, were evaluated by immunohistochemistry using a monoclonal antibody directed against the human BAF250a protein. 5 (22.7% of the 22 pure CCC were entirely BAF250a negative, whereas the remainder showed diffuse immunoreactivity. None of 4 carcinosarcomas and only 1 (12.5% of the 8 mixed carcinomas were BAF250a negative. There was no discernable relationship between BAF250a immunoreactivity status and tumor architectural patterns (solid, papillary or tubulocystic areas or cell type (flat, hobnail or polygonal. Of the 22 patients with pure CCC, 14, 2, 3, and 3 were International Federation of Gynecology and Obstetrics stages 1, II, III and IV respectively. Interestingly, all 5 BAF250a negative cases were late stage [stages III or IV] as compared with 1 of 17 BAF250a positive cases (p=0.0002. Thus, 83% (5/6 of all late stage cases were BAF250a [-], as compared with 0 (0% of the 16 early stage (I or II cases (p=.0002. BAF250a negative and positive cases did not show any statistically significant difference regarding patient age and frequency of lymphovascular invasion or myometrial invasion. As may be anticipated from the concentration of late stage cases in

  19. Nanoparticle labeling identifies slow cycling human endometrial stromal cells

    Science.gov (United States)

    2014-01-01

    Introduction Evidence suggests that the human endometrium contains stem or progenitor cells that are responsible for its remarkable regenerative capability. A common property of somatic stem cells is their quiescent state. It remains unclear whether slow-cycling cells exist in the human endometrium. We hypothesized that the human endometrium contains a subset of slow-cycling cells with somatic stem cell properties. Here, we established an in vitro stem cell assay to isolate human endometrial-derived mesenchymal stem-like cells (eMSC). Methods Single-cell stromal cultures were initially labeled with fluorescent nanoparticles and a small population of fluorescent persistent cells (FPC) remained after culture of 21 days. Two populations of stromal cells, namely FPC and non-FPC were sorted. Results Quantitative analysis of functional assays demonstrated that the FPC had higher colony forming ability, underwent more rounds of self-renewal and had greater enrichment of phenotypically defined prospective eMSC markers: CD146+/CD140b+ and W5C5+ than the non-FPC. They also differentiate into multiple mesenchymal lineages and the expression of lineage specific markers was lower than that of non-FPC. The FPC exhibit low proliferation activities. A proliferation dynamics study revealed that more FPC had a prolonged G1 phase. Conclusions With this study we present an efficient method to label and isolate slow-proliferating cells obtained from human endometrial stromal cultures without genetic modifications. The FPC population could be easily maintained in vitro and are of interest for tissue-repair and engineering perspectives. In summary, nanoparticle labeling is a promising tool for the identification of putative somatic stem or progenitor cells when their surface markers are undefined. PMID:24996487

  20. Decreased hyaluronidase 1 expression is associated with early disease recurrence in human endometrial cancer.

    Science.gov (United States)

    Nykopp, Timo K; Pasonen-Seppänen, Sanna; Tammi, Markku I; Tammi, Raija H; Kosma, Veli-Matti; Anttila, Maarit; Sironen, Reijo

    2015-04-01

    Hyaluronidases (HYAL1 and HYAL2) are key enzymes in the degradation of hyaluronan, and their expression has been altered in various cancer types. We previously showed that hyaluronan accumulation in endometrial carcinomas was correlated with decreased mRNA expression of the HYAL genes. In this study, we analyzed HYAL1 and HYAL2 protein expressions in normal and precancerous endometrial tissues and in endometrial carcinomas. We also investigated whether the protein levels were associated with clinicopathological factors, invasion, and disease recurrence. A total of 343 tissue specimens from normal, atrophic, hypertrophic, and neoplastic endometria were analyzed immunohistochemically for HYAL1 and HYAL2 expressions. The results were correlated with clinicopathological factors, the expression of the epithelial-mesenchymal transition marker, E-cadherin, and disease recurrence. Reduced HYAL1 expression was associated with the progression of endometrial carcinomas towards higher grades and also with large tumor sizes, lymph node metastasis, and lymphovascular invasion. Reduced expression of both HYAL1 and HYAL2 was associated with deep myometrial invasion. HYAL2 expression was primarily constant in neoplastic tissues, but its expression was altered in different phases of the endometrial cycle. In addition, a reduction in HYAL1 expression was associated with the depletion of E-cadherin. In a multivariate analysis, reduced HYAL1 expression was an independent prognostic factor for early disease recurrence (HR 5.13, 95% CI: 1.131-23.270, p=0.034). This study showed that reduced HYAL1 expression was associated with endometrial carcinoma aggressiveness, which further supported the role of hyaluronan degradation in cancer progression. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity.

    Science.gov (United States)

    Chen, Joseph C; Hoffman, Jacquelyn R; Arora, Ripla; Perrone, Lila A; Gonzalez-Gomez, Christian J; Vo, Kim Chi; Laird, Diana J; Irwin, Juan C; Giudice, Linda C

    2016-02-01

    To develop a protocol for cryopreservation and recovery of human endometrial epithelial cells (eECs) retaining molecular and functional characteristics of endometrial epithelium in vivo. In vitro study using human endometrial cells. University research laboratory. Endometrial biopsies were obtained from premenopausal women undergoing benign gynecologic procedures. Primary eECs were cryopreserved in 1% fetal bovine serum/10% dimethylsulfoxide in Defined Keratinocyte Serum-Free Medium (KSFM). Recovered cells were observed for endometrial stromal fibroblast (eSF) contamination and subsequently evaluated for morphology, gene expression, and functional characteristics of freshly cultured eECs and in vivo endometrial epithelium. Analysis of eEC morphology and the absence of eSF contamination; evaluation of epithelial-specific gene and protein expression; assessment of epithelial polarity. Endometrial epithelial cells recovered after cryopreservation (n = 5) displayed epithelial morphology and expressed E-cadherin (CDH1), occludin (OCLN), claudin1 (CLDN1), and keratin18 (KRT18). Compared with eSF, recovered eECs displayed increased (Phuman endometrial epithelium in vivo. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  2. CXCL12/CXCR4 axis induces proliferation and invasion in human endometrial cancer.

    Science.gov (United States)

    Liu, Pingping; Long, Ping; Huang, Yu; Sun, Fengyi; Wang, Zhenyan

    2016-01-01

    Since that we have previously found CXCL12/CXCR4, an important biological axis is highly transcribed in several cancer cells. We aim to investigate whether CXCL12/CXCR4 axis regulates critical processes in neoplastic transformation that affects endometrial cancer cell biology. The expression levels of CXCR4 were analyzed in human normal endometrial tissue, simple hyperplasia, atypical hyperplasia and endometrial cancer cells by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Serum CXCL12 was measured by Enzyme-Linked Immunosorbent Assay (ELISA) in Ishikawa endometrial cancer cell line. To study the biological function of CXCL12/CXCR4 in endometrial cancer, short interfering RNA silencing of CXCR4 was established to analyze the roles of CXCL12/CXCR4 in proliferation, migration, invasion and apoptosis of Ishikawa cells in vitro. The expression level of CXCR4 in endometrial cancer tissue was higher as compared to atypical hyperplasia, simple hyperplasia and normal cycling endometrium cells. Ishikawa cells secreted CXCL12 spontaneously and continuously for 96 hrs in culture. The proliferation, migration and invasion of Ishikawa cells was significantly induced, and the apoptosis was significantly reduced by CXCL12 in combination with CXCR4. Moreover, CXCR4 silencing could significantly antagonize all these functions. CXCL12/CXCR4 axis plays an important role in the proliferation, invasion and metastasis of endometrial cancer, indicating that CXCR4 could be the target for the treatment of endometrial cancer.

  3. Comparative results of three short brachytherapy schedules as exclusive treatment in postoperative endometrial carcinoma.

    Science.gov (United States)

    Rovirosa, Ángeles; Herreros, Antonio; Camacho, Cristina; Ascaso, Carlos; Sánchez, Joan; Cortés, Stepphania; Sabater, Sebastià; Solà, Jordi; Torné, Aureli; Arenas, Meritxell

    2017-08-08

    To compare vaginal control and treatment toxicity of three different high-dose-rate brachytherapy schedules as exclusive treatment in postoperative endometrial carcinoma. From 2003 to 2015, three different schedules were used as postoperative treatment for 146 patients (p) with intermediate-risk endometrial carcinoma. Group 1 (41 p): six fractions of 4-6 Gy, 3-4 fractions per week; Group 2 (59 p): four fractions of 5-6 Gy administered daily; Group 3 (46 p): 6 Gy × 3 fractions in three consecutive days. The dose was prescribed at 5 mm of applicator surface using an active treatment length of 2.5 cm. Toxicity scores were evaluated using the Radiation Therapy Oncology Group scores for bladder and rectum and the objective criteria of late effects of normal tissues-subjective, objective, management, analytic for vagina. Statistics used were group descriptions calculating their means, medians, and ranges. Bivariate analysis was evaluated using variance models and χ(2) tests. The mean followup was as follows: Group 1: 88 months, Group 2: 75 months, and 41 months in Group 3. No vaginal relapses were found. Late toxicity ≥ G2: rectum: 0 p in the three groups (0%). Bladder: Group 1: 1 p (2.4%), Group 2: 0%, and Group 3: 0%. Vagina: Group 1: 4 p (9.5%); Group 2: 9 p (15.3%); and Group 3:10 p (21.8%). There were no differences in late toxicity among the three groups of patients for rectum (p = 0.83), bladder (p = 0.58), and vagina (p = 0.67); the expected global risk of complications for rectum, bladder, and vagina is 0.8%, 0.8%, and 28.8%, respectively. Similar results in vaginal control and complications were achieved with the three schedules. The use of three fractions of 6 Gy administered daily is the best option for patient comfort and convenience and use of resources. Nonetheless, specific studies are needed to demonstrate the best cost-efficacy regime. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  4. Fifteen-Year Radiotherapy Outcomes of the Randomized PORTEC-1 Trial for Endometrial Carcinoma

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    Creutzberg, Carien L., E-mail: c.l.creutzberg@lumc.nl [Department of Clinical Oncology, Leiden University Medical Center (Netherlands); Nout, Remi A. [Department of Clinical Oncology, Leiden University Medical Center (Netherlands); Lybeert, Marnix L.M. [Department of Radiotherapy, Catharina Hospital Eindhoven (Netherlands); Warlam-Rodenhuis, Carla C. [Department of Radiation Oncology, University Medical Center Utrecht (Netherlands); Jobsen, Jan J. [Department of Radiotherapy, Medisch Spectrum Twente, Enschede (Netherlands); Mens, Jan-Willem M. [Department of Radiation Oncology, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Lutgens, Ludy C.H.W. [MAASTRO clinic, Maastricht (Netherlands); Pras, Elisabeth [Department of Radiotherapy, University Medical Center Groningen (Netherlands); Poll-Franse, Lonneke V. van de [Comprehensive Cancer Centre South, Eindhoven and Center of Research on Psychology in Somatic Diseases, Tilburg University (Netherlands); Putten, Wim L.J. van [Department of Biostatistics, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam (Netherlands)

    2011-11-15

    Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. Patients and Methods: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. Results: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.

  5. Value of detection of serum human epididymis secretory protein 4 and carbohydrate antigen 125 in diagnosis of early endometrial cancer of different pathological subtypes.

    Science.gov (United States)

    Liu, Xingui; Zhao, Fengting; Hu, Linli; Sun, Yingpu

    2015-01-01

    This study explored the value of detection of human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125) from serum in diagnosis of early endometrial cancer of different pathological subtypes and discussed the mechanism of HE4 and CA125 in diagnosis. In this study, enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect HE4 and CA125 from serum in endometrial cancer and control groups. Besides, the concentration of HE4 and CA125 was compared in these two groups, and the expression of CA125 and HE4 and clinicopathological characteristics in patients with endometrial cancer were also analyzed. Compared with the control group, the expression of HE4 was much higher in serum of patients with endometrial cancer, while there was no obvious change in the expression of CA125. The threshold detection value was acquired by receiver operating characteristic analysis method, that is, 141.5 pmol/L and 54.5 U/L, respectively. When comparing the concentration of HE4 in patients with endometrial cancer at the early stage (stage I) with healthy people, the difference therein had statistical significance, but there was no obvious difference in CA125. HE4 and CA125 in diagnosis of endometrial cancer in the stages I and II were found with no statistically significant difference. The difference of HE4 in the stages II and III had statistical significance while the difference of CA125 had no statistical significance. The specificity of both HE4 and CA125 was 95%, and the sensitivity of HE4 to uterine papillary serous carcinomas was higher than that to endometrioid adenocarcinoma. Thus, the serum HE4 is much better than CA125 in detecting the endometrial cancer at an early stage.

  6. Concomitant endometrial and gallbladder metastasis in advanced multiple metastatic invasive lobular carcinoma of the breast: A rare case report.

    Science.gov (United States)

    Bezpalko, Kseniya; Mohamed, Mohamed A; Mercer, Leo; McCann, Michael; Elghawy, Karim; Wilson, Kenneth

    2015-01-01

    At time of presentation, fewer than 10% of patients have metastatic breast cancer. The most common sites of metastasis in order of frequency are bone, lung, pleura, soft tissue, and liver. Breast cancer metastasis to the uterus or gallbladder is rare and has infrequently been reported in the English literature. A 47 year old female with a recent history of thrombocytopenia presented with abnormal vaginal bleeding. Pelvic ultrasound revealed multiple uterine fibroids and endometrial curettings revealed cells consistent with lobular carcinoma of the breast. Breast examination revealed edema and induration of the lower half of the right breast. Biopsy of the right breast revealed invasive lobular carcinoma. Bone marrow aspiration obtained at a previous outpatient visit revealed extensive involvement by metastatic breast carcinoma. Shortly after discharge, the patient presented with acute cholecystitis and underwent cholecystectomy. Microscopic examination of the gallbladder revealed metastatic infiltrating lobular carcinoma. The final diagnosis was invasive lobular carcinoma of the right breast with metastasis to the bone marrow, endometrium, gallbladder, regional lymph nodes, and peritoneum. The growth pattern of invasive lobular carcinoma of the breast is unique and poses a challenge in diagnosing the cancer at an early stage. Unlike other types of breast cancer, it tends to metastasize more to the peritoneum, ovary, and gastrointestinal tract. Metastasis to the endometrium or gallbladder is rare. Metastatic spread should be considered in the differential diagnosis of patients with invasive lobular breast carcinoma presenting with abnormal vaginal bleeding or acute cholecystitis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Endometrial carcinoma: merit of magnetic resonance in pre-surgical staging; Carcinoma de endometrio: valor de la estadificacion prequirurgica por resonancia magnetica

    Energy Technology Data Exchange (ETDEWEB)

    Fernandez, E.; Barrera, M. C.; Gervas, C.; Salvador, E.; Rivero, B. [Hospital Donostia. San sebastian (Spain); Sentis, M. [Corporacio Sanitaria Pare Tauli. Sabadell (Spain)

    2003-07-01

    To evaluate MR capacity in assessing deep myometrial and cervical infiltrations in cases of endometrial carcinoma. A series of 30 consecutively diagnosed endometrial cancer patients was pre-surgically evaluated by means of magnetic resonance (MR). TSE-T2 sequences with fat saturation and dynamic FFe sequence were used after gadolinium administration. A correlation with post-surgical histological stating was made. There were then determined sensitivity (S), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) for the deep myometrial infiltration and cervical invasion. Cases of overestimation and underestimation were analyzed. Values obtained for myometrium and cervix were, respectively, S of 67% and 63%, SP of 89% and 91%, PPV of 80% and 71% and NPV of 80% and 87%. Two cases each were over valued for myometrial infiltration and cervix: four cases and 3 cases, respectively, were undervalues. MR stating in cases of endometrial carcinoma is a highly reliable diagnostic technique, but it does present certain limitations. (Author) 19 refs.

  8. [Effects of pathological assessment of endometrial tissue in fertility-sparing treatment with progestin for endometrial carcinoma of stage I a and complex atypical hyperplasia].

    Science.gov (United States)

    Gong, Qinglin; Chen, Xiaoduan; Xie, Xing

    2014-09-01

    To assess the efficacy and pathological change of fertility-sparing treatment with progestin for endometrial carcinoma (EC) of stage I a and complex atypical hyperplasia (CAH) and to observe the prognosis of the treatment. Nine EC patients of stage I a and 21 CAH patients aged under 40 years who desired childbearing and retaining their fertility were enrolled into this study. All patients were given a daily oral high-dose of progestin with duration of treatment ranging from 6 to 9 months. Diagnostic curettage was performed every 3 months as a modality for seeing the histologic change of neoplastic tissues and endometrial tissue. A careful and long- term follow- up is necessary for patients with complete response (CR). During the first period of fertility-sparing management, according to histologic change, 5 EC patients and 18 CAH patients showed CR with no evidence of endometrial adenocarcinoma or hyperplasia, 2 EC patients and 2 CAH patients showed partial response with a regression to complex or simple hyperplasia without atypia, 2 EC patients and 1 CAH patient showed stable disease or progressive disease. Accordingly, a total of 26 patients showed CR (26 of 30 patients). The median time to CR was 6 months (range, 3 to 21 months) of progestin treatment. The median follow-up time was 55.5 months (range, 24 to 104 months) and all patients were alive. During follow-up, among the 26 patients with CR, 3 of 6 EC patients achieved CR recurred disease after a median time interval of 10 months (range, 6 to 51 months), 7 of 20 CAH patients achieved CR had recurrent disease after a median time interval of 12 months (range, 6 to 55 months). Four of 7 CAH with recurrent disease achieved CR to progestin re-treatment. Eight of 26 patients achieved CR continued a further 3 or 6 months of consolidation therapy, 3 of them had recurrent disease, the remaining 18 stopped progesterone treatment after CR and 7 patients had recurrent disease; there was no significant statistical

  9. Characteristics of Human Endometrial Stem Cells in Tissue and Isolated Cultured Cells: An Immunohistochemical Aspect.

    Science.gov (United States)

    Fayazi, Mehri; Salehnia, Mojdeh; Ziaei, Saeideh

    2016-01-01

    The aim of this study was to investigate the percentage of the stem cells population in human endometrial tissue sections and cultured cells at fourth passage. Human endometrial specimens were divided into two parts, one part for morphological studies and the other part for in vitro culture. Full thickness of human normal endometrial sections and cultured endometrial cells at fourth passage were analyzed via immunohistochemistry for CD146 and some stemness markers such as Oct4, Nanog, Sox2, and Klf4 and the expression of typical mesenchymal stem cell markers CD90, CD105. 11.88 ± 1.29% of human endometrial cells whitin tissue sections expressed CD146 marker vs. 28±2.3% of cultured cells, CD90 and CD105 were expressed by functionalis stroma (85±2.4 and 89±3.2%) than basalis stroma (16±1.4 and 17±1.9%), respectively (Pendometrial stromal cells in endometrial sections vs. 12±3.1% and 8±2.9% of cultured cells, respectively. They reside near the glands in the basal layer of endometrium. Sox2 and Klf4 were not commonly expressed in tissue samples and cultured cells. CD9 and EpCAM were expressed by epithelial cells of the endometrium, rather than by stroma or perivascular cells. The human endometrial stem cells and pluripotency markers may be localized more in basalis layer of endometrium. The immunostaining observations of endometrial cells at fourth passage were correlated with the immunohistochemistry data.

  10. Prevalence of Human Papillomavirus in endometrial cancer: a systematic review and meta-analysis.

    Science.gov (United States)

    Olesen, Tina Bech; Svahn, Malene Frøsig; Faber, Mette Tuxen; Duun-Henriksen, Anne Katrine; Junge, Jette; Norrild, Bodil; Kjaer, Susanne K

    2014-07-01

    HPV is a common sexually transmitted infection and is considered to be a necessary cause of cervical cancer. The anatomical proximity to the cervix has led researchers to investigate whether Human Papillomavirus (HPV) has a role in the etiology of endometrial cancer. We conducted a systematic review and meta-analysis to investigate the pooled prevalence of HPV DNA in endometrial cancer. Using meta-regression, we further analyzed whether factors such as geographical region, HPV DNA detection method, publication year and tissue type were associated with HPV prevalence. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for studies providing data on HPV prevalence in cases with endometrial cancer and in controls with normal or hyperplastic endometrial tissue. We identified 28 papers (29 studies) examining the prevalence of HPV DNA in tumor tissue from endometrial cancer comprising altogether 1026 cases of endometrial cancer. The HPV prevalence varied considerably from 0% to 61.1%. From the random effects meta-analysis, the pooled prevalence of HPV DNA in endometrial cancer was 10.0% (95% CI: 5.2-16.2) with large between-study heterogeneity (I(2)=88.2%, pendometrial cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Isolation and primary culture of various cell types from whole human endometrial biopsies

    OpenAIRE

    Barros, Flavio; Brosens, Jan J.; Brighton, Paul (Paul J.)

    2016-01-01

    The isolation and primary culture of cells from human endometrial biopsies provides valuable experimental material for reproductive and gynaecological research. Whole endometrial biopsies are collected from consenting women and digested with collagenase and DNase I to dissociate cells from the extracellular matrix. Cell populations are then isolated through culturing, filtering and magnetic separation using cell-surface antigen markers. Here we provide a comprehensive protocol on how to isola...

  12. Endometrial CRISP3 is regulated throughout the mouse estrous and human menstrual cycle and facilitates adhesion and proliferation of endometrial epithelial cells.

    Science.gov (United States)

    Evans, Jemma; D'Sylva, Rebecca; Volpert, Marianna; Jamsai, Duangporn; Merriner, Donna Jo; Nie, Guiying; Salamonsen, Lois A; O'Bryan, Moira K

    2015-04-01

    The endometrium (the mucosal lining of the uterus) is a dynamic tissue that undergoes extensive remodeling, secretory transformation in preparation for implantation of an embryo, inflammatory and proteolytic activity during menstruation, and rapid postmenstrual repair. A plethora of local factors influence these processes. Recently, a cysteine-rich protein, CRISP3, a clade of the CRISP, antigen 5, pathogenesis-related (CAP) protein superfamily, has been implicated in uterine function. The localization, regulation, and potential function of CRISP3 in both the human and mouse endometrium is described. CRISP3 localizes to the luminal and glandular epithelium of the endometrium within both species, with increased immunoreactivity during the proliferative phase of the human cycle. CRISP3 also localizes to neutrophils, particularly within the premenstrual human endometrium and during the postbreakdown repair phase of a mouse model of endometrial breakdown and repair. Endometrial CRISP3 is produced by primary human endometrial epithelial cells and secreted in vivo to accumulate in the uterine cavity. Secreted CRISP3 is more abundant in uterine lavage fluid during the proliferative phase of the menstrual cycle. Human endometrial epithelial CRISP3 is present in both a glycosylated and a nonglycosylated form in vitro and in vivo. Treatment of endometrial epithelial cells in vitro with recombinant CRISP3 enhances both adhesion and proliferation. These data suggest roles for epithelial and neutrophil-derived CRISP3 in postmenstrual endometrial repair and regeneration. © 2015 by the Society for the Study of Reproduction, Inc.

  13. SPARC was overexpressed in human endometrial cancer stem-like cells and promoted migration activity.

    Science.gov (United States)

    Yusuf, Nurismangul; Inagaki, Tetsunori; Kusunoki, Soshi; Okabe, Hitomi; Yamada, Izumi; Matsumoto, Akemi; Terao, Yasuhisa; Takeda, Satoru; Kato, Kiyoko

    2014-08-01

    We previously demonstrated that side-population (SP) cells found in human endometrial cancer tissue have features of cancer stem cells (CSCs). Endometrial cancer SP cells show enhanced migration, the potential to differentiate into the mesenchymal cell lineage, and they are associated with the epithelial-mesenchymal transition (EMT). In this study, we analyzed the expression and function of a specific protein, SPARC (secreted protein acidic and rich in cysteine) which we found to be up-regulated in endometrial cancer. We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP (NSP) cells. We used the MetaCore package to identify the Gene GO pathway MAPs associated with the up-regulated genes. Here, we investigated the expression and functions of SPARC, one of the genes up-regulated in endometrial CSCs. We established SPARC-overexpressing cells by transfecting endometrial cancer cells (Ishikawa cells [IK-SPARC cells]). We characterized these cells' growth rate, tumorigenicity, migration and invasion activity. The levels and locations of SPARC protein expression in Hec1SP cells-derived tumors and endometrial cancer tissues were examined by immunohistochemistry. SPARC was detected by microarray expression analysis during screens for up-regulated genes in SP and NSP CSC. The level of SPARC expression was enhanced in Hec1 SP cells compared with that in Hec1 non-SP cells. SPARC enhanced fibronectin expression and promoted migration activity in IK cells. SPARC expression suppressed tumor growth but promoted formation of tumor stroma. SPARC was expressed in endometrial cancer tissues, in particular, poorly differentiated endometrioid adenocarcinoma, clear and serous adenocarcinoma,but not in normal endometrial tissue. This is the first report of overexpression of SPARC in endometrial cancer stem-like cells. SPARC expression is associated with cell migration and stroma formation. Copyright © 2014 Elsevier

  14. Value of cervical cytology in diagnosing endometrial carcinoma in women with postmenopausal bleeding

    NARCIS (Netherlands)

    van Doom, Helena C.; Opmeer, Brent C.; Kooi, G. Sjarlot; Ewing-Graham, Patrica C.; Kruitwagen, Roy F. P. M.; Mol, Ben W. J.

    2009-01-01

    OBJECTIVE: To assess the accuracy of the cervical smear in the diagnosis of endometrial cancer in women with postmenopausal bleeding, with an emphasis on the diagnostic relevance of normal endometrial cells. STUDY DESIGN: Women presenting with abnormal postmenopausal bleeding, not using hormone

  15. Outcome and management of pathological stage I endometrial carcinoma patients with involvement of the lower uterine segment.

    Science.gov (United States)

    Phelan, C; Montag, A G; Rotmensch, J; Waggoner, S E; Yamada, S D; Mundt, A J

    2001-12-01

    The objective was to evaluate the clinicopathologic characteristics and outcome of pathologic stage I endometrial carcinoma patients with lower uterine segment (LUS) involvement. We retrospectively reviewed the characteristics and outcomes of pathologic stage I endometrial carcinoma patients treated with primary surgery at our institution between 1988 and 1998. The significance of LUS involvement was examined with univariate and multivariate analyses. Median patient follow-up was 37.3 months. Of the 98 cases reviewed, 41 (42%) had LUS involvement. No differences were seen in the clinicopathologic features, extent of surgical staging, or adjuvant therapies between patients with and without LUS involvement. Univariate analysis revealed that grade, lymphovascular invasion (LVI), myometrial invasion (MI), and histology were correlated with recurrence. While the 5-year actuarial disease-free survival was worse in women with LUS involvement (80.3 vs 94.0%) compared to those without, this difference did not reach statistical significance (P = 0.14). Moreover, after controlling for pathologic features in a multivariate model, LUS involvement was not correlated with patient outcome (P = 0.98; hazard rate 0.97; 95% confidence interval 0.24, 4.0). LUS was also not correlated with pelvic recurrence. Of 25 low-risk patients (superficial MI and grade 1-2 disease) with LUS involvement, none recurred in the pelvis following surgery alone. In contrast, pelvic recurrence was common (5/12 or 41.6%) in high-risk patients (deep MI and/or grade 3 tumors) following surgery alone regardless of LUS involvement. LUS involvement is common in pathologic stage I endometrial carcinoma but is not correlated with a worse outcome. Moreover, in the absence of adverse pathologic features, LUS involvement is not associated with an increased risk of pelvic recurrence and should not be used as an indication for adjuvant radiation therapy. (c)2001 Elsevier Science.

  16. Comparison of dynamic contrast-enhanced magnetic resonance imaging with T2-weighted imaging for preoperative staging of early endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Zheng L

    2015-07-01

    Full Text Available Linfeng Zheng,1,2 Sujuan Zheng,3 Xiaochun Yuan,1 Xifu Wang,1 Zhuoli Zhang,2 Guixiang Zhang1 1Department of Radiology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 3Department of Obstetrics and Gynecology, Dengfeng People’s Hospital, Zhengzhou, People’s Republic of China Purpose: This study aimed to compare dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI with T2-weighted imaging (T2WI for the preoperative staging of early endometrial carcinoma. Methods: This retrospective study included 22 subjects with early endometrial carcinoma who underwent 3.0 T MRI examination prior to hysterectomy. DCE-MRI and T2WI were evaluated for the preoperative staging of endometrial carcinoma. The sensitivity, specificity, positive predictive value (PPV, negative predictive value (NPV, and accuracy of DCE-MRI and T2WI were assessed and compared using the revised International Federation of Gynecology and Obstetrics surgical staging guidelines (2009 as the reference standard. Results: Out of the 22 cases of endometrial carcinoma, the use of the reference standard method led to the staging of 14 as IA and eight as IB. The sensitivity, specificity, PPV, NPV, and accuracy of DCE-MRI for preoperative staging were 100% (95% confidence interval: 0.73–1.0, 62.5% (95% CI: 0.26–0.90, 82.4% (95% CI: 0.56–0.95, 100% (95% CI: 0.46–1.0, and 86.4%, respectively, and these values were 85.7% (95% CI: 0.56–0.97, 75% (95% CI: 0.36–0.96, 85.7% (95% CI: 0.56–0.97, 75% (95% CI: 0.36–0.96, and 81.8%, respectively, for T2WI. Thus, the sensitivity and accuracy of DCE-MRI were greater than those of T2WI for preoperative endometrial carcinoma staging. Conclusion: DCE-MRI was more sensitive but less specific than T2WI for the preoperative staging of early endometrial carcinoma. DCE-MRI may serve as a

  17. Endometrial ablation

    Science.gov (United States)

    Hysteroscopy - endometrial ablation; Laser thermal ablation; Endometrial ablation - radiofrequency; Endometrial ablation - thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ...

  18. Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells.

    Directory of Open Access Journals (Sweden)

    Naoko Koyama

    Full Text Available Telmisartan, an angiotensin II receptor type 1 blocker, is often used as an antihypertension drug, and it has also been characterized as a peroxisome proliferator-activated receptor-gamma (PPARγ ligand. The purpose of this study was to elucidate the antitumor effects of telmisartan on endometrial cancer cells. We treated three endometrial cancer cell lines with various concentrations of telmisartan, and we investigated the effects of the telmisartan on the cell proliferation, apoptosis, and their related measurements in vitro. We also administered telmisartan to nude mice with experimental tumors to determine its in vivo effects and toxicity. All three endometrial cancer cell lines were sensitive to the growth-inhibitory effect of telmisartan. The induction of apoptosis was confirmed in concert with the altered expression of genes and proteins related to the apoptosis. We also observed that DNA double-strand breaks (DSBs were induced in HHUA (human endometrial cancer cells by telmisartan treatment. In addition, experiments in nude mice showed that telmisartan significantly inhibited human endometrial tumor growth, without toxic side effects. Our results suggest that telmisartan might be a new therapeutic option for the treatment of endometrial cancers.

  19. Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells.

    Directory of Open Access Journals (Sweden)

    Irene Cervelló

    Full Text Available During reproductive life, the human endometrium undergoes around 480 cycles of growth, breakdown and regeneration should pregnancy not be achieved. This outstanding regenerative capacity is the basis for women's cycling and its dysfunction may be involved in the etiology of pathological disorders. Therefore, the human endometrial tissue must rely on a remarkable endometrial somatic stem cells (SSC population. Here we explore the hypothesis that human endometrial side population (SP cells correspond to somatic stem cells. We isolated, identified and characterized the SP corresponding to the stromal and epithelial compartments using endometrial SP genes signature, immunophenotyping and characteristic telomerase pattern. We analyzed the clonogenic activity of SP cells under hypoxic conditions and the differentiation capacity in vitro to adipogenic and osteogenic lineages. Finally, we demonstrated the functional capability of endometrial SP to develop human endometrium after subcutaneous injection in NOD-SCID mice. Briefly, SP cells of human endometrium from epithelial and stromal compartments display genotypic, phenotypic and functional features of SSC.

  20. Endometrial Serous Carcinoma: Its Molecular Characteristics and Histology-Specific Treatment Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Nakayama, Kentaro, E-mail: kn88@med.shimane-u.ac.jp [Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501 (Japan); Nakayama, Naomi [Department of Biochemistry, Shimane University School of Medicine, Izumo 6938501 (Japan); Ishikawa, Masako; Miyazaki, Kohji [Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501 (Japan)

    2012-08-07

    Endometrial cancer is the fourth most common malignancy in women, with most cases being classified as early stage endometrioid tumors that carry a favorable prognosis. The endometrial serous histological subtype (ESC), however, while only accounting for 10% of all endometrial cancers is responsible for a disproportionate number of deaths. Unlike the estrogen-dependent, well differentiated endometrioid tumors, which are commonly associated with a younger age of onset, ESCs are estrogen-independent and tend to present at an advanced stage and in older women. Treatment for ESC entails aggressive surgery and multimodal adjuvant therapy. In this review, we describe the clinical behavior, molecular aspects, and treatment strategies for ESC.

  1. Flotillin-1 protein is upregulated in human endometrial cancer and localization shifts from epithelial to stromal with increasing tumor grade.

    Science.gov (United States)

    Winship, Amy Louise; Rainczuk, Kate; Dimitriadis, Evdokia

    2016-01-01

    Endometrial cancer is the most common invasive gynecological malignancy. Flotillin-1 is an integral membrane protein and estrogen responsive gene. Flotillin-1 expression and localization in human endometrial cancers grades 1-3 was investigated using real-time RT-PCR and immunohistochemistry. Flotillin-1 mRNA levels were unchanged in endometrial cancer versus benign endometrium. Flotillin-1 protein was significantly reduced in the epithelial compartment with increasing tumor grade, although levels increased in the tumor stroma across grades. We have identified a novel factor in human endometrial cancer and observed a shift in epithelial to stromal localization with increasing tumor grade in women.

  2. Comparative analyses of postoperative complications and prognosis of different surgical procedures in stage II endometrial carcinoma treatment

    Directory of Open Access Journals (Sweden)

    Yin H

    2016-02-01

    Full Text Available Hongmei Yin,1 Ting Gui2 1Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, 2Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Objective: To investigate the impact of surgical resection extent on the postoperative complications and the prognosis in patients with stage II endometrial cancer. Methods: A total of 54 patients were retrospectively reviewed, 35 patients underwent subradical hysterectomy and 19 patients received radical hysterectomy, both with simultaneous bilateral salpingo-oophorectomy and pelvic and paraaortic lymphadenectomy. Results: Comparing the surgical outcomes in subradical hysterectomy group vs radical hysterectomy group, there were no significant differences in operative time, estimated blood loss, and hospital stay. After surgery, 37.1% vs 36.8% patients received postoperative radiotherapy in the subradical hyster­ectomy group vs radical hysterectomy group, without statistically significant difference. As for postoperative complications, the early postoperative complication rate in patients who underwent subradical hysterectomy was 14.3%, significantly lower than that in patients submitted to radical hysterectomy (14.3% vs 42.1%, with P=0.043. However, there was no significant difference in late postoperative complication rate between the two surgical procedures. Regarding the clinical prognosis, patients receiving the subradical hysterectomy showed similar survival to their counterparts undergoing the radical procedures. The relapse rate was 5.71% vs 5.26%, respectively, without significant difference. There were no deaths in both surgical groups. Conclusion: For stage II endometrial carcinoma, subradical hysterectomy presented with less early postoperative complications and similar survival duration and recurrence

  3. Role of endocervical curettage in the preoperative staging of endometrial carcinoma

    NARCIS (Netherlands)

    Bijen, Claudia B. M.; de Bock, Geertruida H.; ten Hoor, Klaske A.; Nijman, Hans W.; Hollema, Harry; Mourits, Marian J. E.

    Objective, The presence of cervical involvement is important to establish a rational treatment for endometrial cancer patients. We investigated the value of preoperative endocervical curettage (ECC) in predicting cervical involvement. Methods. Preoperative ECC of 290 patients with clinical stage I

  4. HIF-1α and GLUT-1 Expression in Atypical Endometrial Hyperplasia, Type I and II Endometrial Carcinoma: A Potential Role in Pathogenesis.

    Science.gov (United States)

    Al-Sharaky, Dalia Rifaat; Abdou, Asmaa Gaber; Wahed, Moshira Mohammed Abdel; Kassem, Hend Abdou

    2016-05-01

    Hypoxia-Inducible Factor 1α (HIF-1α) is one of the major adaptive responses to hypoxia, regulating the activity of glucose transporter -1 (GLUT-1), responsible for glucose uptake. To evaluate the immunohistochemical expression of both HIF-1α and GLUT-1 in type I and II endometrial carcinoma and their correlation with the available clinicopathologic variables in each type. A retrospective study was conducted on archival blocks diagnosed from pathology department between April 2010 and August 2014 included 9 cases of atypical hyperplasia and 67 cases of endometrial carcinoma. Evaluation of both HIF-1α and GLUT-1 expression using standard immunohistochemical techniques performed on cut sections from selected paraffin embedded blocks. Descriptive analysis of the variables and statistical significances were calculated by non-parametric chi-square test using the Statistical Package for the Social Sciences version 12.0 (SPSS). HIF-1α was expressed in epithelial (88.9%, 52.2%, 61.2% and 50%) and stromal (33.3%, 74.6%. 71.4% and 83.3%) components of hyperplasia, total cases of EC, type I and II EC, respectively. GLUT-1 was expressed in the epithelial component of 88.9%, 98.5%, 98% and 100% of hyperplasia, total EC cases, type I and II EC, respectively. The necrosis related pattern of epithelial HIF-1α expression was in favour of type II (p=0.018) and grade III (p=0.038). HIF-1α H-score was associated with high apoptosis in both type I and total cases of EC (p=0.04). GLUT-1 H-score was negatively correlated with apoptotic count (p=0.04) and associated with high grade (p=0.003) and advanced stage in total EC (p=0.004). GLUT-1 H-score was correlated with the pattern of HIF-1α staining in all cases of EC (p= 0.04). The role of HIF-1α in epithelial cells may differ from that of stromal cells in EC; however they augment the expression of each other supporting the crosstalk between them. The stepwise increase in H- score of GLUT-1 in the studied cases implies its

  5. Kisspeptin-10 inhibits stromal-derived factor 1-induced invasion of human endometrial cancer cells.

    Science.gov (United States)

    Schmidt, Elena; Haase, Maike; Ziegler, Elke; Emons, Günter; Gründker, Carsten

    2014-02-01

    The cross talk between metastatic cancer cells and target sites is critical for the development and progression of metastases. Disruption of this interaction will allow to design mechanism-based effective and specific therapeutic interventions for metastases. We have established a coculture system of cells derived from different tumor entities and MG63 human osteoblastlike cells to analyze tumor cell invasion. Recently, we have shown that breast cancer cell invasion was dramatically increased when cocultured with MG63 cells.Using this model, we have now analyzed whether stromal-derived factor 1 (SDF-1) is responsible for human endometrial cancer cell invasion and whether kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion of endometrial cancer cells in vitro. Invasion was quantified by assessment of endometrial cancer cell migration rate through an artificial basement membrane in a modified Boyden chamber during coculture with MG63 cells or after treatment with SDF-1α, SDF-1β, or the combination of both SDF-1 isoforms. In addition, the role of SDF-1 in invasion of endometrial cancer cells was analyzed by blocking SDF-1 secretion during coculture with MG64 cells. Furthermore, the effects of KP-10 treatment on MG63 coculture-driven and SDF-1-induced invasion were analyzed. Endometrial cancer cell invasion was significantly increased when cocultured with MG63 cells. Treatment with KP-10 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. This effect was significant in a dose window of 10(-13) to 10(-11) mol/L. During coculture, SDF-1 protein expression of MG63 cells was significantly increased. The MG63 coculture-induced increase of endometrial cancer cell invasion could be blocked by anti-SDF-1 antibodies. Treatment of endometrial cancer cells in monoculture (without MG63) with SDF-1α, SDF-1β, or the combination of both isoforms resulted in a significant increase of endometrial cancer

  6. Improved outcome of high grade, early 1 stage endometrioid endometrial carcinoma with adjuvant chemotherapy and radiotherapy : Comparison of 2 treatment strategies

    NARCIS (Netherlands)

    Reynaers, Eline Aem; Jutzi, Leah; Ezendam, N.P.M.; Kwon, Janice S.; Pijnenborg, Johanna M.a.

    2017-01-01

    Objective: patients with high grade endometrioid endometrial carcinoma have a high risk of recurrence, even in early stage. To determine the benefit of a more aggressive adjuvant treatment approach, different treatment strategies of 2 referral centers were compared. Materials and methods: outcome of

  7. Improved Outcome of High-Grade, Early 1-Stage Endometrioid Endometrial Carcinoma With Adjuvant Chemotherapy and Radiotherapy: Comparison of 2 Treatment Strategies

    NARCIS (Netherlands)

    Reynaers, E.A.; Jutzi, L.; Ezendam, N.P.; Kwon, J.S.; Pijnenborg, J.M.A.

    2017-01-01

    OBJECTIVE: Patients with high-grade endometrioid endometrial carcinoma have a high risk of recurrence, even in early stage. To determine the benefit of a more aggressive adjuvant treatment approach, different treatment strategies of 2 referral centers were compared. MATERIALS AND METHODS: Outcome of

  8. Less gastrointestinal toxicity after adjuvant radiotherapy on a small pelvic field compared to a standard pelvic field in patients with endometrial carcinoma

    NARCIS (Netherlands)

    de Jong, Renske A.; Pras, Elisabeth; Boezen, H. Marike; van der Zee, Ate G. J.; Mourits, Marian J. E.; Arts, Henriette J. G.; Aalders, Jan G.; Slot, Annerie; Timmer, Paul R.; Hollema, Harry; Nijman, Hans W.

    Objective: Radiotherapy is associated with short-term and long-term morbidity. This study compared toxicity rates among patients with endometrial carcinoma (EC) treated with adjuvant external beam radiation therapy (EBRT) on a small pelvic field (SmPF) in comparison with a standard pelvic field

  9. Reversed glucose and fatty acids transporter expression in human endometrial cancer.

    Science.gov (United States)

    Knapp, P; Chabowski, A; Harasiuk, D; Górski, J

    2012-06-01

    Cancer cells exhibit accelerated rates of metabolism favoring glucose over fatty acid (FA) utilization. For both energy substrates, protein-mediated transport plays an essential role in facilitating glucose or FA movement across plasma membrane into the cells. Scarce data exist regarding the expression of glucose and/or FA transporter in cancer tissue. Therefore, we examined glucose (GLUT-1, GLUT-3, GLUT-4) and FA (FAT/CD36, FABPpm, FATP-1) transporter expressions at the protein and post-transcript (mRNA) levels in 35 endometrial carcinomas (G1, type endometrioid, FIGO I) and compared them with normal endometrial mucosa (n=10). Endometrial cancer tissue had significantly greater protein expression of GLUT-1, GLUT-3, and GLUT-4 (+ 40%; + 20%; + 24%; ptransporter expression ( - 25%; p0.05 respectively). Interestingly, mRNA content closely mirrors the changes, but only for glucose transporters and not fatty acid transporters. These results suggest the presence of metabolic switch of energy utilization in endometrial cancers favoring glucose consumption as the major source of energy. © Georg Thieme Verlag KG Stuttgart · New York.

  10. NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer.

    Science.gov (United States)

    Sasnauskienė, Aušra; Jonušienė, Violeta; Krikštaponienė, Aurelija; Butkytė, Stasė; Dabkevičienė, Daiva; Kanopienė, Daiva; Kazbarienė, Birutė; Didžiapetrienė, Janina

    2014-01-01

    Notch signaling is a conserved developmental pathway, which plays an important role in the regulation of cell proliferation, differentiation and death. Deregulation of Notch pathway has been connected with the carcinogenesis in a variety of cancers. The aim of this study was to investigate the level of the Notch signaling pathway proteins (NOTCH1, 3, 4 and JAG2) in the samples from human endometrial cancer. The amount of the Notch receptors NOTCH1, 3, 4 and ligand JAG2 protein was determined by Western blot analysis in the samples from stage I endometrial cancer and adjacent nontumor endometrial tissue of 22 patients. The level of NOTCH4 receptor was 1.7 times lower in stage I endometrial cancer as compared with the healthy tissue of the same patients (P=0.04). The protein level of ligand JAG2 was significantly reduced by 2.5 times in stage IB endometrial adenocarcinoma samples (P=0.01). It was reduced in the majority of stage IB adenocarcinomas. There were no significant changes in the protein amount of NOTCH1 and NOTCH3 receptors comparing stage I endometrial adenocarcinoma and healthy tissues. The reduced amount of NOTCH4 and JAG2 proteins and the decreased level of mRNA coding Notch proteins, as reported in our previous studies, supports the notion that Notch pathway has rather tumor-suppressive than oncogenic role in human endometrial cancer cells. It suggests that Notch pathway activation is a potential therapeutic target. Copyright © 2014 Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  11. Steroids Regulate CXCL4 in the Human Endometrium During Menstruation to Enable Efficient Endometrial Repair.

    Science.gov (United States)

    Maybin, Jacqueline A; Thiruchelvam, Uma; Madhra, Mayank; Saunders, Philippa T K; Critchley, Hilary O D

    2017-06-01

    Repair of the endometrial surface at menstruation must be efficient to minimize blood loss and optimize reproductive function. The mechanism and regulation of endometrial repair remain undefined. To determine the presence/regulation of CXCL4 in the human endometrium as a putative repair factor at menses. Endometrial tissue was collected throughout the menstrual cycle from healthy women attending the gynecology department. Menstrual blood loss was objectively measured in a subset, and heavy menstrual bleeding (HMB) was defined as >80 mL per cycle. Monocytes were isolated from peripheral blood. CXCL4 messenger RNA (mRNA) and protein were identified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The function/regulation of endometrial CXCL4 was explored by in vitro cell culture. CXCL4 mRNA concentrations were significantly increased during menstruation. Intense staining for CXCL4 was detected in late secretory and menstrual tissue, localized to stromal, epithelial and endothelial cells. Colocalization identified positive staining in CD68+ macrophages. Treatment of human endometrial stromal and endothelial cells (hESCs and HEECs, respectively) with steroids revealed differential regulation of CXCL4. Progesterone withdrawal resulted in significant increases in CXCL4 mRNA and protein in hESCs, whereas cortisol significantly increased CXCL4 in HEECs. In women with HMB, CXCL4 was reduced in endothelial cells during the menstrual phase compared with women with normal menstrual bleeding. Cortisol-exposed macrophages displayed increased chemotaxis toward CXCL4 compared with macrophages incubated with estrogen or progesterone. These data implicate CXCL4 in endometrial repair after menses. Reduced cortisol at the time of menses may contribute to delayed endometrial repair and HMB, in part by mechanisms involving aberrant expression of CXCL4.

  12. Interval Between Hysterectomy and Start of Radiation Treatment Is Predictive of Recurrence in Patients With Endometrial Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Cattaneo, Richard [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Hanna, Rabbie K. [Division of Gynecologic Oncology, Department of Women' s Health Services, Henry Ford Hospital, Detroit, Michigan (United States); Jacobsen, Gordon [Public Health Science, Henry Ford Hospital, Detroit, Michigan (United States); Elshaikh, Mohamed A., E-mail: melshai1@hfhs.org [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States)

    2014-03-15

    Purpose: Adjuvant radiation therapy (RT) has been shown to improve local control in patients with endometrial carcinoma. We analyzed the impact of the time interval between hysterectomy and RT initiation in patients with endometrial carcinoma. Methods and Materials: In this institutional review board-approved study, we identified 308 patients with endometrial carcinoma who received adjuvant RT after hysterectomy. All patients had undergone hysterectomy, oophorectomy, and pelvic and para-aortic lymph node evaluation from 1988 to 2010. Patients' demographics, pathologic features, and treatments were compared. The time interval between hysterectomy and the start of RT was calculated. The effects of time interval on recurrence-free (RFS), disease-specific (DSS), and overall survival (OS) were calculated. Following univariate analysis, multivariate modeling was performed. Results: The median age and follow-up for the study cohort was 65 years and 72 months, respectively. Eighty-five percent of the patients had endometrioid carcinoma. RT was delivered with high-dose-rate brachytherapy alone (29%), pelvic RT alone (20%), or both (51%). Median time interval to start RT was 42 days (range, 21-130 days). A total of 269 patients (74%) started their RT <9 weeks after undergoing hysterectomy (group 1) and 26% started ≥9 weeks after surgery (group 2). There were a total of 43 recurrences. Tumor recurrence was significantly associated with treatment delay of ≥9 weeks, with 5-year RFS of 90% for group 1 compared to only 39% for group 2 (P<.001). On multivariate analysis, RT delay of ≥9 weeks (P<.001), presence of lymphovascular space involvement (P=.001), and higher International Federation of Gynecology and Obstetrics grade (P=.012) were independent predictors of recurrence. In addition, RT delay of ≥9 weeks was an independent significant predictor for worse DSS and OS (P=.001 and P=.01, respectively). Conclusions: Delay in administering adjuvant RT after

  13. Cellular binding proteins for vitamin A in human carcinomas and in normal tissues.

    Science.gov (United States)

    Palan, P R; Romney, S L

    1980-11-01

    Blinded analyses of the concentrations of binding proteins for retinol and retinoic acid (CRABP) in homogenates of cancer and normal tissue aliquots obtained from human cervix, endometrium, ovary, breast, and lung were carried out by the sucrose gradient ultracentrifugation technique. In carcinomas of the cervix and endometrium, CRABP mean values of 50.4 and 123.2 pmol/g tissue, respectively were detected. Such concentrations represent a 3- and 4-fold increase over the mean values of CRABP in the normal cervix (16.9 pmol/g) and normal endometrium (30.8 pmol/g), respectively. In carcinomas of the ovary, the mean CRABP level was 128.6 pmol/g compared to the maximal mean value of less than or equal to 0.46 pmol/g in the normal ovary. Elevated levels of CRABP were also found in breast and lung carcinomas compared to the amounts detected in the same patient in normal tissue aliquots of the same organ. The differences between CRABP concentrations in cervical, endometrial, ovarian, and breast carcinomas and those in normal tissue are statistically significant. In contrast, cellular retinol-binding protein concentrations were reduced in the endometrial, ovarian, breast, and lung carcinomas compared to normal tissues. There were no significant differences between the log-mean concentrations of cellular retinol-binding proteins in the cytosols from tissue aliquots of carcinoma of the cervix and those in the cytosols from tissue aliquots of normal cervix.

  14. Endometrial Hyperplasia

    Science.gov (United States)

    ... Management Education & Events Advocacy For Patients About ACOG Endometrial Hyperplasia Home For Patients Search FAQs Endometrial Hyperplasia ... Spanish Endometrial Hyperplasia FAQ147, May 2011 PDF Format Endometrial Hyperplasia Gynecologic Problems What is endometrial hyperplasia? How ...

  15. Fibulin-5 localisation in human endometrial cancer shifts from epithelial to stromal with increasing tumour grade, and silencing promotes endometrial epithelial cancer cell proliferation.

    Science.gov (United States)

    Winship, Amy Louise; Rainczuk, Kate; Ton, Amanda; Dimitriadis, Eva

    2016-07-01

    Endometrial cancer is the most common invasive gynaecological malignancy. While endocrine, genetic and inflammatory factors are thought to contribute to its pathogenesis, its precise etiology and molecular regulators remain poorly understood. Fibulin-5 is an extracellular matrix (ECM) protein that inhibits cell growth and invasion in several cancer cell types and is downregulated in a number of types of human cancer. However, it is unknown whether fibulin-5 plays a role in endometrial tumourigenesis. In the current report, the expression and localisation of fibulin-5 in type I endometrioid human endometrial cancers of grades (G) 1-3 was investigated using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Fibulin-5 mRNA was found to be significantly reduced in whole tumour tissues from women across G1-3 compared with benign endometrium (Pendometrial epithelial cancer cells expressing fibulin-5 stimulated cell adhesion and proliferation in vitro . Fibulin-5 mRNA expression in Ishikawa cells was induced by transforming growth factor-β and fibulin-5 in turn activated extracellular signal-regulated kinases (ERK1/2), suggesting that it may act via the mitogen-activated protein kinase pathway. In summary, the present study identified fibulin-5 as a downregulated ECM gene in human endometrial cancer and observed a shift from epithelial to stromal protein localisation with increasing tumour grade in women. These data suggest that loss of fibulin-5 function may promote endometrial cancer progression by enhancing epithelial cell adhesion and proliferation.

  16. Tibial bone metastasis as an initial presentation of endometrial carcinoma diagnosed by fine-needle aspiration cytology: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Sarag Aboujafar Boukhar

    2015-01-01

    Full Text Available Endometrial cancer is the most common gynecologic malignancy in the United States. However, bony metastasis is infrequent and exceptionally rare as the initial presentation. We report a case of a 77-year-old female with a clinically silent endometrial carcinoma who presented with a left tibial metastasis as the first manifestation of her disease. Ours is only the third case diagnosed by fine-needle aspiration (FNA cytology, and the first to detail the cytomorphologic features of metastatic endometrial cancer to bone. These microscopic findings, including three-dimensional cohesive clusters with cellular overlapping and cuboidal to columnar cells exhibiting low nuclear: cytoplasmic ratios and partially vacuolated cytoplasm, differ significantly from those of endometrial carcinoma on a Papanicolaou test. The tumor bore similarity to the more commonly encountered metastatic colon cancer, but immunohistochemical staining enabled reliable distinction between these entities. A review of osseous metastases of endometrial cancer demonstrates a predilection for bones of the lower extremity and pelvis with a predominance of the endometrioid histologic subtype. In about a quarter of the cases, the bony metastasis was the first manifestation of the cancer. FNA was an effective diagnostic modality for this unusual presentation of a common malignancy. Awareness of this entity and its differential diagnosis is essential for accurate and timely diagnosis.

  17. The effect of stem cell factor on proliferation of human endometrial CD146+ cells

    Directory of Open Access Journals (Sweden)

    Mehri Fayazi

    2016-07-01

    Full Text Available Background: Stem cell factor (SCF is a transcriptional factor which plays crucial roles in normal proliferation, differentiation and survival in a range of stem cells. Objective: The aim of the present study was to examine the proliferation effect of different concentrations of SCF on expansion of human endometrial CD146+ cells. Materials and Methods: In this experimental study, total populations of isolated human endometrial suspensions after fourth passage were isolated by magnetic activated cell sorting (MACS into CD146+ cells. Human endometrial CD146+ cells were karyotyped and tested for the effect of SCF on proliferation of CD146+ cells, then different concentrations of 0, 12.5, 25, 50 and 100 ng/ml was carried out and mitogens-stimulated endometrial CD146+ cells proliferation was assessed by MTT assay. Results: Chromosomal analysis showed a normal metaphase spread and 46XX karyotype. The proliferation rate of endometrial CD146P + P cells in the presence of 0, 12.5, 25, 50 and 100 ng/ml SCF were 0.945±0.094, 0.962±0.151, 0.988±0.028, 1.679±0.012 and 1.129±0.145 respectively. There was a significant increase in stem/ stromal cell proliferation following in vitro treatment by 50 ng/ml than other concentrations of SCF (p=0.01. Conclusion: The present study suggests that SCF could have effect on the proliferation and cell survival of human endometrial CD146P+P cells and it has important implications for medical sciences and cell therapies

  18. The effect of stem cell factor on proliferation of human endometrial CD146(+) cells.

    Science.gov (United States)

    Fayazi, Mehri; Salehnia, Mojdeh; Ziaei, Saeideh

    2016-07-01

    Stem cell factor (SCF) is a transcriptional factor which plays crucial roles in normal proliferation, differentiation and survival in a range of stem cells. The aim of the present study was to examine the proliferation effect of different concentrations of SCF on expansion of human endometrial CD146(+) cells. In this experimental study, total populations of isolated human endometrial suspensions after fourth passage were isolated by magnetic activated cell sorting (MACS) into CD146(+) cells. Human endometrial CD146(+) cells were karyotyped and tested for the effect of SCF on proliferation of CD146(+) cells, then different concentrations of 0, 12.5, 25, 50 and 100 ng/ml was carried out and mitogens-stimulated endometrial CD146(+) cells proliferation was assessed by MTT assay. Chromosomal analysis showed a normal metaphase spread and 46XX karyotype. The proliferation rate of endometrial CD146(+) cells in the presence of 0, 12.5, 25, 50 and 100 ng/ml SCF were 0.945±0.094, 0.962±0.151, 0.988±0.028, 1.679±0.012 and 1.129±0.145 respectively. There was a significant increase in stem/ stromal cell proliferation following in vitro treatment by 50 ng/ml than other concentrations of SCF (p=0.01). The present study suggests that SCF could have effect on the proliferation and cell survival of human endometrial CD146(+) cells and it has important implications for medical sciences and cell therapies.

  19. COUP-TFII Regulates Human Endometrial Stromal Genes Involved in Inflammation

    Science.gov (United States)

    Li, Xilong; Large, Michael J.; Creighton, Chad J.; Lanz, Rainer B.; Jeong, Jae-Wook; Young, Steven L.; Lessey, Bruce A.; Palomino, Wilder A.; Tsai, Sophia Y.

    2013-01-01

    Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis. PMID:24176914

  20. Inhibition of Adhesion, Proliferation, and Invasion of Primary Endometriosis and Endometrial Stromal and Ovarian Carcinoma Cells by a Nonhyaluronan Adhesion Barrier Gel

    Directory of Open Access Journals (Sweden)

    Stefan P. Renner

    2015-01-01

    Full Text Available Endometriosis is a chronic disease of women in the reproductive age, defined as endometrial cells growing outside of the uterine cavity and associated with relapses. Relapses are hypothesized to correlate with incomplete surgical excision or result from nonrandom implantation of new endometrial implants in adjacent peritoneum. Thus, surgical excision could lead to free endometriotic cells or tissue residues, which readhere, grow, and invade into recurrent lesions. Barrier agents are frequently used to prevent postoperative adhesions. We tested if the absorbable cell adhesion barrier gel Intercoat consisting of polyethylene oxide and sodium carboxymethyl cellulose could inhibit cellular adhesion, proliferation, and invasion of primary endometriosis and endometrial cells. Due to an association of endometriosis with ovarian carcinoma, we tested two ovarian carcinoma cell lines. Prior to cell seeding, a drop of the barrier gel was placed in cell culture wells in order to test inhibition of adherence and proliferation or coated over a polymerized collagen gel to assay for prevention of invasion. Results showed that the barrier gel significantly inhibited cell adherence, proliferation, and invasion of endometriosis and endometrial stromal cells as well as ovarian carcinoma cells in culture. Our findings could help to prevent local cell growth/invasion and possible consequent recurrences.

  1. Inhibition of adhesion, proliferation, and invasion of primary endometriosis and endometrial stromal and ovarian carcinoma cells by a nonhyaluronan adhesion barrier gel.

    Science.gov (United States)

    Renner, Stefan P; Strissel, Pamela L; Beckmann, Matthias W; Lermann, Johannes; Burghaus, Stefanie; Hackl, Janina; Fasching, Peter A; Strick, Reiner

    2015-01-01

    Endometriosis is a chronic disease of women in the reproductive age, defined as endometrial cells growing outside of the uterine cavity and associated with relapses. Relapses are hypothesized to correlate with incomplete surgical excision or result from nonrandom implantation of new endometrial implants in adjacent peritoneum. Thus, surgical excision could lead to free endometriotic cells or tissue residues, which readhere, grow, and invade into recurrent lesions. Barrier agents are frequently used to prevent postoperative adhesions. We tested if the absorbable cell adhesion barrier gel Intercoat consisting of polyethylene oxide and sodium carboxymethyl cellulose could inhibit cellular adhesion, proliferation, and invasion of primary endometriosis and endometrial cells. Due to an association of endometriosis with ovarian carcinoma, we tested two ovarian carcinoma cell lines. Prior to cell seeding, a drop of the barrier gel was placed in cell culture wells in order to test inhibition of adherence and proliferation or coated over a polymerized collagen gel to assay for prevention of invasion. Results showed that the barrier gel significantly inhibited cell adherence, proliferation, and invasion of endometriosis and endometrial stromal cells as well as ovarian carcinoma cells in culture. Our findings could help to prevent local cell growth/invasion and possible consequent recurrences.

  2. EXPRESSION OF AHR AND ARNT MRNA IN CULTURED HUMAN ENDOMETRIAL EXPLANTS EXPOSED TO TCDD

    Science.gov (United States)

    Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD.Pitt JA, Feng L, Abbott BD, Schmid J, Batt RE, Costich TG, Koury ST, Bofinger DP.Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.Endom...

  3. Diagnostic role of circulating YKL-40 in endometrial carcinoma patients: a meta-analysis of seven related studies.

    Science.gov (United States)

    Cheng, Daye; Sun, Ying; He, Hu

    2014-12-01

    In the past decade, several studies have suggested a possible link between circulating YKL-40 levels and endometrial carcinoma (EC), but have arrived at inconsistent results. Therefore, we conducted the present meta-analysis and aim to disclose a more comprehensive evaluation of the sensitivity, specificity, and diagnostic accuracy of YKL-40 in EC. We systematically searched PubMed, Embase, Web of Science, Science Direct, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure databases for studies that evaluated the diagnostic value of YKL-40 in endometrial cancer. The STATA software 12.0 and Meta-Disc software were used to test the heterogeneity and to evaluate the overall test performance. A total of seven studies including 234 EC cases and 300 controls were included in our meta-analysis. The summary estimates of YKL-40 for EC diagnosis indicated a moderately high diagnostic accuracy for circulating YKL-40, with a sensitivity of 0.74, a specificity of 0.87, a PLR of 5.74, a NLR of 0.30, a DOR of 19.14, and an AUC of 0.80. On the basis of our meta-analysis, therefore, circulating YKL-40 could be promising and meaningful in the diagnosis of EC.

  4. Post operative radiation therapy in endometrial carcinoma : reducing overtreatment and improving quality of life

    NARCIS (Netherlands)

    Nout, Remi Abubakar

    2013-01-01

    This thesis describes the results of the first en second Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trials. The 15-year results of PORTEC-1 confirm the importance of the prognostic factors age, grade and depth of myometrial invasion for selection of patients with

  5. Direct effects of metformin in the endometrium: a hypothetical mechanism for the treatment of women with PCOS and endometrial carcinoma.

    Science.gov (United States)

    Shao, Ruijin; Li, Xin; Feng, Yi; Lin, Jin-Fang; Billig, Håkan

    2014-05-11

    Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, its cellular and molecular mechanisms of anti-cancer action in the endometrium of women with polycystic ovary syndrome (PCOS) have not yet been fully elucidated. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are known to be involved in metformin uptake and excretion in cells. In this article, we discuss the novel therapeutic possibilities for early-stage endometrial carcinoma (EC) in women with PCOS focusing on metformin, which might have a direct effect in the endometrium through the OCTs and MATEs. We then review the molecular mechanism(s) of the action of metformin in the endometrium and highlight possible mechanistic insights into the inhibition of cell proliferation and tumor growth and, ultimately, the reversal of early-stage EC into normal endometria in women with PCOS.

  6. DNA mismatch repair protein MSH2 dictates cellular survival in response to low dose radiation in endometrial carcinoma cells.

    LENUS (Irish Health Repository)

    Martin, Lynn M

    2013-07-10

    DNA repair and G2-phase cell cycle checkpoint responses are involved in the manifestation of hyper-radiosensitivity (HRS). The low-dose radioresponse of MSH2 isogenic endometrial carcinoma cell lines was examined. Defects in cell cycle checkpoint activation and the DNA damage response in irradiated cells (0.2 Gy) were evaluated. HRS was expressed solely in MSH2+ cells and was associated with efficient activation of the early G2-phase cell cycle checkpoint. Maintenance of the arrest was associated with persistent MRE11, γH2AX, RAD51 foci at 2 h after irradiation. Persistent MRE11 and RAD51 foci were also evident 24 h after 0.2 Gy. MSH2 significantly enhances cell radiosensitivity to low dose IR.

  7. Thyroid-stimulating hormone receptor and thyroid hormone receptors are involved in human endometrial physiology.

    Science.gov (United States)

    Aghajanova, Lusine; Stavreus-Evers, Anneli; Lindeberg, Maria; Landgren, Britt-Marie; Sparre, Lottie Skjöldebrand; Hovatta, Outi

    2011-01-01

    To study the expression, distribution, and function of thyroid-stimulating hormone receptor (TSHR) and thyroid hormone receptors (TR) α1, α2, and β1 in human endometrium. Experimental clinical study. University hospital. 31 fertile women. Endometrial biopsy samples obtained throughout the menstrual cycle. Real-time reverse transcriptase polymerase chain reaction, immunohistochemistry and Western blot to study the expression of TSHR, TRα1, TRα2, and TRβ1 messenger RNA (mRNA) and proteins in human endometrium. We found TSHR, TRα1, TRα2 and TRβ1 mRNA and proteins expressed in human endometrium. Immunostaining for TSHR in the luminal epithelium and TRα1 and β1 in the glandular and luminal epithelium increased statistically significantly on luteinizing hormone (LH) days 6 to 9, coinciding with appearance of pinopodes. Endometrial stromal and Ishikawa cells expressed mRNA for TSHR, TR, and iodothyronine deiodinases 1-3. After 48 hours, TSH significantly increased leukemia inhibitory factor (LIF) and LIF receptor (LIFR) messenger RNA (mRNA) in endometrial stromal cells, but decreased their expression in Ishikawa cells. Glucose transporter 1 mRNA was up-regulated by TSH in Ishikawa cells. We found that TSH statistically significantly increased secretion of free triiodothyronine (T3) and total thyroxin (T4) by Ishikawa cells compared with nonstimulated cells. Thyroid hormones are directly involved in endometrial physiology. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  8. Platelets are a possible regulator of human endometrial re-epithelialization during menstruation.

    Science.gov (United States)

    Suginami, Koh; Sato, Yukiyasu; Horie, Akihito; Matsumoto, Hisanori; Kyo, Satoru; Araki, Yoshihiko; Konishi, Ikuo; Fujiwara, Hiroshi

    2017-01-01

    The human endometrium periodically breaks down and regenerates. As platelets have been reported to contribute to the tissue remodeling process, we examined the possible involvement of platelets in endometrial regeneration. The distribution of extravasating platelets throughout the menstrual cycle was immunohistochemically examined using human endometrial tissues. EM-E6/E7/hTERT cells, a human endometrial epithelial cell-derived immortalized cell line, were co-cultured with platelets, and the effects of platelets on the epithelialization response of EM-E6/E7/hTERT cells were investigated by attachment and permeability assays, immunohistochemical staining, and Western blot analysis. Immunohistochemical study showed numerous extravasated platelets in the subluminar stroma during the menstrual phase. The platelets promoted the cell-to-matrigel attachment of EM-E6/E7/hTERT cells concomitantly with the phosphorylation of focal adhesion kinase. They also promoted cell-to-cell contact among EM-E6/E7/hTERT cells in parallel with E-cadherin expression. These results indicate the possible involvement of platelets in the endometrial epithelial re-epithelialization process. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Angiogenesis Following Three-Dimensional Culture of Isolated Human Endometrial Stromal Cells

    Directory of Open Access Journals (Sweden)

    Navid Esfandiari

    2008-01-01

    Full Text Available Background: Endometriosis is the presence of endometrial tissue outside of the uterine cavity andis the most common gynecologic disorder in women of reproductive age. We have preliminaryevidence that in the presence of a 3-dimensional (3-D fibrin matrix, human endometrial glands,stroma, and neovascularization can develop in vitro, mimicking the earliest stages of endometriosis.The aim of the present study was to determine if angiogenesis can be developed in a 3-D culture ofhuman stromal cells in vitro.Materials and Methods: This was an in vitro study of human endometrial biopsies in 3-D cultureof fibrin matrix and conducted at a university affiliated infertility center. Biopsies were taken fromten normal ovulating women undergoing infertility treatment. The samples obtained from fundusof the uterine cavity were minced, stromal cells isolated and placed in a 3-D fibrin matrix culturesystem. Degree of proliferation of stromal cells, invasion of the fibrin matrix, gland formation, vesselsprouting and immunohistochemical characterization of cellular components were recorded.Results: Three-dimensional culture of human stromal cells formed sheets of cells in the fibrinmatrix. By 3-4 weeks, endothelial cell branching was observed and rudimentary capillary-likestructures formed and endothelial cells confirmed by CD31 immunostaining.Conclusion: These data show that stromal cells from endometrial explants can proliferate andinvade a fibrin matrix in vitro generating new vessels. This procedure represents a controlled,quantifiable model for the study of angiogenesis during the menstrual cycle, and in conditions suchas endometriosis and cancer.

  10. Verification of microRNA expression in human endometrial adenocarcinoma.

    Science.gov (United States)

    Jurcevic, Sanja; Klinga-Levan, Karin; Olsson, Björn; Ejeskär, Katarina

    2016-04-02

    MicroRNAs are small non-coding RNAs that have been implicated in tumor initiation and progression. In a previous study we identified 138 miRNAs as differentially expressed in endometrial adenocarcinoma compared to normal tissues. One of these miRNAs was miRNA-34a, which regulates several genes involved in the Notch pathway, which is frequently altered in endometrial cancer. The aims of this study were to verify the differential expression of a subset of miRNAs and to scrutinize the regulatory role of mir-34a on the target genes NOTCH1 and DLL1. Twenty-five miRNAs that were previously identified as differentially expressed were subjected to further analysis using qPCR. To investigate the regulation of NOTCH1 and DLL1 by mir-34a, we designed gain- and loss-of-function experiments in Ishikawa and HEK293 cell lines by transfection with a synthetic mir-34a mimic and a mir-34a inhibitor. Of the 25 validated miRNAs, seven were down-regulated and 18 were up-regulated compared to normal endometrium, which was fully consistent with our previous findings. In addition, the up-regulation of mir-34a led to a significant decrease in mRNA levels of NOTCH1 and DLL1, while down-regulation led to a significant increase in mRNA levels of these two genes. We verified both up-regulated and down-regulated miRNAs in the tumor samples, indicating various roles of microRNAs during tumor development. Mir-34a functions as a regulator by decreasing the expression of NOTCH1 and DLL1. Our study is the first to identify a correlation between mir-34a and its target genes NOTCH1 and DLL1 in endometrial adenocarcinoma.

  11. Human S100A10 plays a crucial role in the acquisition of the endometrial receptivity phenotype.

    Science.gov (United States)

    Bissonnette, Laurence; Drissennek, Loubna; Antoine, Yannick; Tiers, Laurent; Hirtz, Christophe; Lehmann, Sylvain; Perrochia, Hélène; Bissonnette, François; Kadoch, Isaac-Jacques; Haouzi, Delphine; Hamamah, Samir

    2016-05-03

    In assisted reproduction, about 30% of embryo implantation failures are related to inadequate endometrial receptivity. To identify molecules involved in endometrial receptivity acquisition, we investigated, using a SELDI-TOF approach, the protein expression profile of early-secretory and mid-secretory endometrium samples. Among the proteins upregulated in mid-secretory endometrium, we investigated the function of S100A10 in endometrial receptivity and implantation process. S100A10 was expressed in epithelial and stromal cells of the endometrium of fertile patients during the implantation windows. Conversely, it was downregulated in the mid-secretory endometrium of infertile patients diagnosed as non-receptive. Transcriptome analysis of human endometrial epithelial and stromal cells where S100A10 was silenced by shRNA revealed the deregulation of 37 and 256 genes, respectively, related to components of the extracellular matrix and intercellular connections. Functional annotations of these deregulated genes highlighted alterations of the leukocyte extravasation signaling and angiogenesis pathways that play a crucial role during implantation. S100A10 silencing also affected the migration of primary endometrial epithelial and stromal cells, decidualization and secretory transformation of primary endometrial stromal cells and epithelial cells respectively, and promoted apoptosis in serum-starved endometrial epithelial cells. Our findings identify S100A10 as a player in endometrial receptivity acquisition.

  12. Genetics of Endometrial Cancers

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Okuda

    2010-01-01

    Full Text Available Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non-endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%–30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A β-catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non-endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non-endometrioid carcinomas.

  13. T2 relaxometry mapping in demonstrating layered uterine architecture: parameter optimization and utility in endometrial carcinoma and adenomyosis: a feasibility study.

    Science.gov (United States)

    Ghosh, Adarsh; Singh, Tulika; Bagga, Rashmi; Srinivasan, Radhika; Singla, Veenu; Khandelwal, Niranjan

    2018-01-01

    We evaluate the feasibility of T 2 relaxometry mapping of the uterus and demonstrate its diagnostic utility in endometrial carcinoma and adenomyosis and discuss the optimum imaging parameters as used in our institute. Institute review board approval was obtained and multispin echo (MSE) imaging of the pelvis was done with variable time to echo in three patients, two with endometrial carcinoma and one with adenomyosis. T 2 parametric maps and curves were plotted and the T 2 times of the diseased endometrium, superficial and deep myometrium were established. T2 mapping of the uterus is feasible and demonstrated the four-layered uterine architecture with T 2 times of the diseased endometrium, inner myometrium and the outer myometrium being determined. The fourth myometrial layer was demonstrated in all the three cases on the parametric maps. The two cases with endometrial carcinoma had thinning and irregularity of the myometrial fourth layer which helped in predicting superficial myometrium invasion. Thickening of the fourth myometrial layer was demonstrated in the case with adenomyosis, which we believe might be a new imaging finding of adenomyosis. Thinning and irregularity of the myometrial fourth layer in cases of endometrial malignancy might help in identification of superficial myoinvasion-this might be a new imaging armamentarium in nulliparous females where uterine preservation might be a consideration. The T 2 relaxation times of the myometrium and endometrium described here will help optimize the time to echo for the acquisition of MSE for relaxometry of the female pelvis. Advances in knowledge: Thinning and irregularity of the fourth myometrial layer helps in the identification of superficial myometrial invasion with a greater confidence and helps triage patients for uterine preservation when necessary. T 2 relaxometry might be undertaken in those nulliparous women with endometrial carcinoma in whom demonstration of no myometrial invasion will make them

  14. Extracellular Matrix Dynamics in Scar-Free Endometrial Repair: Perspectives from Mouse In Vivo and Human In Vitro Studies1

    National Research Council Canada - National Science Library

    Jemma Evans; Tu'uhevaha Kaitu'u-Lino; Lois A. Salamonsen

    2011-01-01

    .... Utilizing an in vivo mouse model of postmenstrual repair and an in vitro model of human endometrial re-epithelialization, we determined the dynamic changes in expression of ECM and related factors...

  15. VSV-hIFNbeta-NIS in Treating Patients With Stage IV or Recurrent Endometrial Cancer

    Science.gov (United States)

    2017-11-16

    Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Metastatic Endometrioid Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Recurrent Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IV Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  16. Human papillomavirus DNA in aerodigestive squamous carcinomas ...

    African Journals Online (AJOL)

    A series of 10 oesophageal and 10 laryngeal squamous carcinomas was examined by means of immuno cytochemistry and in situ DNA hybridisation to demonstrate human papillomavirus (HPV) infection. Changes in the epithelium adjacent to the carcinoma were found in 5 of 10 oesophageal and 7 of 10 laryngeal ...

  17. Critical analysis of cases of endometrial carcinoma of the uterine corpus incidentally diagnosed after incomplete surgery for other indications. Three case reports and a review of the literature

    Directory of Open Access Journals (Sweden)

    Małgorzata Gajewska

    2014-11-01

    Full Text Available Incidental diagnosis of endometrial carcinoma after the operation for presumed benign disease is rare. At present, there are no recognized guidelines on optimal management of uterine malignancy diagnosed after incomplete surgery for other indications and the reported experience is limited. Although the risk of histological diagnosis of endometrial carcinoma in the uterus removed for pre-operatively diagnosed benign disease is very low, one should always bear in mind that it may indeed occur. Omission of certain diagnostic procedures prior to hysterectomy may result in incidental finding of a malignancy at or after surgery, even when preoperative imaging studies reveal benign disease. Many centres develop their own strategies, although in most cases the adnexa and cervix are removed and thorough exploration of the abdominal cavity is performed. Also, in view of the technical difficulties involved in removing the uterus and adnexa via the vagina and a potential high risk of cancer either developing in the cervical stump or disseminated from inadvertently morcellated uterine fragments, one should carefully consider the potential benefits and risks of supracervical hysterectomy. We present three patients with endometrial carcinoma diagnosed after hysterectomy, who subsequently underwent completion surgery. A review of the literature follows, which presents opinions from international centres.

  18. Oncogene alterations in endometrial carcinosarcomas.

    Science.gov (United States)

    Biscuola, Michele; Van de Vijver, Koen; Castilla, María Ángeles; Romero-Pérez, Laura; López-García, María Ángeles; Díaz-Martín, Juan; Matias-Guiu, Xavier; Oliva, Esther; Palacios Calvo, José

    2013-05-01

    Endometrial carcinosarcomas are aggressive neoplasias composed of high-grade carcinomatous and sarcomatous elements. The pathogenesis and specific genetic alterations underlying these tumors are still not well known. We analyzed alterations in oncogenes involved in the pathogenesis of endometrial carcinomas that might represent predictive markers for specific therapies. Immunohistochemistry for HER2 (tyrosine kinase-type cell surface receptor HER2) and c-KIT (tyrosine-protein kinase Kit) and fluorescence in situ hybridization for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma receptor tyrosine kinase) were carried out for 76 endometrial carcinosarcoma samples on sequential tissue microarray sections. Analysis of 238 mutations across 19 common oncogenes was performed on 34 samples using the Sequenom OncoCarta Panel (Sequenom, Hamburg, Germany). We observed EGFR, HER2, and c-KIT expression in 71%, 1.5%, and 2.7% of tumors, respectively. EGFR amplification was detected in 11 of 76 endometrial carcinosarcomas (14.5%). Four samples showed both amplification and aneuploidy (5.2%). ALK amplification together with chromosome 2 polysomy was found in 1.3% of endometrial carcinosarcomas. In total, 23 mutations in 9 different oncogenes were detected in 15 (44.1%) of 34 endometrial carcinosarcomas. Five endometrial carcinosarcomas (14.7%) had 2 or more mutations. Eleven tumors (32.3%) had mutations affecting the PI3K (phosphoinositide-3-kinase)/AKT (v-akt murine thymoma viral oncogene homolog 1) (6 mutations in PIK3CA (PI3K catalytic alpha polypeptide) and 1 in AKT) and/or RAS/BRAF (serine/threonine-protein kinase B-raf) pathway (3 KRAS [kirsten RAS oncogene homolog], 2 NRAS [neuroblastoma RAS viral oncogene homolog], and 1 BRAF). Mutations in PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) and/or KIT were found in 5 endometrial carcinosarcomas (14.7%). Finally, we found mutations in MET (met proto-oncogene [hepatocyte growth factor

  19. NEDD8-mediated neddylation is required for human endometrial stromal proliferation and decidualization.

    Science.gov (United States)

    Liao, Yixin; Jiang, Yaling; He, Hui; Ni, Hao; Tu, Zhaowei; Zhang, Shuang; Wang, Bingyan; Lou, Jiaoying; Quan, Song; Wang, Haibin

    2015-07-01

    Does NEDD8-mediated neddylation regulate human endometrial stromal proliferation and decidualization? Neddylation inhibition by a selective NEDD8-activating enzyme inhibitor, MLN4924, significantly impairs human endometrial stromal cell (HESC) proliferation and decidualization and facilitates cell senescence, via p21 accumulation. Neddylation regulates cell proliferation and tissue remodeling during embryogenesis and tumorigenesis, while human endometrial stroma undergoes sequential proliferation, differentiation, as well as dynamic tissue remodeling during each menstrual cycle. We first analyzed the expression of NEDD8 in human endometrial tissues from 50 subjects, and then explored the consequence of neddylation inhibition by MLN4924 on HESCs proliferation, decidualization and cellular senescence. We collected 50 dated human endometrial tissues from early proliferative stage to late secretory phase of the menstrual cycle and analyzed the NEDD8 expression and cellular location in human endometrium by employing quantitative real-time PCR (qRT-PCR) and immunohistochemistry staining. Similar approaches were also used to explore the mRNA and protein expression of NEDD8 in an immortalized human endometrial stromal cell line (HESC) during proliferation and decidualization (N = 6). An MTS assay was performed to evaluate the effects of neddylation inhibition by MLN4924 on HESC proliferation. Flow cytometry and BrdU incorporation assay were conducted to determine the HESC cell cycle progression in response to MLN4924 exposure during proliferation. We also analyzed F-actin distribution by phalloidin staining and decidual marker gene expression by qRT-PCR to accesses the consequence of neddylation inhibition on HESC decidualization. Immunoblotting analysis of cullin1 and p21, and SA-β-Galactosidase staining were performed to reveal the potential molecular basis for the impaired HESC proliferation, decidualization and cellular senescence. The siRNA technique was applied to

  20. An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations.

    Science.gov (United States)

    Yang, Chieh-Hsiang; Almomen, Aliyah; Wee, Yin Shen; Jarboe, Elke A; Peterson, C Matthew; Janát-Amsbury, Margit M

    2015-07-01

    Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in β-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  1. Early endometrial carcinoma therapy in morbid obesity: A retrospective study comparing open and laparoscopic.

    Science.gov (United States)

    Cheng, Zhengxian; He, Xiaoqing; Zhao, Aihua; Zhang, Qiaoyu; Li, Yali

    2016-06-01

    The present study sought to explore the therapeutic outcome of laparoscopic surgery for the endometrial cancer patients with morbidly obese in china. The morbidly obese patients with clinical stage I or II endometrial cancer received laparoscopic surgery (LS) at the Obstetrics and Gynecology centers of PLA general hospital between November 2012 and November 2014. The clinical outcomes of these surgeries were compared with a historical cohort of similar morbidly obese patients who had received the open surgery (OS). In the present study, the morbidly obesity was defined as the body mass index was bigger than 40 kg/m(2). The basic characteristics of the involved patients, the therapeutic effects of the surgery, as well as the incidence of perioperative complications were systematically compared between the two groups. Totally 120 patients were included in the present study (respectively 60 patients in the LS group and the OS group). There was no statistical difference between the LS group and the OS group in terms of patient age or BMI. However, the incidence of intraoperative complication in the LS group was significantly lower than that in the OS group (5.0% vs. 16.7%; P = 0.04. Moreover, the incidence of postoperative complication in the OS group was higher than that in the LS group (20.0% vs.6.7%; P = 0.03). The length of hospital stay in the LS group was longer than that in the OS group (6 vs.11 days; P = 0.02). Furthermore, the rates of (pelvic) lymph node dissection and para-aortic node dissection in the LS group were not significantly different from the OS group. LS is verified to be a safe and rational therapeutic strategy for the endometrial cancer patients with morbidly obese. The incidence of perioperative complications is significantly lower in comparison with the OS. Copyright © 2016. Published by Elsevier Ltd.

  2. Effects of Excess Copper Ions on Decidualization of Human Endometrial Stromal Cells.

    Science.gov (United States)

    Li, Ying; Kang, Zhen-Long; Qiao, Na; Hu, Lian-Mei; Ma, Yong-Jiang; Liang, Xiao-Huan; Liu, Ji-Long; Yang, Zeng-Ming

    2017-05-01

    The aim of this study was to investigate the effects of copper ions on decidualization of human endometrial stromal cells (HESCs) cultured in vitro. Firstly, non-toxic concentrations of copper D-gluconate were screened in HESCs based on cell activity. Then, the effects of non-toxic concentrations of copper ions (0~250 μM) were examined on decidualization of human endometrial stromal cells. Our data demonstrated that the mRNA expressions of insulin-like growth factor binding protein (IGFBP-1), prolactin (PRL), Mn-SOD, and FOXO1were down-regulated during decidualization following the treatments with 100 or 250 μM copper ions. Meanwhile, the amount of malonaldehyde (MDA) in the supernatant of HESCs was increased. These results showed that in vitro decidualization of HESCs was impaired by copper treatment.

  3. Theories of endometrial carcinogenesis: a multidisciplinary approach.

    Science.gov (United States)

    Sherman, M E

    2000-03-01

    Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. More recent, systematic studies have provided epidemiologic, clinicopathologic, and molecular support for these observations. Specifically, studies suggest that the most common type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usually pursues an indolent clinical course. In contrast, a minority of endometrial carcinomas, best represented by serous carcinoma, do not seem to be related to estrogenic risk factors or elevated serum hormone levels, and these tumors seem to develop from atrophic rather than hyperplastic epithelium. We have proposed that serous carcinomas develop from "endometrial intraepithelial carcinoma," a lesion representing malignant transformation of the endometrial surface epithelium. Whereas endometrioid carcinoma and endometrial hyperplasia are associated with microsatellite instability and ras and PTEN mutations, serous carcinoma and endometrial intraepithelial carcinoma are associated with p53 mutations and abnormal accumulation of p53 protein. Based on these data regarding the pathogenesis of endometrioid and serous carcinoma, we have proposed a dualistic model of endometrial carcinogenesis incorporating a "classic" estrogen-driven pathway and an "alternative" pathway seemingly unrelated to hormones. It is hoped that further studies may permit the extension and modification of this model and that these advances will lead to improved diagnosis, management, and prevention.

  4. miRNA Signature and Dicer Requirement during Human Endometrial Stromal Decidualization In Vitro

    Science.gov (United States)

    Estella, Carlos; Herrer, Isabel; Moreno-Moya, Juan Manuel; Quiñonero, Alicia; Martínez, Sebastián; Pellicer, Antonio; Simón, Carlos

    2012-01-01

    Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells, which is critical for embryo implantation and pregnancy establishment. The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels, however very little is known about the post-transcriptional regulation of this process. miRNAs regulate multiple physiological pathways and their de-regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia. In this study we profile the miRNAs expression throughout human endometrial stromal (hESCs) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process. A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non-decidualized hESCs. Three miRNAs families, miR-181, miR-183 and miR-200, are down-regulated during the decidualization process. Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs. The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization. We have analyzed a battery of decidualization markers such as cell morphology, Prolactin, IGFBP-1, MPIF-1 and TIMP-3 secretion as well as HOXA10, COX2, SP1, C/EBPß and FOXO1 expression in decidualized hESCs with decreased Dicer function. We found decreased levels of HOXA10 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control. Our results provide the miRNA signature of hESC during the decidualization process in vitro. We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization

  5. miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro.

    Directory of Open Access Journals (Sweden)

    Carlos Estella

    Full Text Available Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells, which is critical for embryo implantation and pregnancy establishment. The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels, however very little is known about the post-transcriptional regulation of this process. miRNAs regulate multiple physiological pathways and their de-regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia. In this study we profile the miRNAs expression throughout human endometrial stromal (hESCs decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process. A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non-decidualized hESCs. Three miRNAs families, miR-181, miR-183 and miR-200, are down-regulated during the decidualization process. Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs. The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization. We have analyzed a battery of decidualization markers such as cell morphology, Prolactin, IGFBP-1, MPIF-1 and TIMP-3 secretion as well as HOXA10, COX2, SP1, C/EBPß and FOXO1 expression in decidualized hESCs with decreased Dicer function. We found decreased levels of HOXA10 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control. Our results provide the miRNA signature of hESC during the decidualization process in vitro. We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human

  6. Improved Survival Endpoints With Adjuvant Radiation Treatment in Patients With High-Risk Early-Stage Endometrial Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Elshaikh, Mohamed A., E-mail: melshai1@hfhs.org [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Vance, Sean; Suri, Jaipreet S. [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Mahan, Meredith [Public Health Science, Henry Ford Hospital, Detroit, Michigan (United States); Munkarah, Adnan [Division of Gynecologic Oncology, Department of Women' s Health Services, Henry Ford Hospital, Detroit, Michigan (United States)

    2014-02-01

    Purpose/Objective(s): To determine the impact of adjuvant radiation treatment (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with high-risk 2009 International Federation of Gynecology and Obstetrics stage I-II endometrial carcinoma. Methods and Materials: We identified 382 patients with high-risk EC who underwent hysterectomy. RFS, DSS, and OS were calculated from the date of hysterectomy by use of the Kaplan-Meier method. Cox regression modeling was used to explore the risks associated with various factors on survival endpoints. Results: The median follow-up time for the study cohort was 5.4 years. The median age was 71 years. All patients underwent hysterectomy and salpingo-oophorectomy, 93% had peritoneal cytology, and 85% underwent lymphadenectomy. Patients with endometrioid histology constituted 72% of the study cohort, serous in 16%, clear cell in 7%, and mixed histology in 4%. Twenty-three percent of patients had stage II disease. Adjuvant management included RT alone in 220 patients (57%), chemotherapy alone in 25 patients (7%), and chemoradiation therapy in 27 patients (7%); 110 patients (29%) were treated with close surveillance. The 5-year RFS, DSS, and OS were 76%, 88%, and 73%, respectively. On multivariate analysis, adjuvant RT was a significant predictor of RFS (P<.001) DSS (P<.001), and OS (P=.017). Lymphovascular space involvement was a significant predictor of RFS and DSS (P<.001). High tumor grade was a significant predictor for RFS (P=.038) and DSS (P=.025). Involvement of the lower uterine segment was also a predictor of RFS (P=.049). Age at diagnosis and lymphovascular space involvement were significant predictors of OS: P<.001 and P=.002, respectively. Conclusion: In the treatment of patients with high-risk features, our study suggests that adjuvant RT significantly improves recurrence-free, disease-specific, and overall survival in patients with early-stage endometrial carcinoma

  7. Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers.

    Science.gov (United States)

    Altmäe, Signe; Koel, Mariann; Võsa, Urmo; Adler, Priit; Suhorutšenko, Marina; Laisk-Podar, Triin; Kukushkina, Viktorija; Saare, Merli; Velthut-Meikas, Agne; Krjutškov, Kaarel; Aghajanova, Lusine; Lalitkumar, Parameswaran G; Gemzell-Danielsson, Kristina; Giudice, Linda; Simón, Carlos; Salumets, Andres

    2017-08-30

    Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.

  8. Biobanking human endometrial tissue and blood specimens: standard operating procedure and importance to reproductive biology research and diagnostic development.

    Science.gov (United States)

    Sheldon, Elizabeth; Vo, Kim Chi; McIntire, Ramsey A; Aghajanova, Lusine; Zelenko, Zara; Irwin, Juan C; Giudice, Linda C

    2011-05-01

    To develop a standard operating procedure (SOP) for collection, transport, storage of human endometrial tissue and blood samples, subject and specimen annotation, and establishing sample priorities. The SOP synthesizes sound scientific procedures, the literature on ischemia research, sample collection and gene expression profiling, good laboratory practices, and the authors' experience of workflow and sample quality. The National Institutes of Health, University of California, San Francisco, Human Endometrial Tissue and DNA Bank. Women undergoing endometrial biopsy or hysterectomy for nonmalignant indications. Collecting, processing, storing, distributing endometrial tissue and blood samples under approved institutional review board protocols and written informed consent from participating subjects. Standard operating procedure. The SOP addresses rigorous and consistent subject annotation, specimen processing and characterization, strict regulatory compliance, and a reference for researchers to track collection and storage times that may influence their research. The comprehensive and systematic approach to the procurement of human blood and endometrial tissue in this SOP ensures the high quality, reliability, and scientific usefulness of biospecimens made available to investigators by the National Institutes of Health, University of California, San Francisco, Human Endometrial Tissue and DNA Bank. The detail and perspective in this SOP also provides a blueprint for implementation of similar collection programs at other institutions. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  9. Pioneer Factors FOXA1 and FOXA2 Assist Selective Glucocorticoid Receptor Signaling in Human Endometrial Cells.

    Science.gov (United States)

    Whirledge, Shannon; Kisanga, Edwina P; Taylor, Robert N; Cidlowski, John A

    2017-11-01

    Successful pregnancy relies on dynamic control of cell signaling to achieve uterine receptivity and the necessary biological changes required for endometrial decidualization, embryo implantation, and fetal development. Glucocorticoids are master regulators of intracellular signaling and can directly regulate embryo implantation and endometrial remodeling during murine pregnancy. In immortalized human uterine cells, we have shown that glucocorticoids and estradiol (E2) coregulate thousands of genes. Recently, glucocorticoids and E2 were shown to coregulate the expression of Left-right determination factor 1 (LEFTY1), previously implicated in the regulation of decidualization. To elucidate the molecular mechanism by which glucocorticoids and E2 regulate the expression of LEFTY1, immortalized and primary human endometrial cells were evaluated for gene expression and receptor recruitment to regulatory regions of the LEFTY1 gene. Glucocorticoid administration induced expression of LEFTY1 messenger RNA and protein and recruitment of the glucocorticoid receptor (GR) and activated polymerase 2 to the promoter of LEFTY1. Glucocorticoid-mediated recruitment of GR was dependent on pioneer factors FOXA1 and FOXA2. E2 was found to antagonize glucocorticoid-mediated induction of LEFTY1 by reducing recruitment of GR, FOXA1, FOXA2, and activated polymerase 2 to the LEFTY1 promoter. Gene expression analysis identified several genes whose glucocorticoid-dependent induction required FOXA1 and FOXA2 in endometrial cells. These results suggest a molecular mechanism by which E2 antagonizes GR-dependent induction of specific genes by preventing the recruitment of the pioneer factors FOXA1 and FOXA2 in a physiologically relevant model. Copyright © 2017 Endocrine Society.

  10. Progesterone receptor content in endometrial carcinoma correlates with serum levels of free estradiol

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

    1993-01-01

    between estrogen receptor content and any of the serum sex hormones. The progesterone/estrogen receptor ratio, calculated from the biochemical values, correlated positively (p levels of free estradiol. This relation was not affected by tumor histologic grade or stage. Furthermore......OBJECTIVE. To study a possible relationship between serum levels of estrogens and androgens and the tumor content of estrogen receptors and progesterone receptors in endometrial cancer. STUDY DESIGN. Fifty postmenopausal patients were included. Receptors were determined biochemically in tissue...... cytosol by dextran charcoal-coated assay and immunohistochemically on frozen sections. Serum sex hormones were measured by radioimmunoassays. MAIN FINDINGS. Tumor biochemical progesterone receptor content correlated positively (p levels. No correlations were observed...

  11. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.

    Science.gov (United States)

    Friel, Anne M; Zhang, Ling; Pru, Cindy A; Clark, Nicole C; McCallum, Melissa L; Blok, Leen J; Shioda, Toshi; Peluso, John J; Rueda, Bo R; Pru, James K

    2015-01-28

    during chemotherapeutic stress. In sum, these in vitro and in vivo findings demonstrate that PGRMC1 plays a prominent role in the growth and chemoresistance of human endometrial tumors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Silencing nc886, a Non-Coding RNA, Induces Apoptosis of Human Endometrial Cancer Cells-1A In Vitro.

    Science.gov (United States)

    Hu, Zhuoying; Zhang, Hongyu; Tang, Liangdan; Lou, Meng; Geng, Yanqing

    2017-03-16

    BACKGROUND The role that nc886, a non-coding microRNA, plays in human endometrial cancer is unknown. The present study aimed to describe the functional role of nc886 in human endometrial cancer-1A (HEC-1A) cell line, which may provide another target for human endometrial cancer treatment. MATERIAL AND METHODS The expression levels of nv886 in normal human endometrial tissue and the early phase and late phase of human endometrial cancer tissues were determined and compared by fluorescence in situ hybridization (FISH). Small interference RNA (siRNA) was used to inhibit nc886, and cell proliferation was evaluated with the MTT test. mRNA levels of PKR, NF-κB, vascular endothelial growth factor (VEGF), and caspase-3 were determined against glyceraldehyde 3-phosphate dehydrogenase (GAPDH between the HEC-1A control group and the silenced group (nc886 silenced with siRNA) by real-time reverse transcription polymerase chain reaction (RT-PCR). The protein levels of PKR (total and phosphorylated form), NF-κB, VEGF, and caspase-3 were determined against GAPDH by Western blotting, and cell apoptosis was determined by flow cytometry. RESULTS Our results indicated that a higher level of nc886 was expressed in the late phase of human endometrial cancer tissue, less than in the early phase but still higher than in normal human endometrial tissue. After nc886 was silenced, protein levels of p-PKR (phosphorylated PKR) and caspase-3 were increased, whereas NF-κB and VEGF were decreased. CONCLUSIONS The rate of apoptosis in the silenced group was increased and the rate of cell proliferation was slower in comparison to the control.

  13. [Endometrial carcinoma: An histopathological and histoprognotic study about 62 patients in a center in the Tunisian north].

    Science.gov (United States)

    Doghri, Raoudha; Yahyaoui, Yosra; Gabsi, Azza; Driss, Maha; Boujelbene, Nadia; Charfi, Lamia; Amel, Mezlini; Mrad, Karima

    2018-02-01

    Endometrial cancer is the most prevalent gynecological cancer in occident and the third most common cancer among women in Tunisia. It is dominated by carcinoma. The identification of prognostic factors allows a better understanding of its outcome and guides its therapeutic approach. We propose to describe the clinicopathological features and identify the histoprognostic factors of this cancer. It is a retrospective analysis of a series of 62 total hysterectomy specimens with bilateral salpingo-oophorectomy from women with primary carcinoma of the endometrium, colligated in Anatomy Laboratory and Pathology Salah Azaiz Institute of Tunis over a period of 5 years, from January 2003 to December 2007. The median age was 60 years. At the time of diagnosis, 25% of patients were nulliparous and 86% were menopaused. The endometrioid adenocarcinoma was the most common, accounting for 84% of cases (5% of them were grade 3). A myometrial invasion superior or equal to 50% was observed in 40% of cases. 42% of cases were classified as stage IA, 14% in stage IB, 16% in stage II, 18% stage III and 10% in stage IV. 22% of patients had nodal involvement. Overall survival at 5 years was 81%. In multivariate analysis, stage IV, nodal involvement and brachytherapy have influenced this rate. Event-free survival at 5 years was 71%. It was directly related to stage and nodal involvement. Stage, histological type, tumor grade, invasion of more than half of the myometrium and lymph node involvement were the most important adverse prognostic factors, dictating an appropriate management of these tumors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Elevated MiR-222-3p promotes proliferation and invasion of endometrial carcinoma via targeting ERα.

    Directory of Open Access Journals (Sweden)

    Binya Liu

    Full Text Available MicroRNAs play key roles in tumor proliferation and invasion. Here we show distinct expression of miR-222-3p between ERα-positive and ERα-negative endometrial carcinoma (EC cell lines and primary tumors, and investigation of its relationship with ERα and other clinical parameters. In vitro, the function of miR-222-3p was examined in RL95-2 and AN3CA cell lines. MiR-222-3p expression was negatively correlated with ERα. Over-expressed miR-222-3p in RL95-2 cells promoted cell proliferation, enhanced invasiveness and induced a G1 to S phase shift in cell cycle. Furthermore, the miR-222-3p inhibitor decreased the activity of AN3CA cells to proliferate and invade. In vivo, down-regulated miR-222-3p of AN3CA cells inhibited EC tumor growth in a mouse xenograft model. Additionally, miR-222-3p increased raloxifene resistance through suppressing ERα expression in EC cells. In conclusion, miR-222-3p plays a significant role in the regulation of ERα expression and could be potential targets for restoring ERα expression and responding to antiestrogen therapy in a subset of ECs.

  15. Perfluorooctanoic acid induces human Ishikawa endometrial cancer cell migration and invasion through activation of ERK/mTOR signaling.

    Science.gov (United States)

    Ma, Zhinan; Liu, Xiaoqiu; Li, Fujun; Wang, Yixong; Xu, Yang; Zhang, Mei; Zhang, Xiaoqian; Ying, Xiaoyan; Zhang, Xuesen

    2016-10-11

    Perfluorooctanoic acid (PFOA) is a common environmental pollutant that has been associated with various diseases, including cancer. We explored the molecular mechanisms underlying PFOA-induced endometrial cancer cell invasion and migration. PFOA treatment enhanced migration and invasion by human Ishikawa endometrial cancer cells, which correlated with decreased E-cadherin expression, a marker of epithelial-mesenchymal transition. PFOA also induced activation of ERK1/2/mTOR signaling. Treatment with rapamycin, an mTOR inhibitor, antagonized the effects of PFOA and reversed the effects of PFOA activation in a xenograft mouse model of endometrial cancer. Consistent with these results, pre-treatment with rapamycin abolished PFOA-induced down-regulation of E-cadherin expression. These results indicate that PFOA is a carcinogen that promotes endometrial cancer cell migration and invasion through activation of ERK/mTOR signaling.

  16. Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity.

    Science.gov (United States)

    Winship, Amy; Ton, Amanda; Van Sinderen, Michelle; Menkhorst, Ellen; Rainczuk, Katarzyna; Griffiths, Meaghan; Cuman, Carly; Dimitriadis, Evdokia

    2017-08-29

    Human blastocysts that fail to implant following IVF secrete elevated levels of miR-661, which is taken up by primary human endometrial epithelial cells (HEECs) and impairs their adhesive capability. MicroRNA miR-661 downregulates mouse double minute homologue 2 (MDM2) and MDM4 in other epithelial cell types to activate p53; however, this has not been examined in the endometrium. In this study MDM2 protein was detected in the luminal epithelium of the endometrium, the site of blastocyst attachment, during the mid secretory receptive phase of the menstrual cycle. The effects of miR-661 on gene expression in and adhesion of endometrial cells was also examined. MiR-661 overexpression consistently downregulated MDM2 but not MDM4 or p53 gene expression in the Ishikawa endometrial epithelial cell line and primary HEEC. Adhesion assays were performed on the real-time monitoring xCELLigence system and by co-culture using Ishikawa cells and HEECs with HTR8/SVneo trophoblast spheroids. Targeted siRNA-mediated knockdown of MDM2 in endometrial epithelial cells reduced Ishikawa cell adhesion (Phuman blastocyst-secreted miR-661 reduces endometrial epithelial cell adhesion; via downregulation of MDM2. These findings suggest that MDM2 contributes to endometrial-blastocyst adhesion, implantation and infertility in women.

  17. Effect of Adding Human Chorionic Gonadotropin to The Endometrial Preparation Protocol in Frozen Embryo Transfer Cycles

    Directory of Open Access Journals (Sweden)

    Maryam Eftekhar

    2012-01-01

    Full Text Available Background: Human chorionic gonadotropin (HCG, one of the initial embryonic signals, isprobably a major regulator of the embryo-endometrial relationship. This study aims to assess theadvantage of HCG supplementation during the secretory phase of hormonally prepared cycles forthe transfer of cryopreserved-thawed embryos.Materials and Methods: This study was a randomized clinical trial. Infertile women who werecandidates for frozen-thawed embryo transfers entered the study and were divided into two groups,HCG and control. The endometrial preparation method was similar in both groups: all women receivedestradiol valerate (6 mg po per day from the second day of the menstrual cycle and progesteronein oil (100 mg intramuscular (I.M. when the endometrial thickness reached 8 mm. Estradiol andprogesterone were continued until the tenth week of gestation. In the HCG group, patients received anHCG 5000 IU injection on the first day of progesterone administration and the day of embryo transfer.Results: In this study, 130 couples participated: 65 in the HCG group and 65 in the control group.There was no statistically significant difference between groups regarding basic characteristics.Implantation rate, chemical pregnancy, clinical pregnancy, ongoing pregnancy, and abortion rateswere similar in both groups.Conclusion: Although HCG has some advantages in assisted reproductive technology (ARTcycles, our study did not show any benefit of HCG supplementation during the secretory phase offrozen cycles (Registration Number: IRCT201107266420N4.

  18. Anti-Proliferative Effects of Siegesbeckia orientalis Ethanol Extract on Human Endometrial RL-95 Cancer Cells

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    Chi-Chang Chang

    2014-12-01

    Full Text Available Endometrial cancer is a common malignancy of the female genital tract. This study demonstrates that Siegesbeckia orientalis ethanol extract (SOE significantly inhibited the proliferation of RL95-2 human endometrial cancer cells. Treating RL95-2 cells with SOE caused cell arrest in the G2/M phase and induced apoptosis of RL95-2 cells by up-regulating Bad, Bak and Bax protein expression and down-regulation of Bcl-2 and Bcl-xL protein expression. Treatment with SOE increased protein expression of caspase-3, -8 and -9 dose-dependently, indicating that apoptosis was through the intrinsic and extrinsic apoptotic pathways. Moreover, SOE was also effective against A549 (lung cancer, Hep G2 (hepatoma, FaDu (pharynx squamous cancer, MDA-MB-231 (breast cancer, and especially on LNCaP (prostate cancer cell lines. In total, 10 constituents of SOE were identified by Gas chromatography-mass analysis. Caryophyllene oxide and caryophyllene are largely responsible for most cytotoxic activity of SOE against RL95-2 cells. Overall, this study suggests that SOE is a promising anticancer agent for treating endometrial cancer.

  19. Diagnostic accuracy of endometrial thickness to exclude polyps in women with postmenopausal bleeding

    NARCIS (Netherlands)

    Timmermans, Anne; Gerritse, Maaike B. E.; Opmeer, Brent C.; Jansen, Frank W.; Mol, Ben W. J.; Veersema, Sebastiaan

    2008-01-01

    PURPOSE: To determine the accuracy of endometrial thickness measurement with transvaginal ultrasonography (TVUS) to diagnose endometrial polyps in women with postmenopausal bleeding in whom a carcinoma has been ruled out. METHODS: In women with postmenopausal bleeding, endometrial thickness was

  20. Molecular Genetic Study of Human Esophageal Carcinoma

    Science.gov (United States)

    1991-07-16

    virus have been shown to be the causative agent for human cancer, as human papilloma - virus ( HPV ) was associated with...F.J., Syrjanen, S., Shen, Q., J.I, H., & Kyrjanen, K. Human papilloma virus ( HPV ) DNA in esophageal precursor lesions and squamous cell carcinomas...genital tumors. Gene products, such as SV40 tumor antigen, Ela and Elb in adenovirus, E6 and E7 protein of human papilloma virus type 16 and type

  1. High-Grade Squamous Intraepithelial Lesion Cytology With Negative High-Risk Human Papillomavirus Tests Rarely Diagnoses Endometrial Cancer.

    Science.gov (United States)

    Pretorius, Robert G; Peterson, Patricia

    2015-07-01

    We hypothesized that women with cervical cytologic results of high-grade squamous intraepithelial lesion (HSIL) and negative high-risk human papillomavirus (HR-HPV) test results would have a high risk of having endometrial cancer and would benefit from routine endometrial biopsy. Reports of women with cytologic results of HSIL and negative HR-HPV test results were found in an electronic colposcopy database; their charts were reviewed. Rates of endometrial cancer for cytologic results of HSIL and negative HR-HPV test results were compared to a historical series for cytologic results of HSIL with positive HR-HPV and cytologic results of atypical glandular cells (AGCs) and negative HR-HPV test results. Between August 10, 1998, and April 20, 2013, 56 women were evaluated in our colposcopy clinics for cytologic results of HSIL and negative HR-HPV test results; of these 56 women, 1 (1.8%) was diagnosed with endometrial cancer. No endometrial cancer was diagnosed during the follow-up (median = 63 mo) after colposcopy. The risk for endometrial cancer with cytologic results of HSIL and negative HR-HPV test results (1.8%, 1/56) did not differ from that of a historical series from 2007 to 2009 from the same colposcopy clinic in 223 women with cytologic results of HSIL and positive HR-HPV test results (0.0%, 0/223; p = .2) and was lower than the risk for endometrial cancer from the historical series from 2007 to 2009 in women with cytologic results of AGC and negative HR-HPV test results (14.4%, 4/27; p = .04). Women with cytologic results of HSIL and negative HR-HPV test results are more like those with cytologic results of HSIL and positive HR-HPV test results than those with cytologic results of AGC and negative HR-HPV test results and would unlikely to benefit from routine endometrial biopsy at the time of colposcopy.

  2. Increased SLIT immunoreactivity as a biomarker for recurrence in endometrial carcinoma.

    Science.gov (United States)

    Ma, Shulan; Liu, Xishi; Geng, Jian-Guo; Guo, Sun-Wei

    2010-01-01

    We sought to investigate the potential predictive value of SLIT/ROBO1 immunoreactivity in recurrent and nonrecurrent endometrial cancer (EC), and the relationship between SLIT/Roundabout (ROBO1) immunoreactivity and microvessel density (MVD) in EC. From a total of 815 consecutive patients histologically diagnosed with EC who had undergone surgery we retrieved 45 patients who had confirmed recurrence and randomly selected 110 patients without recurrence. Their paraffin-embedded tissue blocks were also retrieved and subjected to immunohistochemistry for pan-SLIT and ROBO1. MVD counts were evaluated by CD34 immunohistochemistry. Univariate and multivariate analyses were performed to evaluate the effect of SLIT/ROBO1 on recurrence risk with adjustment for other known risk factors. Immunoreactivity to pan-SLIT and ROBO1 was higher in recurrence patients than that in nonrecurrence patients. Both SLIT and ROBO1 immunoreactivities were positively correlated with MVD. Cox regression analysis identified SLIT, along with age and International Federation of Gynecology and Obstetrics stage, as risk factors for recurrence. The resultant discrimination model yielded estimated and cross-validated sensitivity and specificity of 79% and 85%, respectively. Increased immunoreactivity to SLIT is an important factor for recurrence of EC, likely through attracting endothelial cells and promoting neovascularization. Thus, the SLIT immunoreactivity is likely a promising biomarker for recurrence and the SLIT/ROBO1 system may be a potential target for reducing the recurrence risk in EC. 2010 Mosby, Inc.

  3. Multiple myeloma with pleural involvement after pelvic radiotherapy for endometrial carcinoma

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    Bulent Karagoz

    2013-08-01

    Full Text Available Although ionizing radiation is strongest factor linked to multiple myeloma, increased myeloma risk has not been fully explained after pelvic radiation. Pleural involvement of MM is also rare. We present a MM case with pleural involvement as an unusual presentation diagnosed in fifth years of pelvic radiotherapy. A sixty-two-year-old woman with dyspnea and a mass in forehead was admitted to our clinic. Before five year, the patient had received pelvic external beam radiotherapy (RT with dose of 40 Gy for endometrial adenocarcinoma. PET/CT scan detected FDG uptakes in frontal bone, right pleura, and sacrum. Lambda light chain type multiple myeloma with pleural involvement was diagnosed with histopathological examinations of frontal bone mass, bone marrow, and pleural fluid and with serum/urine electroforesis. The patient died in second course of VAD chemotherapy. Although relation between increased myeloma risk and pelvic radiation is not clear and pleural involvement is rare, multiple myeloma should be included to the differential diagnosis in patients received pelvic radiotherapy or in unexplained pleural effusion. [Dis Mol Med 2013; 1(4.000: 87-89

  4. Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo.

    Science.gov (United States)

    Winship, Amy L; Van Sinderen, Michelle; Donoghue, Jacqueline; Rainczuk, Kate; Dimitriadis, Evdokia

    2016-04-01

    Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. IL11 is a cytokine that regulates cell cycle, invasion, and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumors and uterine lavage fluid in women with endometrial cancer, and alters endometrial epithelial cancer cell adhesion and migration in vitro, but its role in endometrial tumorigenesis in vivo is unknown. We injected mice subcutaneously with human-derived Ishikawa or HEC1A endometrial epithelial cancer cells (ectopic), or HEC1A cells into the uterus (orthotopic) to develop endometrial cancer mouse models. Administration of anti-human IL11 receptor (R) α blocking antibody dramatically reduced HEC1A-derived tumor growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared with IgG. Anti-human IL11Rα retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice, suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Rα with anti-mouse IL11Rα antibody did not alter tumor growth, suggesting that cancer epithelial cell IL11 signaling is required for tumor progression. In vitro, anti-human IL11Rα antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse, IL11Rα antibody reduced STAT3, but not ERK, activation in HEC1A cells in vitro and in endometrial tumors in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signaling reduced primary tumor growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo Our data suggest that therapeutically targeting IL11Rα could inhibit endometrial cancer growth and dissemination. Mol Cancer Ther; 15(4); 720-30. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays.

    Science.gov (United States)

    Nguyen, Hong P T; Xiao, L; Deane, James A; Tan, Ker-Sin; Cousins, Fiona L; Masuda, Hirotaka; Sprung, Carl N; Rosamilia, Anna; Gargett, Caroline E

    2017-11-01

    Is there a specific surface marker that identifies human endometrial epithelial progenitor cells with adult stem cell activity using in vitro assays? N-cadherin isolates clonogenic, self-renewing human endometrial epithelial progenitor cells with high proliferative potential that differentiate into cytokeratin+ gland-like structures in vitro and identifies their location in some cells of gland profiles predominantly in basalis endometrium adjacent to the myometrium. Human endometrium contains a small population of clonogenic, self-renewing epithelial cells with high proliferative potential that differentiate into large gland-like structures, but their identity and location is unknown. Stage-specific embryonic antigen-1 (SSEA-1) distinguishes the epithelium of basalis from functionalis and is a marker of human post-menopausal (Post-M) endometrial epithelium. Prospective observational study of endometrial epithelial cells obtained from hysterectomy samples taken from 50 pre-menopausal (Pre-M) and 24 Post-M women, of which 4 were from women who had taken daily estradiol valerate 2 mg/day for 8 weeks prior. Gene profiling was used to identify differentially expressed surface markers between fresh EpCAM (Epithelial Cell Adhesion Molecule)-magnetic bead-selected basalis-like epithelial cells from Post-M endometrium compared with predominantly functionalis epithelial cells from Pre-M endometrium and validated by qRT-PCR. In vitro clonogenicity and self-renewal assays were used to assess the stem/progenitor cell properties of magnetic bead-sorted N-cadherin+ and N-cadherin- epithelial cells. The cellular identity, location and phenotype of N-cadherin+ cells was assessed by dual colour immunofluorescence and confocal microscopy for cytokeratin, proliferative status (Ki-67), ERα, SSEA-1, SOX9 and epithelial mesenchymal transition (EMT) markers on full thickness human endometrium. CDH2 (N-cadherin gene) was one of 11 surface molecules highly expressed in Post-M compared to

  6. Human endometrial cell coculture reduces the endocrine disruptor toxicity on mouse embryo development

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    Lee Myeong-Seop

    2012-04-01

    Full Text Available Abstract Backgrounds Previous studies suggested that endocrine disruptors (ED are toxic on preimplantation embryos and inhibit development of embryos in vitro culture. However, information about the toxicity of endocrine disruptors on preimplantation development of embryo in human reproductive environment is lacking. Methods Bisphenol A (BPA and Aroclor 1254 (polychlorinated biphenyls were used as endocrine disruptors in this study. Mouse 2-cell embryos were cultured in medium alone or vehicle or co-cultured with human endometrial epithelial layers in increasing ED concentrations. Results At 72 hours the percentage of normal blastocyst were decreased by ED in a dose-dependent manner while the co-culture system significantly enhanced the rate and reduced the toxicity of endocrine disruptors on the embryonic development in vitro. Conclusions In conclusion, although EDs have the toxic effect on embryo development, the co-culture with human endometrial cell reduced the preimplantation embryo from it thereby making human reproductive environment protective to preimplantation embryo from the toxicity of endocrine disruptors.

  7. Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion

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    Carly Cuman

    2015-10-01

    Full Text Available Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM from blastocysts that failed to implant (non-implanted compared to blastocysts that implanted (implanted. Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs. miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure.

  8. Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion.

    Science.gov (United States)

    Cuman, Carly; Van Sinderen, Michelle; Gantier, Michael P; Rainczuk, Kate; Sorby, Kelli; Rombauts, Luk; Osianlis, Tiki; Dimitriadis, Evdokia

    2015-10-01

    Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM) from blastocysts that failed to implant (non-implanted) compared to blastocysts that implanted (implanted). Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs). miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure.

  9. Sildenafil Effect on Nitric Oxide Secretion by Normal Human Endometrial Epithelial Cells Cultured In vitro

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    Farzaneh Chobsaz

    2011-01-01

    Full Text Available Background: Sildenafil is a selective inhibitor of cyclic-guanosine monphosphat-specificphosphodiesterase type 5. It increases intracellular nitric oxide (NO production in some cells.There are reports on its positive effect on uterine circulation, endometrial thickness, and infertilityimprovement. Endometrial epithelial cells (EEC play an important role in embryo attachment andimplantation. The present work investigates the effect of sildenafil on human EEC and their NOsecretion in vitro.Materials and Methods: In this experimental in vitro study, endometrial biopsies (n=10 werewashed in a phosphate buffered solution (PBS and digested with collagenase I (2 mg/ml in DMEM/F12 medium at 37°C for 90 minutes. Epithelial glands were collected by sequential filtrationthrough nylon meshes (70 and 40 μm pores, respectively. Epithelial glands were then treated withtrypsin to obtain individual cells. The cells were counted and divided into four groups: control and1, 10, and 20 μM sildenafil concentrations. Cells were cultured for 15 days at 37ºC and 5% CO2; themedia were changed every 3 days, and their supernatants were collected for the NO assay. NO wasmeasured by standard Greiss methods. Data were analyzed by one way ANOVA.Results: There was no significant difference between groups in cell count and NO secretion, but thelevel of NO increased slightly in the experimental groups. The 10 μM dose showed the highest cellcount. EEC morphology changed into long spindle cells in the case groups.Conclusion: Sildenafil (1, 10, and 20 μM showed a mild proliferative effect on human EECnumbers, but no significant change was seen in NO production.

  10. Human Endometrial Stromal Cells Are Highly Permissive To Productive Infection by Zika Virus.

    Science.gov (United States)

    Pagani, Isabel; Ghezzi, Silvia; Ulisse, Adele; Rubio, Alicia; Turrini, Filippo; Garavaglia, Elisabetta; Candiani, Massimo; Castilletti, Concetta; Ippolito, Giuseppe; Poli, Guido; Broccoli, Vania; Panina-Bordignon, Paola; Vicenzi, Elisa

    2017-03-10

    Zika virus (ZIKV) is a recently re-emerged flavivirus transmitted to humans by mosquito bites but also from mother to fetus and by sexual intercourse. We here show that primary human endometrial stromal cells (HESC) are highly permissive to ZIKV infection and support its in vitro replication. ZIKV envelope expression was detected in the endoplasmic reticulum whereas double-stranded viral RNA colocalized with vimentin filaments to the perinuclear region. ZIKV productive infection also occurred in the human T-HESC cell line together with the induction of interferon-β (IFN-β) and of IFN-stimulated genes. Notably, in vitro decidualization of T-HESC with cyclic AMP and progesterone upregulated the cell surface expression of the ZIKV entry co-receptor AXL and boosted ZIKV replication by ca. 100-fold. Thus, endometrial stromal cells, particularly if decidualized, likely represent a crucial cell target of ZIKV reaching them, either via the uterine vasculature in the viremic phase of the infection or by sexual viral transmission, and a potential source of virus spreading to placental trophoblasts during pregnancy.

  11. Preoperative Serum Human Epididymis Protein 4 Levels in Early Stage Endometrial Cancer: A Prospective Study.

    Science.gov (United States)

    Fanfani, Francesco; Restaino, Stefano; Cicogna, Stefania; Petrillo, Marco; Montico, Marcella; Perrone, Emanuele; Radillo, Oriano; De Leo, Rossella; Ceccarello, Matteo; Scambia, Giovanni; Ricci, Giuseppe

    2017-07-01

    The aim of the study was to evaluate the prognostic value of human epididymis protein 4 (HE4) and cancer antigen 125 markers with pathological prognostic factor to complete the preoperative clinical panel and help the treatment planning. This prospective multicenter study was conducted in 2 gynecologic oncology centers between 2012 and 2014 (Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and Catholic University of the Sacred Heart in Rome, Italy). We enrolled 153 patients diagnosed with clinical early (International Federation of Gynecology and Obstetrics stages I-II) type I endometrial cancer. Human epididymis protein 4 levels seemed to be strictly related to age (P endometrial cancer type I versus type II (P = 0.86), the lymphovascular infiltration (P = 0.12), and the cervical invasion (P = 0.6). We established a new variable, considering 3 high-risk tumor features: MI of greater than 50% and/or histological G3 and/or type II. Human epididymis protein 4 levels significantly increase in high-risk tumors (high risk HE4, 93.6 pmol/L vs low-medium risk, 65.5 pmol/L; P < 0.001). A preoperative HE4 evaluation could help stratify patients with deep invasion and/or metastatic disease and is correlated with other relevant prognostic factors to be considered to tailor an adequate surgical strategy.

  12. Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility.

    Science.gov (United States)

    Bolnick, Alan D; Bolnick, Jay M; Kilburn, Brian A; Stewart, Tamika; Oakes, Jonathan; Rodriguez-Kovacs, Javier; Kohan-Ghadr, Hamid-Reza; Dai, Jing; Diamond, Michael P; Hirota, Yasushi; Drewlo, Sascha; Dey, Sudhansu K; Armant, D Randall

    2016-09-01

    Is protein expression of the muscle segment homeobox gene family member MSX1 altered in the human secretory endometrium by cell type, developmental stage or fertility? MSX1 protein levels, normally elevated in the secretory phase endometrium, were significantly reduced in endometrial biopsies obtained from women of infertile couples. Molecular changes in the endometrium are important for fertility in both animals and humans. Msx1 is expressed in the preimplantation mouse uterus and regulates uterine receptivity for implantation. The MSX protein persists a short time, after its message has been down-regulated. Microarray analysis of the human endometrium reveals a similar pattern of MSX1 mRNA expression that peaks before the receptive period, with depressed expression at implantation. Targeted deletion of uterine Msx1 and Msx2 in mice prevents the loss of epithelial cell polarity during implantation and causes infertility. MSX1 mRNA and cell type-specific levels of MSX1 protein were quantified from two retrospective cohorts during the human endometrial cycle. MSX1 protein expression patterns were compared between fertile and infertile couples. Selected samples were dual-labeled by immunofluorescence microscopy to localize E-cadherin and β-catenin in epithelial cells. MSX1 mRNA was quantified by PCR in endometrium from hysterectomies (n = 14) determined by endometrial dating to be in the late-proliferative (cycle days 10-13), early-secretory (cycle days 14-19) or mid-secretory (cycle days 20-24) phase. MSX1 protein was localized using high-throughput, semi-quantitative immunohistochemistry with sectioned endometrial biopsy tissues from fertile (n = 89) and infertile (n = 89) couples. Image analysis measured stain intensity specifically within the luminal epithelium, glands and stroma during the early-, mid- and late- (cycle days 25-28) secretory phases. MSX1 transcript increased 5-fold (P endometrial cellular compartments. MSX1 protein decreased (P human MSX2 is not

  13. Interaction of human trophoblast cells with gland-like endometrial spheroids: a model system for trophoblast invasion.

    Science.gov (United States)

    Buck, V U; Gellersen, B; Leube, R E; Classen-Linke, I

    2015-04-01

    Do maternal endometrial epithelial cell (EEC) differentiation and polarity impact the invasive capacity of extravillous trophoblast (EVT) cells during early human implantation? In a three dimensional (3D) confrontation co-culture the invasiveness of the human trophoblast cell line AC-1M88 was inversely correlated with the degree of differentiation and polarization of human endometrial adenocarcinoma cell spheroids. In a previous study desmosomal and adherens junction proteins were shown to spread from a subapically restricted lateral position to the entire lateral membrane in human glandular EECs during the implantation window of the menstrual cycle. Whether this change in EEC junction localization has an impact on the interaction of EVT cells with glandular EECs during early human implantation is not known. A new 3D cell culture system was developed in order to mimic early implantation events in humans. As a model for the invasion of endometrial glands by EVT cells, spheroids of three differently differentiated and polarized endometrial adenocarcinoma cell lines were confronted with an EVT cell line in co-culture experiments. Three human adenocarcinoma EEC lines were chosen for this study because of their differences in differentiation and polarization: HEC-1-A, which is well differentiated and highly polarized, Ishikawa, which is well differentiated and moderately polarized, and RL95-2, which is moderately differentiated and poorly polarized. When the cell lines were grown in reconstituted basement membrane, they formed gland-like, multicellular spheroids. The degree of polarization within the different EEC spheroids was assessed by 3D confocal immunofluorescence microscopy detecting the basal membrane protein integrin α6, the apical tight junction-associated protein ZO-1 and the desmosomal plaque protein desmoplakin 1/2 (Dsp). Cells of the human EVT cell line AC-1M88, which is a fusion cell line of primary EVT cells and choriocarcinoma-derived JEG-3 cells, were

  14. Lymph node dissection in atypical endometrial hyperplasia.

    Science.gov (United States)

    Taşkın, Salih; Kan, Özgür; Dai, Ömer; Taşkın, Elif A; Koyuncu, Kazibe; Alkılıç, Ayşegül; Güngör, Mete; Ortaç, Fırat

    2017-09-01

    The rate of concomitant endometrial carcinoma in patients with atypical endometrial hyperplasia is high. We aimed to investigate the role of lymphadenectomy in deciding adjuvant treatment in patients with concomitant atypical endometrial hyperplasia and endometrial carcinoma. Women with atypical endometrial hyperplasia were enrolled in this retrospective study. Lymph node dissection was performed in only some patients who gave informed consent if their surgeon elected to do so, or if the intraoperative findings necessitated. The final histopathologic evaluations of surgical specimens were compared with endometrial biopsy results. Eighty eligible patients were evaluated. Seventy-two (90%) patients had complex hyperplasia with atypia, and 8 (10%) patients had simple hyperplasia with atypia. Hysterectomy and bilateral salpingo-oophorectomy were performed to all patients; 37 also underwent lymph node dissection. Lymph node dissection was extended to the paraaortic region in 9 of 37 patients. The concomitant endometrial carcinoma rate was 50%. Two patients had lymph node metastasis. Among 40 cases of carcinoma, 17 had deep myometrial invasion and/or cervical or ovarian involvement or grade 2 tumors with superficial myometrial invasion on hysterectomy specimens; 27.5% of all carcinomas were stage Ib or higher. The concomitant endometrial carcinoma rate was high in patients with atypical endometrial hyperplasia. Nearly half of these patients had risk factors for extrauterine spread. Lymph node dissection might be helpful to decide adjuvant treatment.

  15. Leukemia inhibitory factor increases the proliferation of human endometrial stromal cells and expression of genes related to pluripotency

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    Mojdeh Salehnia

    2017-08-01

    Full Text Available Background: Concerning the low population of human endometrial mesenchymal cells within the tissue and their potential application in the clinic and tissue engineering, some researches have been focused on their in vitro expansion. Objective: The aim of this study was to evaluate the effect of leukemia inhibitory factor (LIF as a proliferative factor on the expansion and proliferation of human endometrial stromal cells. Materials and Methods: In this experimental study, the isolated and cultured human endometrial stromal cells from women at ovulatory phase aged 20-35 years, after fourth passage were divided into control and LIF-treated groups. In the experimental group, the endometrial cells were treated by 10 ng/ml LIF in culture media and the cultured cells without adding LIF considered as control group. Both groups were evaluated and compared for proliferation rate using MTT assay, for CD90 marker by flow cytometric analysis and for the expression of Oct4, Nanog, PCNA and LIFr genes using real-time RT-PCR. Results: The proliferation rate of control and LIF-treated groups were 1.17±0.17 and 1.61±0.06 respectively and there was a significant increase in endometrial stromal cell proliferation following in vitro treatment by LIF compared to control group (p=0.049. The rate of CD90 positive cells was significantly increased in LIFtreated group (98.96±0.37% compared to control group (94.26±0.08% (p=0.0498. Also, the expression ratio of all studied genes was significantly increased in the LIFtreated group compared to control group (p=0.0479. Conclusion: The present study showed that LIF has a great impact on proliferation, survival, and maintenance of pluripotency of human endometrial stromal cells and it could be applicable in cell therapies.

  16. Leukemia inhibitory factor increases the proliferation of human endometrial stromal cells and expression of genes related to pluripotency.

    Science.gov (United States)

    Salehnia, Mojdeh; Fayazi, Mehri; Ehsani, Shokreya

    2017-04-01

    Concerning the low population of human endometrial mesenchymal cells within the tissue and their potential application in the clinic and tissue engineering, some researches have been focused on their in vitro expansion. The aim of this study was to evaluate the effect of leukemia inhibitory factor (LIF) as a proliferative factor on the expansion and proliferation of human endometrial stromal cells. In this experimental study, the isolated and cultured human endometrial stromal cells from women at ovulatory phase aged 20-35 years, after fourth passage were divided into control and LIF-treated groups. In the experimental group, the endometrial cells were treated by 10 ng/ml LIF in culture media and the cultured cells without adding LIF considered as control group. Both groups were evaluated and compared for proliferation rate using MTT assay, for CD90 marker by flow cytometric analysis and for the expression of Oct4, Nanog, PCNA and LIFr genes using real-time RT-PCR. The proliferation rate of control and LIF-treated groups were 1.17±0.17 and 1.61±0.06 respectively and there was a significant increase in endometrial stromal cell proliferation following in vitro treatment by LIF compared to control group (p=0.049). The rate of CD90 positive cells was significantly increased in LIF-treated group (98.96±0.37%) compared to control group (94.26±0.08%) (p=0.0498). Also, the expression ratio of all studied genes was significantly increased in the LIF-treated group compared to control group (p=0.0479). The present study showed that LIF has a great impact on proliferation, survival, and maintenance of pluripotency of human endometrial stromal cells and it could be applicable in cell therapies.

  17. Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway.

    Science.gov (United States)

    Chandra, V; Fatima, I; Manohar, M; Popli, P; Sirohi, V K; Hussain, M K; Hajela, K; Sankhwar, P; Dwivedi, A

    2014-08-21

    Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/β-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ERα, PR, PCNA, Wnt7a, FZD6, pGsk3β and β-catenin without affecting the growth of the primary culture of normal endometrial cells. The β-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/β-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of β-catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/β-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway.

  18. LeY oligosaccharide upregulates DAG/PKC signaling pathway in the human endometrial cells.

    Science.gov (United States)

    Li, Yali; Ma, Keli; Sun, Ping; Liu, Shuai; Qin, Huamin; Zhu, Zhengmei; Wang, Xiaoqi; Yan, Qiu

    2009-11-01

    LeY oligosaccharide is stage specifically expressed by the embryo and uterine endometrium, and it plays important roles in embryo implantation. In addition to participating in the recognition and adhesion on fetal-maternal interface, LeY potentially regulates the expression of some implantation-related factors. However, it remains elusive whether it can mediate the involved signaling pathway. In this study, agarose-LeY beads were used to mimic the embryos, and the effects of LeY oligosaccharide on DAG/PKC signaling pathway was studied in human endometrial epithelial cells. Results showed that LeY could significantly trigger the activation of cPKCalpha and cPKCbeta2, and their translocation from the cytosol to the plasma membrane. The cellular DAG content was also upregulated, and the activation of PLCgamma1 was promoted. On the contrary, DAG/PKC signaling pathway was significantly inhibited when anti-LeY antibody was used after confirmation of LeY expression in human endometrial epithelial cells by immunohistochemistry and flow cytometry. These results suggest that LeY oligosaccharide acts as a signal molecule to modulate DAG/PKC signaling pathway.

  19. The orphan nuclear receptor Nur77 regulates decidual prolactin expression in human endometrial stromal cells

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    Jiang, Yue; Hu, Yali; Zhao, Jing; Zhen, Xin [Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008 (China); Yan, Guijun, E-mail: yanguijun33@gmail.com [Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008 (China); Sun, Haixiang, E-mail: stevensunz@163.com [Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008 (China)

    2011-01-14

    Research highlights: {yields} Decidually produced PRL plays a key role during pregnancy. {yields} Overexpression of Nur77 increased PRL mRNA expression and enhanced decidual PRL promoter activity. {yields} Knockdown of Nur77 decreased decidual PRL secretion induced by 8-Br-cAMP and MPA. {yields} Nur77 is a novel transcription factor that plays an active role in decidual prolactin expression. -- Abstract: Prolactin (PRL) is synthesized and released by several extrapituitary tissues, including decidualized stromal cells. Despite the important role of decidual PRL during pregnancy, little is understood about the factors involved in the proper regulation of decidual PRL expression. Here we present evidence that the transcription factor Nur77 plays an active role in decidual prolactin expression in human endometrial stromal cells (hESCs). Nur77 mRNA expression in hESCs was significantly increased after decidualization stimulated by 8-Br-cAMP and medroxyprogesterone acetate (MPA). Adenovirus-mediated overexpression of Nur77 in hESCs markedly increased PRL mRNA expression and enhanced decidual PRL promoter (dPRL/-332Luc) activity in a concentration-dependent manner. Furthermore, knockdown of Nur77 in hESCs significantly decreased decidual PRL promoter activation and substantially attenuated PRL mRNA expression and PRL secretion (P < 0.01) induced by 8-Br-cAMP and MPA. These results demonstrate that Nur77 is a novel transcription factor that contributes significantly to the regulation of prolactin gene expression in human endometrial stromal cells.

  20. Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis.

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    Valentijn, A J; Saretzki, G; Tempest, N; Critchley, H O D; Hapangama, D K

    2015-12-01

    How does regulation of telomerase activity (TA) in human endometrial epithelial cells (EEC) by ovarian hormones impact on telomere lengths (TL) and cell proliferation? Healthy endometrial epithelial cell proliferation is characterized by high TA and endometrial TL changes according to the ovarian hormone cycle, with shortest TL observed in the progesterone dominant mid-secretory phase, when TA is lowest, implicating progesterone in the negative regulation of TA and TL. Critical shortening of telomeres may result in permanent cell cycle arrest while the enzyme telomerase maintains telomere length (TL) and replicative capacity of cells. Telomerase expression and activity change in the human endometrium with the ovarian hormone cycle, however the effect of this on endometrial TL and cell growth is not known. A prospective observational study, which included endometrial and blood samples collected from 196 women. We studied endometrial samples from five different groups of women. Endometrial and matched blood TL and circulating steroid hormones were studied in samples collected from 85 women (Group 1). Fresh epithelial and stromal cell isolation and culture in vitro for TL and TA was done on endometrial biopsies collected from a further 74 healthy women not on hormonal therapy (Group 2) and from 5 women on medroxyprogesterone acetate (MPA) for contraception (Group 3). The epithelial TL and telomerase protein expression was examined in active, peritoneal, ectopic endometriotic and matched uterine (eutopic) endometrial samples collected from 10 women with endometriosis (Group 4); the in vivo effect of mifepristone on telomerase protein expression by immunohistochemistry (IHC) was examined in endometrium from 22 healthy women in mid-secretory phase before (n = 8), and after administering 200 mg mifepristone (n = 14) (Group 5). TA was measured by telomere repeat amplification protocol (TRAP) assay; TL by qPCR, and Q-FISH; cell proliferation was assessed by immunoblotting

  1. Determination of Heavy Metal Concentrations in Normal and Pathological Human Endometrial Biopsies and In Vitro Regulation of Gene Expression by Metals in the Ishikawa and Hec-1b Endometrial Cell Line.

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    Erwan Guyot

    Full Text Available It is well known that several metals, such as lead, mercury, cadmium, and vanadium, can mimic the effects of estrogens (metallo-estrogens. Nevertheless, there are only a few studies that have assessed the effects of toxic metals on the female genital tract and, in particular, endometrial tissue. In this context, we measured the concentrations of several trace elements in human endometrial tissue samples from individuals with hyperplasia or adenocarcinoma and in normal tissues. Hyperplasic endometrial tissue has a 4-fold higher concentration of mercury than normal tissue. Mercury can affect both the AhR and ROS signaling pathways. Thus, we investigated the possible toxic effects of mercury by in vitro studies. We found that mercury increases oxidative stress (increased HO1 and NQO1 mRNA levels and alters the cytoskeleton in the human endometrial Ishikawa cell line and to a lesser extent, in the "less-differentiated" human endometrial Hec-1b cells. The results might help to explain a potential link between this metal and the occurrence of endometrial hyperplasia.

  2. Determination of Heavy Metal Concentrations in Normal and Pathological Human Endometrial Biopsies and In Vitro Regulation of Gene Expression by Metals in the Ishikawa and Hec-1b Endometrial Cell Line.

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    Guyot, Erwan; Solovyova, Yevgeniya; Tomkiewicz, Céline; Leblanc, Alix; Pierre, Stéphane; El Balkhi, Souleiman; Le Frère-Belda, Marie-Aude; Lecuru, Fabrice; Poupon, Joël; Barouki, Robert; Aggerbeck, Martine; Coumoul, Xavier

    2015-01-01

    It is well known that several metals, such as lead, mercury, cadmium, and vanadium, can mimic the effects of estrogens (metallo-estrogens). Nevertheless, there are only a few studies that have assessed the effects of toxic metals on the female genital tract and, in particular, endometrial tissue. In this context, we measured the concentrations of several trace elements in human endometrial tissue samples from individuals with hyperplasia or adenocarcinoma and in normal tissues. Hyperplasic endometrial tissue has a 4-fold higher concentration of mercury than normal tissue. Mercury can affect both the AhR and ROS signaling pathways. Thus, we investigated the possible toxic effects of mercury by in vitro studies. We found that mercury increases oxidative stress (increased HO1 and NQO1 mRNA levels) and alters the cytoskeleton in the human endometrial Ishikawa cell line and to a lesser extent, in the "less-differentiated" human endometrial Hec-1b cells. The results might help to explain a potential link between this metal and the occurrence of endometrial hyperplasia.

  3. Carfilzomib induces G2/M cell cycle arrest in human endometrial cancer cells via upregulation of p21Waf1/Cip1and p27Kip1.

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    Zhou, Yuanyuan; Wang, Ke; Zhen, Shuai; Wang, Ruili; Luo, Wenjuan

    2016-12-01

    Carfilzomib is a second-generation tetrapeptide epoxyketone proteasome inhibitor used in current clinical therapy of hematologic malignancies. The mechanism of proteasome inhibition in endometrial cancer is not very clear. Carfilzomib inhibition of type I endometrial carcinoma cell proliferation by inducing cell cycle arrest at the G2/M phase was investigated in our study. HEC-1-A and Ishikawa endometrial carcinoma cell lines and three tumor cell lines were treated by different concentrations of carfilzomib. Methyl thiazolyl tetrazolium (MTT) assay was used to detect cell viability. Flow cytometry was used to analyze the cell cycle. Western blot was used to detect proteins involved in cell cycle progression. Carfilzomib impaired viability of myelogenous leukemia cell line K562, cervical cancer cell line HeLa, hepatocellular carcinoma cell line SMCC-7721, and endometrial carcinoma cell lines HEC-1-A and Ishikawa. The cell cycle was arrested at the G2/M phase in carfilzomib-treated HEC-1-A endometrial carcinoma cells, while it was arrested at both S and G2/M phases in carfilzomib-treated Ishikawa cells. Carfilzomib treatment significantly induced p21 Waf1/ Cip1 and p27, while substantially reduced cyclin D3 and cyclin-dependent kinase 1. This study showed that carfilzomib inhibited endometrial cancer proliferation by upregulating cyclin-dependent kinase inhibitors p21 Waf1/Cip1 and p27 Kip1 , and reducing cyclin-dependent kinase 1 to arrest the cell cycle at the G2/M phase. Copyright © 2016. Published by Elsevier B.V.

  4. Cancer-Related Triplets of mRNA-lncRNA-miRNA Revealed by Integrative Network in Uterine Corpus Endometrial Carcinoma

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    Chenglin Liu

    2017-01-01

    Full Text Available The regulation of transcriptome expression level is a complex process involving multiple-level interactions among molecules such as protein coding RNA (mRNA, long noncoding RNA (lncRNA, and microRNA (miRNA, which are essential for the transcriptome stability and maintenance and regulation of body homeostasis. The availability of multilevel expression data enables a comprehensive view of the regulatory network. In this study, we analyzed the coding and noncoding gene expression profiles of 301 patients with uterine corpus endometrial carcinoma (UCEC. A new method was proposed to construct a genome-wide integrative network based on variance inflation factor (VIF regression method. The cross-regulation relations of mRNA, lncRNA, and miRNA were then selected based on clique-searching algorithm from the network, when any two molecules of the three were shown as interacting according to the integrative network. Such relation, which we call the mRNA-lncRNA-miRNA triplet, demonstrated the complexity in transcriptome regulation process. Finally, six UCEC-related triplets were selected in which the mRNA participates in endometrial carcinoma pathway, such as CDH1 and TP53. The multi-type RNAs are proved to be cross-regulated as to each of the six triplets according to literature. All the triplets demonstrated the association with the initiation and progression of UCEC. Our method provides a comprehensive strategy for the investigation of transcriptome regulation mechanism.

  5. Effect of dentine matrix proteins on human endometrial adult stem-like cells: in vitro regeneration of odontoblasts cells.

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    Tabatabaei, Fahimeh S; Ai, Jafar; Jafarzadeh Kashi, Tahereh S; Khazaei, Mozaffar; Kajbafzadeh, Abdol-Mohammad; Ghanbari, Zinat

    2013-07-01

    Human endometrium has enormous regenerative capacity due to the presence of endometrial stem cells. The present study sought to assess the possibility of differentiation of these cells into odontoblast-like cells by in vitro induction. Endometrial stem-like cells were obtained using enzymatic digestion of the biopsy samples of the endometrium after hysterectomy and cultured in Dulbecco's Modified Eagle's Medium (DMEM) which contained dentine non-collagenous proteins (dNCPs). The results were evaluated using the following assays: analysis of morphology, enzymatic assay for measuring alkaline phosphatase activity, Alizarin Red staining to detect in vitro formation of mineralized nodules, immunofluorescence for detection of dentine sialoprotein (DSP) and dentine-matrix protein (DMP1), and Western blotting for DMP1 expression. Following induction, endometrial stem-like cells demonstrated high alkaline phosphatase activity, and expression of DSP and DMP1 confirmed the odontoblast phenotype. DMP1 level increased in samples treated with dNCPs. Study results indicated that odontoblastic differentiation of endometrial stem cells can be induced by extracellular matrix proteins (e.g. dNCPs). The capacity of endometrial stem-like cells to differentiate into odontoblast-like cells under specific conditions gives new insights into the mechanism of odontogenesis and highlights the potential of such approaches for further research on dental tissue regeneration. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Induction of mitochondrial apoptotic pathway by raloxifene and estrogen in human endometrial stromal ThESC cell line.

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    Nikolic, Ivana; Andjelkovic, Marija; Zaric, Milan; Zelen, Ivanka; Canovic, Petar; Milosavljevic, Zoran; Mitrovic, Marina

    2017-03-01

    Endometrial hyperplasia is a condition that occurs as a result of hormonal imbalance between estrogen and progesterone. Morphological disturbance of endometrial cells occurs consequently leading towards endometrial cancer. In therapy of endometrial hyperplasia SERMs are used to supress effects of locally high estrogen level in uterus. There is strong evidence suggesting that estrogen could be involved in cell death - apoptosis. There are no experimental data demstrating the direct apoptotic effect of both raloxifene and estrogen on the ThESC cell line. The aim of our study wa sto investigate both cytotoxic and apototic mechanism of raloxifene and estrogen - induced death in the ThESC cell line. In order to determine their cytotoxic and apoptotic effects, various doses of raloxifene and estrogen were applied to the ThESC cell line for 24 h. After the treatment MTT assay, FACS analysis and immunofluoroscence method were conducted. The results of this study for the first time demonstrated the cytotoxic and apoptotic effects of raloxifene and estrogen on human endometrial stromal cell line suggesting the involvement of the inner, mitochondrial apoptotic pathway. Our results demonstrated apoptotic effects of investigated drugs in the ThESC cell line through increasing the Bax/Bcl-2 ratio and activation of caspase 3.

  7. PGK1 and GRP78 overexpression correlates with clinical significance and poor prognosis in Chinese endometrial cancer patients.

    Science.gov (United States)

    Guo, Suiqun; Xiao, Yanyi; Li, Danqing; Jiang, Qingping; Zhu, Litong; Lin, Dan; Jiang, Huiping; Chen, Wei; Wang, Lijing; Liu, Chunhua; Fang, Weiyi; Lin, Li

    2018-01-02

    The aim of this study was to measure the expression patterns of PGK1 and GRP78 in normal endometrial tissues and endometrial carcinoma, and associations between their combined effects and the pathological features of endometrial carcinoma. We used 30 normal endometrial tissue samples and 130 endometrial carcinoma samples, and separately evaluated PGK1 and GRP78 protein expression by immunohistochemistry. Scores ranging from 0 to 9 were obtained by multiplying the percentage of positive cells by the staining intensity (0-3). Immunohistochemical analysis revealed increased PGK1 and GRP78 expression in the cytoplasm of endometrial carcinoma cells compared with that in normal endometrial tissues. High PGK1 expression positively correlated with the FIGO stage ( P endometrial carcinoma patients ( P endometrial carcinoma patients correlated significantly with the lymph node status ( P endometrial carcinoma progression.

  8. P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling

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    Nomura Seiji

    2007-01-01

    Full Text Available Abstract Background Hyperglycemia or hyperinsulinemia contributes to poorer endometrial cancer survival. It was shown that P-LAP/IRAP translocates to the plasma membrane in response to insulin stimulation. Recently, we demonstrated that P-LAP/IRAP is associated with a poor prognosis in endometrial adenocarcinoma patients. The aim of this study was to examine whether the malignant potential of endometrial cancer enhanced by P-LAP/IRAP is due to increased glucose uptake via the P-LAP/IRAP-mediated activation of insulin signaling. Methods We transfected P-LAP/IRAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line, and A-MEC-LAP cells expressed a remarkably high level of GLUT4 proteins. Results 3H-2-deoxyglucose uptake which responds to insulin in A-MEC-LAP cells was significantly higher than that of A-MEC-pc cells. A-MEC-LAP cells exhibited a significant growth-stimulatory effect compared to A-MEC-pc cells. A-MEC-LAP cells expressed a remarkably high level of p85PI3K protein compared to A-MEC-pc cells, and showed a higher degree of AKT phosphorylation by insulin stimulation. Conclusion In summary, P-LAP/IRAP was involved in the increasing malignant potential of endometrial cancer mediated by insulin. P-LAP/IRAP was suggested to be a potential new target of molecular-targeted therapy for endometrial cancer.

  9. Soluble Delta-like ligand 1 alters human endometrial epithelial cell adhesive capacity.

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    Van Sinderen, Michelle; Oyanedel, Jennifer; Menkhorst, Ellen; Cuman, Carly; Rainczuk, Katarzyna; Winship, Amy; Salamonsen, Lois; Edgell, Tracey; Dimitriadis, Evdokia

    2017-04-01

    The endometrium undergoes substantial morphological and functional changes to become receptive to embryo implantation and to enable establishment of a successful pregnancy. Reduced Delta-like ligand 1 (DLL1, Notch ligand) in the endometrium is associated with infertility. DLL1 can be cleaved by 'a disintegrin and metalloprotease' (ADAM) proteases to produce a soluble ligand that may act to inhibit Notch signalling. We used an enzyme-linked immunosorbent assay to quantify soluble DLL1 in uterine lavages from fertile and infertile women in the secretory phase of the menstrual cycle. We also determined the cellular location and immunostaining intensity of ADAM12 and 17 in human endometrium throughout the cycle. Functional effects of soluble DLL1 in receptivity were analysed using in vitro adhesion and proliferation assays and gene expression analysis of Notch signalling targets. Soluble DLL1 was significantly increased in uterine lavage samples of infertile women compared with fertile women in the secretory phase of the menstrual cycle. This coincided with significantly increased ADAM17 immunostaining detected in the endometrial luminal epithelium in the mid-secretory phase in infertile women. Soluble DLL1 significantly inhibited the adhesive capacity of endometrial epithelial cells via downregulation of helix-loop-helix and hairy/enhancer of split family member HES1 mRNA. Thus, soluble DLL1 may serve as a suitable target or potential biomarker for receptivity.

  10. Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias.

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    Dosil, Maria Alba; Mirantes, Cristina; Eritja, Núria; Felip, Isidre; Navaridas, Raúl; Gatius, Sònia; Santacana, Maria; Colàs, Eva; Moiola, Cristian; Schoenenberger, Joan Antoni; Encinas, Mario; Garí, Eloi; Matias-Guiu, Xavier; Dolcet, Xavier

    2017-06-01

    PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  11. Fibulin-5 is upregulated in decidualized human endometrial stromal cells and promotes primary human extravillous trophoblast outgrowth.

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    Winship, Amy; Cuman, Carly; Rainczuk, Katarzyna; Dimitriadis, Evdokia

    2015-12-01

    Interactions between the highly invasive trophoblasts and the maternal uterine decidual extracellular matrix (ECM) are crucial in the determination of a successful pregnancy. Fibulin-5 (FBLN5) is a member of the fibulin family that alters cell adhesive and invasive properties and is expressed in human villous cytotrophoblasts. We aimed to determine the expression and immunolocalization of FBLN5 in human first trimester decidua and examine the effect of FBLN5 in trophoblast invasion in vitro using a first trimester placental villous outgrowth assay. We demonstrated that FBLN5 mRNA expression is upregulated in response to cAMP-mediated decidualization of primary human endometrial stromal cells, although FBLN5 itself does not enhance decidualization. We reported for the first time, FBLN5 protein production in first trimester decidual cells and also co-localization to HLAG-positive EVTs in first trimester decidua. Consequently, we investigated the effects of exogenous FBLN5 on placental villous outgrowth in vitro and demonstrated that FBLN5 promotes EVT migration/invasion. This is the first study to identify FBLN5 in decidualized human endometrial stromal cells, first trimester decidua and EVT and determine a functional role for FBLN5 in human EVTs, suggesting that decidual and or EVT-derived FBLN5 regulates EVT invasion and placentation in women. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

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    Chun-E Ren

    2015-03-01

    Full Text Available Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

  13. Effects of vaginal cylinder position on dose distribution in patients with endometrial carcinoma in treatment of vaginal cuff brachytherapy

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    Yurday Ozdemir

    2017-06-01

    Full Text Available Purpose: To investigate the impact of different cylinder positions on dosimetry of critical structures in patients with endometrial carcinoma undergoing three-dimensional image-based vaginal cuff brachytherapy (VCB. Material and methods: We delivered VCB at a dose of 4 Gy to a depth of 5 mm in the vaginal cuff of 15 patients using three different cylinder positions (neutral [N], parallel [P], and angled [A] according to the longitudinal axis of the patient. We analyzed the dose-volume distribution and volumetric variability of the rectum and bladder. We converted the total doses to equivalent doses in 2 Gy (EQD 2 using a linear-quadratic model (a/b = 3 Gy. Results : The mean rectum volume for the N, P, and A positions was 68.2 ± 22.7 cc, 79.3 ± 33.7 cc, and 74.2 ± 29.6 cc, respectively. The mean rectum volume for the P position was significantly larger than that for the N position (p = 0.03. Relative to the N position, the A position resulted in a lower total EQD 2 in the highest irradiated 2 cc (D 2cc ; p = 0.001, 1 cc (D 1cc ; p = 0.004, and 0.1 cc (D 0.1cc ; p = 0.047 of the rectum. Similarly, the P position resulted in a lower EQD 2 in the D 2cc (p = 0.018 and D 1cc (p = 0.024 of the rectum relative to the N position. In the bladder, the P position resulted in a higher EQD 2 in the D 2cc relative to the N position (p = 0.02. There was no dosimetric difference between the P and A positions in either the rectum or the bladder. Conclusions : Vaginal cuff brachytherapy in the P and A positions is significantly superior to that in the N position in terms of rectum dosimetry. The bladder dose in the N position is considerably lower than that in the other positions.

  14. Growth and hormonal responsiveness of human endometrial stromal cells in culture.

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    Holinka, C F

    1988-06-01

    The present review describes and discusses published results on growth and hormonal responsiveness of human endometrial stromal cells in culture. The proliferative potential of serially subcultured cells, that is, the number of cell doublings before cells enter mitotic senescence and cease to divide, was unusually high in stromal cells from several endometrial specimens, a property that may reflect the unique proliferative capacity of human endometrium when compared to other adult tissues. Fluorescent visualization of microfilaments revealed distinct age-related changes in the distribution of cytoskeletal fibers. Addition of ovarian steroids to the culture medium of stromal cells resulted in significant morphologic changes. From comparative studies using different culture media it became evident that medium components remarkably influenced cell morphology during early culture periods in an irreversible manner. Cultured stromal cells yielded interesting results in experiments designed to define the role of polyamines in growth regulation. Proliferation was greatly inhibited when polyamine levels were reduced by specific inhibition of ornithine decarboxylase, the first and rate limiting enzyme in polyamine synthesis which produces putrescine by catalytic conversion from ornithine. The antiproliferative effects were reversed by addition of putrescine to the culture medium. These results clearly establish a causal link between polyamine depletion and growth deficiencies and reveal an essential function of polyamines in stromal cell proliferation. Hormonally regulated parameters in cultured stromal cells include aromatase activity, pregnancy-associated plasma protein-A, 51K secreted protein, prolactin and laminin. The hormonally regulated production of prolactin and laminin, both considered markers of decidualization, together with morphologic changes of stromal cells to decidual-like cells, strongly suggest that human endometrial stromal cells, when subjected to

  15. SSEA-1 isolates human endometrial basal glandular epithelial cells: phenotypic and functional characterization and implications in the pathogenesis of endometriosis.

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    Valentijn, A J; Palial, K; Al-Lamee, H; Tempest, N; Drury, J; Von Zglinicki, T; Saretzki, G; Murray, P; Gargett, C E; Hapangama, D K

    2013-10-01

    Can the basal epithelial compartment of the human endometrium be defined by specific markers? Human endometrial epithelial cells from the basalis express nuclear SOX9 and the cell-surface marker SSEA-1, with some cells expressing nuclear β-catenin. In vitro, primary endometrial epithelial cells enriched for SSEA-1+ show some features expected of the basalis epithelium. The endometrial glands of the functionalis regenerate from the basalis gland stumps following menstruation. Endometriosis is thought to originate from abnormal dislocation of the basalis endometrium. In the highly regenerative intestinal epithelium, SOX9 and nuclear β-catenin are more highly expressed in the intestinal crypt, the stem/progenitor cell region. A large prospective observational study analysing full-thickness human endometrial hysterectomy samples from 115 premenopausal women, 15 post-menopausal women and ectopic endometriotic lesions from 20 women with endometriosis. Full-thickness endometrium from hysterectomy tissues was analysed by immunohistochemistry for SSEA-1, SOX9 and β-catenin. Primary human endometrial epithelial cells from short-term cultures were sorted into SSEA1+/- fractions with a cell sorter or magnetic beads and analysed for markers of differentiation and pluripotency and telomere lengths (TLs) using qPCR, telomerase activity [telomere repeat amplification protocol (TRAP)] and growth in 3D culture. Similar to the intestinal crypt epithelium, human endometrial basal glandular epithelial cells expressed nuclear SOX9 and contained a rare subpopulation of cells with nuclear β-catenin suggestive of an activated Wnt pathway. The embryonic stem cell-surface marker, SSEA-1, also marked the human endometrial basal glandular epithelial cells, and isolated SSEA-1(+) epithelial cells grown in monolayer showed significantly higher expression of telomerase activity, longer mean TLs, lower expression of genes for steroid receptors and produced a significantly higher number of

  16. Endometrial cancer arising from atypical complex hyperplasia: The significance in an endometrial biopsy and a diagnostic challenge

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    Byun, Jung Mi; Jeong, Dae Hoon; Kim, Young Nam; Cho, En Bee; Cha, Ju Eun; Sung, Moon Su; Lee, Kyung Bok

    2015-01-01

    Objective We investigated the features of endometrial hyperplasia with concurrent endometrial cancer that had been diagnosed by endometrial sampling. Further, we attempted to identify an accurate differential diagnostic method. Methods We retrospectively studied 125 patients who underwent a diagnostic endometrial biopsy or were diagnosed after the surgical treatment of other gynecological lesions, such as leiomyoma or polyps. Patients were diagnosed between January 2005 and December 2013 at Busan Paik Hospital. Clinical and histopathological characteristics were compared in patients who had atypical endometrial hyperplasia with and without concurrent endometrial cancer. Results The patients were grouped based on the final pathology reports. One hundred seventeen patients were diagnosed with endometrial hyperplasia and eight patients were diagnosed with endometrioid adenocarcinoma arising from atypical hyperplasia. Of the 26 patients who had been diagnosed with atypical endometrial hyperplasia by office-based endometrial biopsy, eight (30.8%) were subsequently diagnosed with endometrial cancer after they had undergone hysterectomy. The patients with endometrial cancer arising from endometrial hyperplasia were younger (39.1 vs. 47.2 years, P=0.0104) and more obese (body mass index 26.1±9.6 vs. 23.8±2.8 kg/m2, P=0.3560) than the patients with endometrial hyperplasia. The correlation rate between the pathology of the endometrial samples and the final diagnosis of endometrial hyperplasia was 67.3%. Conclusion In patients with atypical endometrial hyperplasia, the detection of endometrial cancer before hysterectomy can decrease the risk of suboptimal treatment. The accuracy of endometrial sampling for the diagnosis of concurrent endometrial carcinoma was much lower than that for atypical endometrial hyperplasia. Therefore, concurrent endometrial carcinoma should be suspected and surgical intervention should be considered in young or obese patients who present with

  17. Proteomic analysis identifies interleukin 11 regulated plasma membrane proteins in human endometrial epithelial cells in vitro

    Science.gov (United States)

    2011-01-01

    Background During the peri-implantation period, the embryo adheres to an adequately prepared or receptive endometrial surface epithelium. Abnormal embryo adhesion to the endometrium results in embryo implantation failure and infertility. Endometrial epithelial cell plasma membrane proteins critical in regulating adhesion may potentially be infertility biomarkers or targets for treating infertility. Interleukin (IL) 11 regulates human endometrial epithelial cells (hEEC) adhesion. Its production is abnormal in women with infertility. The objective of the study was to identify IL11 regulated plasma membrane proteins in hEEC in vitro using a proteomic approach. Methods Using a 2D-differential in-gel electrophoresis (DIGE) electrophoresis combined with LCMS/MS mass spectrometry approach, we identified 20 unique plasma membrane proteins differentially regulated by IL11 in ECC-1 cells, a hEEC derived cell line. Two IL11 regulated proteins with known roles in cell adhesion, annexin A2 (ANXA2) and flotillin-1 (FLOT1), were validated by Western blot and immunocytochemistry in hEEC lines (ECC-1 and an additional cell line, Ishikawa) and primary hEEC. Flotilin-1 was further validated by immunohistochemistry in human endometrium throughout the menstrual cycle (n = 6-8/cycle). Results 2D-DIGE analysis identified 4 spots that were significantly different between control and IL11 treated group. Of these 4 spots, there were 20 proteins that were identified with LCMS/MS. Two proteins; ANXA2 and FLOT1 were chosen for further analyses and have found to be significantly up-regulated following IL11 treatment. Western blot analysis showed a 2-fold and a 2.5-fold increase of ANXA2 in hEEC membrane fraction of ECC-1 and Ishikawa cells respectively. Similarly, a 1.8-fold and a 2.3/2.4-fold increase was also observed for FLOT1 in hEEC membrane fraction of ECC-1 and Ishikawa cells respectively. In vitro, IL11 induced stronger ANXA2 expression on cell surface of primary hEEC and ECC-1 whilst

  18. Proteomic analysis identifies interleukin 11 regulated plasma membrane proteins in human endometrial epithelial cells in vitro

    Directory of Open Access Journals (Sweden)

    Stanton Peter G

    2011-05-01

    Full Text Available Abstract Background During the peri-implantation period, the embryo adheres to an adequately prepared or receptive endometrial surface epithelium. Abnormal embryo adhesion to the endometrium results in embryo implantation failure and infertility. Endometrial epithelial cell plasma membrane proteins critical in regulating adhesion may potentially be infertility biomarkers or targets for treating infertility. Interleukin (IL 11 regulates human endometrial epithelial cells (hEEC adhesion. Its production is abnormal in women with infertility. The objective of the study was to identify IL11 regulated plasma membrane proteins in hEEC in vitro using a proteomic approach. Methods Using a 2D-differential in-gel electrophoresis (DIGE electrophoresis combined with LCMS/MS mass spectrometry approach, we identified 20 unique plasma membrane proteins differentially regulated by IL11 in ECC-1 cells, a hEEC derived cell line. Two IL11 regulated proteins with known roles in cell adhesion, annexin A2 (ANXA2 and flotillin-1 (FLOT1, were validated by Western blot and immunocytochemistry in hEEC lines (ECC-1 and an additional cell line, Ishikawa and primary hEEC. Flotilin-1 was further validated by immunohistochemistry in human endometrium throughout the menstrual cycle (n = 6-8/cycle. Results 2D-DIGE analysis identified 4 spots that were significantly different between control and IL11 treated group. Of these 4 spots, there were 20 proteins that were identified with LCMS/MS. Two proteins; ANXA2 and FLOT1 were chosen for further analyses and have found to be significantly up-regulated following IL11 treatment. Western blot analysis showed a 2-fold and a 2.5-fold increase of ANXA2 in hEEC membrane fraction of ECC-1 and Ishikawa cells respectively. Similarly, a 1.8-fold and a 2.3/2.4-fold increase was also observed for FLOT1 in hEEC membrane fraction of ECC-1 and Ishikawa cells respectively. In vitro, IL11 induced stronger ANXA2 expression on cell surface of primary h

  19. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability.

    Science.gov (United States)

    Boretto, Matteo; Cox, Benoit; Noben, Manuel; Hendriks, Nikolai; Fassbender, Amelie; Roose, Heleen; Amant, Frédéric; Timmerman, Dirk; Tomassetti, Carla; Vanhie, Arne; Meuleman, Christel; Ferrante, Marc; Vankelecom, Hugo

    2017-05-15

    The endometrium, which is of crucial importance for reproduction, undergoes dynamic cyclic tissue remodeling. Knowledge of its molecular and cellular regulation is poor, primarily owing to a lack of study models. Here, we have established a novel and promising organoid model from both mouse and human endometrium. Dissociated endometrial tissue, embedded in Matrigel under WNT-activating conditions, swiftly formed organoid structures that showed long-term expansion capacity, and reproduced the molecular and histological phenotype of the tissue's epithelium. The supplemented WNT level determined the type of mouse endometrial organoids obtained: high WNT yielded cystic organoids displaying a more differentiated phenotype than the dense organoids obtained in low WNT. The organoids phenocopied physiological responses of endometrial epithelium to hormones, including increased cell proliferation under estrogen and maturation upon progesterone. Moreover, the human endometrial organoids replicated the menstrual cycle under hormonal treatment at both the morpho-histological and molecular levels. Together, we established an organoid culture system for endometrium, reproducing tissue epithelium physiology and allowing long-term expansion. This novel model provides a powerful tool for studying mechanisms underlying the biology as well as the pathology of this key reproductive organ. © 2017. Published by The Company of Biologists Ltd.

  20. Obesity and the Endometrium: Adipocyte-Secreted Proinflammatory TNFα Cytokine Enhances the Proliferation of Human Endometrial Glandular Cells

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    Sangeeta Nair

    2013-01-01

    Full Text Available Obesity, a state of chronic inflammation, is associated with poor fertility and low implantation rates and is a well-documented risk factor for endometrial cancer. Adipokines, such as tumor necrosis factor alpha, play an important role in initiation of endometrial cancer. The aim of this study is to evaluate in vitro effects of human adipocyte cells (SW872 on growth of endometrial glandular epithelial cells (EGE. Methods. We measured cell proliferation and expression of cell-growth proteins—proliferating cell nuclear antigen, cyclin D1, cyclin-dependent kinase-1, and apoptotic markers (BCL-2 and BAK in human EGE cells cocultured with SW872 cells. EGE cells were also evaluated in SW872-conditioned media neutralized with anti-TNFα antibody. Results. A significant increase in EGE cell proliferation was observed in both SW872-conditioned media and in coculture (P<0.05. We observed an upregulation of proliferation markers PCNA, cyclin D1, CDK-1, and BCL-2 and decrease in BAK (P<0.05. Neutralization of SW872-conditioned media using anti-TNFα antibodies reversed EGE cell proliferation as indicated by BCL-2 expression. Conclusions. Adipocytes have potent proliferative paracrine effect on EGE cells which may be, in part, mediated via TNFα. Further understanding of the role of obesity in endometrial carcinogenesis should lead to better preventative and therapeutic strategies.

  1. Endometrial gene expression in early pregnancy: lessons from human ectopic pregnancy.

    Science.gov (United States)

    Savaris, Ricardo F; Hamilton, Amy E; Lessey, Bruce A; Giudice, Linda C

    2008-10-01

    Human endometrium undergoes modifications in preparation for embryonic implantation. This study investigated in vivo the endocrine effects of pregnancy on the endometrium, using the model of ectopic pregnancy. Endometrial biopsies from 9 subjects with ectopic pregnancy (Preg) were compared with 8 and 6 samples of mid and late secretory endometrium, respectively. After hybridizing with Affymetrix HGU133 Plus 2 chips, data were analyzed using GeneSpring GX and Ingenuity Pathways Analysis. From 54,675 genes, 3021 genes were significantly differentiated when mid-secretory endometrium was compared with the Preg (Volcano plot; P or=2-fold change).The complement and coagulation cascade, phospholid degradation, glycosphingolipid biosynthesis (globoseries), retinol metabolism, antigen presentation pathway, glycosphingolipid biosynthesis, and O-glycan biosynthesis were main significant canonical pathways found in Preg samples. Validation was done with reverse transcriptase polymerase chain reaction. In conclusion, the ectopic embryo has a significant impact, by an endocrine mechanism, on endometrium, when compared with the window of implantation.

  2. Endometrial cancer

    Science.gov (United States)

    ... to your hormones increase your risk of endometrial cancer: Estrogen replacement therapy without the use of progesterone History of endometrial polyps Infrequent periods Never being pregnant Obesity Polycystic ovary syndrome (PCOS) Starting menstruation at an ...

  3. Endometrial polyps

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007636.htm Endometrial polyps To use the sharing features on this ... or many polyps. Causes The exact cause of endometrial polyps in women is not known. They tend ...

  4. Prognostic value of human epididymis protein 4 in endometrial cancer and its utility for surgical staging.

    Science.gov (United States)

    Minar, Lubos; Klabenesova, Ivanka; Jandakova, Eva; Zlamal, Filip; Bienertova-Vasku, Julie

    2015-10-01

    An optimal surgical staging in the group of patients with the high-risk type of endometrial cancer is often limited by age and serious internal comorbidities. Therefore, in this study we focused on human epididymis protein 4 and its contribution to the preoperative differentiation of prognostically distinct groups of patients and to individualized surgical treatment as compared with cancer antigen (CA) 125 and imaging methods. The study included 115 patients with endometrioid adenocarcinoma diagnosed through endometrial biopsy. Before the final operation, blood sampling was performed for the determination of human epididymis protein 4 (HE4) and CA125 levels. Serum levels of both biomarkers were analyzed in relation to individual prognostic factors (stage of disease, depth of myometrial invasion, tumor grade, risk type of disease). In the case of HE4, we demonstrated a statistically significant difference (P < 0.001) between patients with low and high risk of the disease. In our model, achieving the maximum sum of sensitivity and specificity, HE4 shows a sensitivity of 72.4% and a specificity of 75.4% for the cut-off 76.5 pmol/L and is a better predictor in distinguishing the high-risk patients than CA125 (area under the curve 0.77 for HE vs 0.71 for CA125). HE4 is a marker that could complement the findings of imaging techniques and that may be useful in decision-making on how to individualize surgical staging. The possibility of its introduction as an independent marker in routine practice remains, at the moment however, limited. The optimal cut-off for HE4 has not been established yet and further studies are needed. © 2015 Japan Society of Obstetrics and Gynecology.

  5. Whole Genome Pathway Analysis Identifies an Association of Cadmium Response Gene Loss with Copy Number Variation in Mutant p53 Bearing Uterine Endometrial Carcinomas.

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    Joe Ryan Delaney

    Full Text Available Massive chromosomal aberrations are a signature of advanced cancer, although the factors promoting the pervasive incidence of these copy number alterations (CNAs are poorly understood. Gatekeeper mutations, such as p53, contribute to aneuploidy, yet p53 mutant tumors do not always display CNAs. Uterine Corpus Endometrial Carcinoma (UCEC offers a unique system to begin to evaluate why some cancers acquire high CNAs while others evolve another route to oncogenesis, since about half of p53 mutant UCEC tumors have a relatively flat CNA landscape and half have 20-90% of their genome altered in copy number.We extracted copy number information from 68 UCEC genomes mutant in p53 by the GISTIC2 algorithm. GO term pathway analysis, via GOrilla, was used to identify suppressed pathways. Genes within these pathways were mapped for focal or wide distribution. Deletion hotspots were evaluated for temporal incidence.Multiple pathways contributed to the development of pervasive CNAs, including developmental, metabolic, immunological, cell adhesion and cadmium response pathways. Surprisingly, cadmium response pathway genes are predicted as the earliest loss events within these tumors: in particular, the metallothionein genes involved in heavy metal sequestration. Loss of cadmium response genes were associated with copy number changes and poorer prognosis, contrasting with 'copy number flat' tumors which instead exhibited substantive mutation.Metallothioneins are lost early in the development of high CNA endometrial cancer, providing a potential mechanism and biological rationale for increased incidence of endometrial cancer with cadmium exposure. Developmental and metabolic pathways are altered later in tumor progression.

  6. Functional expression of transient receptor potential channels in human endometrial stromal cells during the luteal phase of the menstrual cycle.

    Science.gov (United States)

    De Clercq, Katrien; Held, Katharina; Van Bree, Rieta; Meuleman, Christel; Peeraer, Karen; Tomassetti, Carla; Voets, Thomas; D'Hooghe, Thomas; Vriens, Joris

    2015-06-01

    Are members of the transient receptor potential (TRP) channel superfamily functionally expressed in the human endometrial stroma? The Ca(2+)-permeable ion channels TRPV2, TRPV4, TRPC6 and TRPM7 are functionally expressed in primary endometrial stromal cells. Intercellular communication between epithelial and stromal endometrial cells is required to initiate decidualization, a prerequisite for successful implantation. TRP channels are possible candidates as signal transducers involved in cell-cell communication, but no fingerprint is available of the functional distribution of TRP channels in the human endometrium during the luteal phase of the menstrual cycle. Endometrial biopsy samples (previously frozen) from patients of reproductive age with regular menstrual cycles, who were undergoing diagnostic laparoscopic surgery for pain and/or infertility, were analysed. Samples were obtained from the menstrual (Days 1-5, n = 3), follicular (Days 6-14, n = 6), early luteal (Days 15-20, n = 5) and late luteal (Days 21-28, n = 5) phases. In addition, a total of 13 patient samples taken during the luteal phase were used to set up primary cell cultures for further experiments. Quantitative real-time PCR (qRT-PCR), immunocytochemistry, Fura2-based Ca(2+)-microfluorimetry and whole-cell patch clamp experiments were performed to study the functional expression pattern of TRP channels. Specific pharmacological agents, such as Δ(9)-tetrahydrocannabinol, GSK1016790A and 1-oleoyl-2-acetyl-glycerol, were used to functionally assess the expression of TRPV2, TRPV4 and TRPC6, respectively. Expression of TRPV2, TRPV4, TRPC1, TRPC4, TRPC6, TRPM4 and TRPM7 was detected at the mRNA level in endometrial biopsies (n = 19) and in primary endometrial stromal cell cultures obtained from patients during the luteal phase (n = 5) of the menstrual cycle. Messenger RNA levels of TRPV2, TRPC4 and TRPC6 were significantly increased (P endometrial stromal cells. Ca(2+)-microfluorimetry revealed

  7. MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

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    Hong-Xia Chen

    2017-02-01

    Full Text Available Objective: The purpose of this study is to explore the effects of microRNA-29b (miR-29b regulating MAPK/ERK and PI3K/Akt signaling pathways on angiogenesis in endometrial carcinoma (EC by targeting VEGFA. Methods: Between February 2013 and April 2015, 126 EC patients admitted to the Second Affiliated Hospital of Nanchang University were randomly selected, with 126 EC tissues and the corresponding adjacent normal tissues collected after surgery. The human EC cell lines RL-95-2 and HEC-1-B and human endometrial cells were assigned to the normal group (human endometrial cells, the blank group (untransfected RL-95-2 or HEC-1-B cells, the pMIR-control group (RL-95-2 or HEC-1-B cells transfected with an empty vector, the pMIR-miR-29b group (RL-95-2 or HEC-1-B cells transfected with the miR-29b plasmid, LNA-control group (RL-95-2 or HEC-1-B cells transfected with an oligonucleotide inhibitors control, the LNA-miR-29b inhibitors group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors, the LNA-miR-29b inhibitors + PD98059 group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors and PD98059, an inhibitor of the MAPK/ERK signaling pathway and the LNA-miR-29b inhibitors + wortmannin group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors and wortmannin, an inhibitor of the PI3K/Akt signaling pathway. qRT-PCR and Western blotting were conducted to detect the miR-29b expression and the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2. Immunohistochemistry (IHC was performed to determine the microvessel density (MVD expression in the EC tissues, adjacent normal tissues and nude-mice. Results: Compared with the adjacent normal tissues, miR-29b expression was down-regulated, the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated, and MVD expression was increased in the EC tissues. Compared with the normal group, miR-29b expression was down

  8. Retrospective study of the prognostic significance of neutrophil-to-lymphocyte ratio for postsurgical outcomes of patients with endometrial carcinoma.

    Science.gov (United States)

    Ding, Ling; Ding, Yi; Mao, Xiao-Hua; Zhao, Jian-Fei; Zhou, Huai-Jun

    2017-09-01

    To evaluate the significance of postoperative inflammatory system response markers in predicting the prognosis of patients with endometrial cancer undergoing surgery. The present retrospective study included patients who underwent surgical treatment for pathology-confirmed endometrial cancer between January 1, 2007, and June 30, 2013, at the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. Potential prognostic factors were investigated by Cox proportional hazards analysis and survival rates were compared using Kaplan-Meier analyses. There were 185 patients with surgically treated endometrial cancer included. Multivariate analyses demonstrated that a preoperative neutrophil-to-lymphocyte ratio (NLR) above 1.81 (P=0.010) and a postoperative NLR above 7.54 (P=0.008) were both independently associated with lower disease free survival. Elevated preoperative and postoperative NLRs were associated with higher tumor stage (P=0.021 and P=0.009, respectively), and only elevated preoperative NLR was associated with lymph node involvement (P=0.023). Preoperative and postoperative NLRs were independently associated with inflammatory system response markers and could be combined to evaluate the prognosis of patients with endometrial cancer following surgery. © 2017 International Federation of Gynecology and Obstetrics.

  9. Identification of optimal reference genes for gene expression normalization in a wide cohort of endometrioid endometrial carcinoma tissues.

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    Chiara Romani

    Full Text Available Accurate normalization is a primary component of a reliable gene expression analysis based on qRT-PCR technique. While the use of one or more reference genes as internal controls is commonly accepted as the most appropriate normalization strategy, many qPCR-based published studies still contain data poorly normalized and reference genes arbitrarily chosen irrespective of the particular tissue and the specific experimental design. To date, no validated reference genes have been identified for endometrial cancer tissues. In this study, 10 normalization genes (GAPDH, B2M, ACTB, POLR2A, UBC, PPIA, HPRT1, GUSB, TBP, H3F3A belonging to different functional and abundance classes in various tissues and used in different studies, were analyzed to determine their applicability. In total, 100 endometrioid endometrial cancer samples, which were carefully balanced according to their tumor grade, and 29 normal endometrial tissues were examined using SYBR Green Real-Time RT-PCR. The expression stability of candidate reference genes was determined and compared by means of geNorm and NormFinder softwares. Both algorithms were in agreement in identifying GAPDH, H3F3A, PPIA, and HPRT1 as the most stably expressed genes, only differing in their ranking order. Analysis performed on the expression levels of all candidate genes confirm HPRT1 and PPIA as the most stably expressed in the study groups regardless of sample type, to be used alone or better in combination. As the stable expression of HPRT1 and PPIA between normal and tumor endometrial samples fulfill the basic requirement of a reference gene to be used for normalization purposes, HPRT1 expression showed significant differences between samples from low-grade and high-grade tumors. In conclusion, our results recommend the use of PPIA as a single reference gene to be considered for improved reliability of normalization in gene expression studies involving endometrial tumor samples at different tumor degrees.

  10. SU-F-T-29: The Important of Each Fraction Image-Guided Planning for Postoperative HDR-Brachytherapy in Endometrial Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Piriyasang, D; Pattaranutaporn, P; Manokhoon, K [Ramathibodi Hospital, Rachatewi, Bangkok (Thailand)

    2016-06-15

    Purpose: Cylindrical applicators are often used for postoperative HDRbrachytherapy in endometrial carcinoma. It has been considered that dosimetric variation between fractions for this treatment is minimal and might not be necessary to perform treatment planning for every fractions. At our institute, it is traditional to perform treatment planning with CT simulation on the first fraction and uses this plan for the rest of treatment. This study was aim to evaluate the errors of critical structure doses between the fractions when simulation and planning were done for first fraction only. Methods: Treatment plans of 10 endometrial carcinoma patients who received postoperative HDR-brachytherapy and underwent CT-simulation for every HDR-fractions at our department were retrospectively reviewed. All of these patients were treated with cylindrical applicator and prescribed dose 15Gy in 3 fractions to 0.5cm from vaginal surface. The treatment plan from the first fraction was used to simulate in second and third CT-simulation. Radiation dose for critical structures in term of Dose-to-2cc (D2cc) were evaluated and compared between planning CT. Results: The D2cc for bladder and rectum were evaluated. For bladder, the mean error of D2cc estimation for second and third fractions was 7.6% (0.1–20.1%, SD=5.7). And the mean error for D2cc of rectum was 8.5% (0.1–29.4%, SD=8.5). Conclusion: The critical structure doses could be significant difference between fractions which may affects treatment outcomes or toxicities. From our data, image-guided brachytherapy at least with CT-Simulation should be done for every treatment fractions.

  11. External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation Alone as Postoperative Therapy in Medium-Risk Endometrial Carcinoma-A Prospective Randomized Study

    Energy Technology Data Exchange (ETDEWEB)

    Sorbe, Bengt, E-mail: bengt.sorbe@orebroll.se [Department of Gynecological Oncology, Oerebro University Hospital, Oerebro (Sweden); Horvath, Gyoergy; Andersson, Hakan [Department of Gynecological Oncology, Sahlgrenska University Hospital, Gothenburg (Sweden); Boman, Karin [Department of Gynecological Oncology, Umea University Hospital, Umea (Sweden); Lundgren, Caroline [Department of Gynecological Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm (Sweden); Pettersson, Birgitta [Medical Products Agency, Uppsala (Sweden)

    2012-03-01

    Purpose: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. Methods and Materials: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. Results: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. Conclusions: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.

  12. Hyaluronan synthases (HAS1-3 and hyaluronidases (HYAL1-2 in the accumulation of hyaluronan in endometrioid endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Kosma Veli-Matti

    2010-09-01

    Full Text Available Abstract Background Hyaluronan accumulation correlates with the degree of malignancy in many solid tumor types, including malignant endometrial carcinomas. To elucidate the mechanism of hyaluronan accumulation, we examined the expression levels of the hyaluronan synthases (HAS1, HAS2 and HAS3 and hyaluronidases (HYAL1 and HYAL2, and correlated them with hyaluronan content and HAS1-3 immunoreactivity. Methods A total of 35 endometrial tissue biopsies from 35 patients, including proliferative and secretory endometrium (n = 10, post-menopausal proliferative endometrium (n = 5, complex atypical hyperplasia (n = 4, grade 1 (n = 8 and grade 2 + 3 (n = 8 endometrioid adenocarcinomas were divided for gene expression by real-time RT-PCR, and paraffin embedded blocks for hyaluronan and HAS1-3 cytochemistry. Results The mRNA levels of HAS1-3 were not consistently changed, while the immunoreactivity of all HAS proteins was increased in the cancer epithelium. Interestingly, HAS3 mRNA, but not HAS3 immunoreactivity, was increased in post-menopausal endometrium compared to normal endometrium (p = 0.003. The median of HYAL1 mRNA was 10-fold and 15-fold lower in both grade 1 and grade 2+3 endometrioid endometrial cancers, as compared to normal endometrium (p = 0.004-0.006, and post-menopausal endometrium (p = 0.002, respectively. HYAL2 mRNA was also reduced in cancer (p = 0.02 and correlated with HYAL1 (r = 0.8, p = 0.0001. There was an inverse correlation between HYAL1 mRNA and the epithelial hyaluronan staining intensity (r = -0.6; P = 0.001. Conclusion The results indicated that HYAL1 and HYAL2 were coexpressed and significantly downregulated in endometrioid endometrial cancer and correlated with the accumulation of hyaluronan. While immunoreactivity for HASs increased in the cancer cells, tumor mRNA levels for HASs were not changed, suggesting that reduced turnover of HAS protein may also have contributed to the accumulation of hyaluronan.

  13. Loss of the cell polarity determinant human Discs-large is a novel molecular marker of nodal involvement and poor prognosis in endometrial cancer.

    Science.gov (United States)

    Sugihara, Takeru; Nakagawa, Shunsuke; Sasajima, Yuko; Ichinose, Takayuki; Hiraike, Haruko; Kondo, Fukuo; Uozaki, Hiroshi; Fukusato, Toshio; Ayabe, Takuya

    2016-04-26

    Recent Drosophila studies showed that Discs-large (Dlg) is critical for regulation of cell polarity and tissue architecture. We investigated the possibility that loss of the human homologue of Drosophila Dlg (DLG1) is involved in endometrial carcinogenesis. We analysed DLG1 expression in 160 endometrial cancers by immunohistochemical staining. Its expression was confirmed by quantitative real-time PCR (RT-PCR). We investigated the roles of DLG1 in growth and invasion by knockdown experiment in endometrial cancer cell lines. Human DLG1 localises at cellular membrane in normal endometrial tissues. Loss of DLG1 was observed in 37 cases (23.1%). Loss of DLG1 was observed in patients with advanced stage and high-grade histology. It was also observed in patients with nodal metastasis, deep myometrial invasion, and negative oestrogen and progesterone receptors. Patients with loss of DLG1 showed poorer overall survival (P=0.0019). Immunohistochemistry data correlated with RT-PCR data. Knockdown of Dlg1 in endometrial cancer cells resulted in accelerated tumour migration and invasion in vitro. Tissue polarity disturbance because of loss of DLG1 was shown to confer more aggressive characteristics to endometrial cancer cells. Our study revealed that DLG1 expression is a novel molecular biomarker of nodal metastasis, high-grade histology, and poor prognosis in endometrial cancer.

  14. Effect of Taoren Quyu Decoction on human endometrial cells and its anti-endometriosis activity in rats.

    Science.gov (United States)

    Liu, Hai-Zhi; Han, Xiao-Xue; Liu, Jia; Zhu, Feng-Cheng; Li, Rui-Man

    2017-07-01

    To study the effect of Taoren Quyu Decoction (TQD) on endometrial cells in patients with endometriosis (EMs) and EMs in rats. A total of 60 female Wistar rats were randomly divided into 4 groups, namely, normal group, model group, positive group and TQD group, each group having 15 rats. Except the normal group, EMs model was established in the other three groups by transplanting the rat autologous endometrium. After 4 weeks of intragastric administration, blood, eutopic and ectopic endometrial tissues of rats in each group were collected to detect the serum levels of estrogen (E2), cancer antigen 125 (CA125), endometrial antibody (EMAb), and expressions of microvessel density (MVD), vascular endothelial growth factor (VEGF) and angiopoietin (Ang-2). The volume of endometriosis cyst was determined simultaneously. For the in vitro culture of human endometrial cells, 4 groups, namely, normal group, model group, positive group and TQD group were used. The positive group and TQD group were treated with danazol and TQD respectively. Then 24 h after the treatment, the expressions of survivin and tumor suppressor gene (p53) of each group were detected. The volumes of the endometriosis cysts in the positive group and the TQD group were significantly reduced compared with the model group (P  0.05). TQD has a significant anti-EMs effect, and its mechanism of action may be related to anti-angiogenesis and promoting apoptosis of ectopic endometrial cell. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  15. Clinicopathological significance of increased ZIC1 expression in human endometrial cancer.

    Science.gov (United States)

    Gu, Xing; Liu, Qin; Yang, Ning; Shen, Jian-fang; Zhang, Xue-gang; Cao, Fang; Ding, Hou-zhong

    2015-12-01

    Zinc finger of the cerebellum (ZIC1), one of ZIC family genes, has been shown to play important roles in many cancers such as gastric cancer and breast cancer. However, there is little known about the expression and significance of ZIC1 in endometrial cancer. The aim of this study was to determine the expression pattern and clinicopathological significance of ZIC1 in endometrial cancer. The mRNA and protein expression of ZIC1 in endometrial cancer tissues was detected using the reverse-transcription polymerase chain reaction and Western blotting, respectively. Immunostaining of ZIC1 in 99 endometrial cancer samples was examined and its associations with clinicopathological parameters were analyzed. Hec-1-B cells were transfected with ZIC1-shRNA or sc-shRNA, and cell proliferation was assayed. Hec-1-B cells stably transfected with ZIC1-shRNA or sc-shRNA were subcutaneously inoculated into nude mice, and the tumor weight was measured. A significantly increased expression of ZIC1 mRNA and protein was observed in endometrial cancer tissues compared to that in normal endometrial tissues (Pendometrial cancer samples (90/99) while light and moderate immunostaining of ZIC1 was only detected in 17 of 30 (56.7%) normal tissues. Moreover, up-regulation of ZIC1 was significantly correlated with age, disease stage, TNM stage and FIGO stage (Pendometrial cancer tissue but not in normal tissue, and positively correlated to the malignant biological behavior of endometrial carcinogenesis.

  16. Endometrial Cancer Screening

    Science.gov (United States)

    ... Treatment Endometrial Cancer Prevention Endometrial Cancer Screening Research Endometrial Cancer Screening (PDQ®)–Patient Version What is screening? ... These are called diagnostic tests . General Information About Endometrial Cancer Key Points Endometrial cancer is a disease ...

  17. Do GnRH analogues directly affect human endometrial epithelial cell gene expression?

    KAUST Repository

    Zhang, Xiaomei

    2010-03-04

    We examined whether Gonadotrophin-releasing hormone (GnRH) analogues [leuprolide acetate (LA) and ganirelix acetate (GA)] modulate gene expression in Ishikawa cells used as surrogate for human endometrial epithelial cells in vitro. The specific aims were: (i) to study the modulatory effect of GnRH analogues by RT-PCR [in the absence and presence of E2 and P4, and cyclic adenosine monophos-phate (cAMP)] on mRNA expression of genes modulated during the window of implantation in GnRH analogues/rFSH-treated assisted reproductive technology cycles including OPTINEURIN (OPTN), CHROMATIN MODIFYING PROTEIN (CHMP1A), PROSAPOSIN (PSAP), IGFBP-5 and SORTING NEXIN 7 (SNX7), and (ii) to analyze the 5\\'-flanking regions of such genes for the presence of putative steroid-response elements [estrogen-response elements (EREs) and P4-response element (PREs)]. Ishikawa cells were cytokeratin+/vimentin2 and expressed ERa,ERb, PR and GnRH-R proteins. At 6 and 24 h, neither LA nor GA alone had an effect on gene expression. GnRH analogues alone or following E2 and/or P4 co-incubation for 24 h also had no effect on gene expression, but P4 significantly increased expression of CHMP1A.E2 + P4 treatment for 4 days, alone or followed by GA, had no effect, but E2 + P4 treatment followed by LA significantly decreased IGFBP-5 expression. The addition of 8-Br cAMP did not modify gene expression, with the exception of IGFBP-5 that was significantly increased. The GnRH analogues did not modify intracellular cAMP levels. We identified conserved EREs for OPN, CHMP1A, SNX7 and PSAP and PREs for SNX7. We conclude that GnRH analogues appear not to have major direct effects on gene expression of human endo-metrial epithelial cells in vitro. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

  18. Derivation of Insulin Producing Cells From Human Endometrial Stromal Stem Cells and Use in the Treatment of Murine Diabetes

    OpenAIRE

    Santamaria, Xavier; Massasa, Efi E; Feng, Yuzhe; Wolff, Erin; Taylor, Hugh S

    2011-01-01

    Pancreatic islet cell transplantation is an effective approach to treat type 1 diabetes, however the shortage of cadaveric donors and limitations due to rejection require alternative solutions. Multipotent cells derived from the uterine endometrium have the ability to differentiate into mesodermal and ectodermal cellular lineages, suggesting the existence of mesenchymal stem cells in this tissue. We differentiated human endometrial stromal stem cells (ESSC) into insulin secreting cells using ...

  19. LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a.

    Science.gov (United States)

    Alowayed, Nour; Salker, Madhuri S; Zeng, Ni; Singh, Yogesh; Lang, Florian

    2016-01-01

    LEFTY2, a suppressor of cell proliferation, tumor growth, regulator of stemness and embryonic differentiation, is a negative regulator of cancer cell reprogramming. Malignant transformation may lead to migration requiring loss of adhesion and gain of migratory activity. Signaling involved in the orchestration of migration, proliferation and spreading of cells include focal adhesion kinase (FAK) and adhesion molecule E-cadherin. The present study explored whether LEFTY2 influences the proliferation marker MKi67, FAK activity, E-cadherin abundance and migration of Ishikawa human endometrial carcinoma cells. Moreover, the study explored the involvement of microRNA-200a (miR-200a), which is known to regulate cellular adhesion by targeting E-Cadherin. FAK activity was estimated from FAK phosphorylation quantified by Western blotting, migration utilizing a wound healing assay, miR-200a and MKi67 expression levels utilizing qRT-PCR, cell proliferation and apoptosis using BrdU and Annexin V staining, respectively, and E-Cadherin (E-Cad) abundance, using confocal microscopy. LEFTY2 (25 ng/ml, 48 hours) treatment was followed by decrease of MKi67 expression, FAK activity and migration. LEFTY2 upregulated miRNA-200a and E-Cad protein level in Ishikawa cells. The effect of LEFTY2 on migration was mimicked by FAK inhibitor PF 573228 (50 µM). Addition of LEFTY2 in the presence of PF-573228 did not result in a further significant decline of migration. In conclusion, LEFTY2 down-regulates MKi67 expression and FAK activity, up-regulates miR-200a and E-cadherin, and is thus a powerful negative regulator of endometrial cell proliferation and migration. © 2016 The Author(s) Published by S. Karger AG, Basel.

  20. Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK–NF-κB signaling pathway

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    Che, Qi; Liu, Bin-Ya; Wang, Fang-Yuan; He, Yin-Yan; Lu, Wen; Liao, Yun [Department of Obstetrics and Gynecology, Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai (China); Gu, Wei, E-mail: krisgu70@163.com [Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai (China); Wan, Xiao-Ping, E-mail: wanxp@sjtu.edu.cn [Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital Affiliated to Tong Ji University, Shanghai (China)

    2014-03-28

    Highlights: • IL-6 could promote endometrial cancer cells proliferation. • IL-6 promotes its own production through an autocrine feedback loop. • ERK and NF-κB pathway inhibitors inhibit IL-6 production and tumor growth. • IL-6 secretion relies on the activation of ERK–NF-κB pathway axis. • An orthotopic nude endometrial carcinoma model confirms the effect of IL-6. - Abstract: Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK–NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.

  1. Human malignant melanoma-derived progestagen-associated endometrial protein immunosuppresses T lymphocytes in vitro.

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    Suping Ren

    Full Text Available Progestagen-associated endometrial protein (PAEP is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow's 2.5mm or greater and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment.

  2. Thrombin impairs human endometrial endothelial angiogenesis; implications for progestin-only contraceptive-induced abnormal uterine bleeding.

    Science.gov (United States)

    Shapiro, John P; Guzeloglu-Kayisli, Ozlem; Kayisli, Umit A; Semerci, Nihan; Huang, S Joseph; Arlier, Sefa; Larsen, Kellie; Fadda, Paolo; Schatz, Frederick; Lockwood, Charles J

    2017-06-01

    Progestin-only contraceptives induce abnormal uterine bleeding, accompanied by prothrombin leakage from dilated endometrial microvessels and increased thrombin generation by human endometrial stromal cell (HESC)-expressed tissue factor. Initial studies of the thrombin-treated HESC secretome identified elevated levels of cleaved chondroitin sulfate proteoglycan 4 (CSPG4), impairing pericyte-endothelial interactions. Thus, we investigated direct and CSPG4-mediated effects of thrombin in eliciting abnormal uterine bleeding by disrupting endometrial angiogenesis. Liquid chromatography/tandem mass spectrometry, enzyme-linked immunosorbent assay (ELISA) and quantitative real-time-polymerase chain reaction (PCR) evaluated conditioned medium supernatant and cell lysates from control versus thrombin-treated HESCs. Pre- and post-Depo medroxyprogesterone acetate (DMPA)-administered endometria were immunostained for CSPG4. Proliferation, apoptosis and tube formation were assessed in human endometrial endothelial cells (HEECs) incubated with recombinant human (rh)-CSPG4 or thrombin or both. Thrombin induced CSPG4 protein expression in cultured HESCs as detected by mass spectrometry and ELISA (p<.02, n=3). Compared to pre-DMPA endometria (n=5), stromal cells in post-DMPA endometria (n=5) displayed stronger CSPG4 immunostaining. In HEEC cultures (n=3), total tube-formed mesh area was significantly higher in rh-CSPG4 versus control (p<.05). However, thrombin disrupted HEEC tube formation by a concentration- and time-dependent reduction of angiogenic parameters (p<.05), whereas CSPG4 co-treatment did not reverse these thrombin-mediated effects. These results suggest that disruption of HEEC tube formation by thrombin induces aberrant angiogenesis and abnormal uterine bleeding in DMPA users. Mass spectrometry analysis identified several HESC-secreted proteins regulated by thrombin. Therapeutic agents blocking angiogenic effects of thrombin in HESCs can prevent or minimize progestin

  3. Regulatory Action of Calcium Ion on Cyclic AMP-Enhanced Expression of Implantation-Related Factors in Human Endometrial Cells.

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    Kazuya Kusama

    Full Text Available Decidualization of human endometrial stroma and gland development is mediated through cyclic AMP (cAMP, but the role of intracellular calcium ion (Ca2+ on cAMP mediated-signaling in human endometrial stroma and glandular epithelia has not been well-characterized. The present study was designed to investigate the role of intracellular Ca2+ on cAMP mediated-decidualization and gland maturation events, which can be identified by the up-regulation of prolactin and IGF-binding protein (IGFBP1 in human endometrial stromal cells (ESCs, and cyclooxygenase 2 (COX2 and prostaglandin E2 (PGE2 and glandular epithelial EM-1 cells. Increases in decidual prolactin and IGFBP-1 transcript levels, induced by cAMP-elevating agents forskolin or dibutyryl cyclic AMP, were inhibited by Ca2+ influx into ESCs with Ca2+ ionophores (alamethicin, ionomycin in a dose-dependent manner. Conversely, inhibitors of Ca2+ influx through L-type voltage-dependent Ca2+ channel (VDCC, nifedipine and verapamil, enhanced the decidual gene expression. Furthermore, dantrolene, an inhibitor of Ca2+ release from the intracellular Ca2+ store, up-regulated prolactin and IGFBP-1 expression. Ca2+ ionophores decreased intracellular cAMP concentrations, whereas nifedipine, verapamil or dantrolene increased cAMP concentrations in ESCs. In glandular epithelial cells, similar responses in COX2 expression and PGE2 production were found when intracellular cAMP levels were up-regulated by decreases in Ca2+ concentrations. Thus, a marked decrease in cytosolic Ca2+ levels caused the elevation of cAMP concentrations, resulting in enhanced expression of implantation-related factors including decidual markers. These findings suggest that fluctuation in cytosolic Ca2+ concentrations alters intracellular cAMP levels, which then regulate differentiation of endometrial stromal and glandular epithelial cells.

  4. Enhanced cyclooxygenase-2 expression levels and metalloproteinase 2 and 9 activation by Hexachlorobenzene in human endometrial stromal cells.

    Science.gov (United States)

    Chiappini, Florencia; Bastón, Juan Ignacio; Vaccarezza, Agustina; Singla, José Javier; Pontillo, Carolina; Miret, Noelia; Farina, Mariana; Meresman, Gabriela; Randi, Andrea

    2016-06-01

    Hexachlorobenzene (HCB) is an organochlorine pesticide that induces toxic reproductive effects in laboratory animals. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is characterized by the presence of functional endometrial tissues outside the uterine cavity. Experimental studies indicate that exposure to organochlorines can interfere with both hormonal regulation and immune function to promote endometriosis. Altered expression of metalloproteinases (MMPs) in patients with endometriosis, suggests that MMPs may play a critical role. In the endometriotic lesions, prostaglandin E2 (PGE2) produced by cyclooxygenase-2 (COX-2), binds to its EP4 receptor (EP4), and via c-Src kinase induces MMPs activation, promoting endometriosis. We examined the HCB action on MMP-2 and MMP-9 activities and expression, COX-2 levels, PGE2 signaling, and the AhR involvement in HCB-induced effects. We have used different in vitro models: (1) human endometrial stromal cell line T-HESC, (2) primary cultures of Human Uterine Fibroblast (HUF), and (3) primary cultures of endometrial stromal cells from eutopic endometrium of control (CESC) and subjects with endometriosis (EESC). Our results show that HCB enhances MMP-2 and MMP-9 activities in T-HESC, HUF and ESC cells. The MMP-9 levels were elevated in all models, while the MMP-2 expression only increased in ESC cells. HCB enhanced COX-2 and EP4 expression, PGE2 secretion and the c-Src kinase activation in T-HESC. Besides, we observed that AhR is implicated in these HCB-induced effects. In conclusion, our results show that HCB exposure could contribute to endometriosis development, affecting inflammation and invasion parameters of human endometrial cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Metformin for endometrial hyperplasia.

    Science.gov (United States)

    Clement, Naomi S; Oliver, Thomas Rw; Shiwani, Hunain; Sanner, Juliane Rf; Mulvaney, Caroline A; Atiomo, William

    2017-10-27

    Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar, OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015. We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no

  6. An inhibitor of K+ channels modulates human endometrial tumor-initiating cells

    Directory of Open Access Journals (Sweden)

    Leslie Kimberly K

    2011-08-01

    Full Text Available Abstract Background Many potassium ion (K+ channels function as oncogenes to sustain growth of solid tumors, but their role in cancer progression is not well understood. Emerging evidence suggests that the early progenitor cancer cell subpopulation, termed tumor initiating cells (TIC, are critical to cancer progression. Results A non-selective antagonist of multiple types of K+ channels, tetraethylammonium (TEA, was found to suppress colony formation in endometrial cancer cells via inhibition of putative TIC. The data also indicated that withdrawal of TEA results in a significant enhancement of tumorigenesis. When the TIC-enriched subpopulation was isolated from the endometrial cancer cells, TEA was also found to inhibit growth in vitro. Conclusions These studies suggest that the activity of potassium channels significantly contributes to the progression of endometrial tumors, and the antagonists of potassium channels are candidate anti-cancer drugs to specifically target tumor initiating cells in endometrial cancer therapy.

  7. Adiponectin Effect on The Viability of Human Endometrial Stromal Cells and mRNA Expression of Adiponectin Receptors

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    Somayeh Bohlouli

    2013-01-01

    Full Text Available Background: Adiponectin is one of the most important adipokines secreted from fattytissue that has a direct inhibitory effect on the development of cancer cells. Adiponectinplays an important role in human reproduction system and fertility of women. Adiponectinconcentration decreases in women with endometriosis and endometrial cancer.The aim of the present study was to investigate the effect of adiponectin on humanendometrial stromal cell (HESC viability as well as mRNA expression of Adipo R1and Adipo R2 receptors.Materials and Methods: In this experimental study, eight endometrial biopsies weretaken and stromal cells were separated by enzymatic digestion and cell filtrations. Stromalcells of each biopsy were divided into four groups: control, 10, 100, and 200 ng/mladiponectin concentrations. The effect of adiponectin on viability of the normal HESCswas studied by trypan blue staining and the relative expression levels of Adipo R1 andR2 were analyzed by semi-quantitative reverse transcription polymerase chain reaction(RT-PCR. Data were analyzed by one way ANOVA and unpaired student’s t test andp<0.05 was considered significant.Results: Adiponectin decreased viability of normal human endometrial stromal cells ina dose and time dependent manner. Expression of Adipo R1 and Adipo R2 receptors didnot change in the presence of adiponectin.Conclusion: Adiponectin can directly influence the viability of HESCs and decreasetheir viability, but it didn’t change expression of adiponectin receptors.

  8. Cervical cytology in serous and endometrioid endometrial cancer

    NARCIS (Netherlands)

    Roelofsen, T.; Geels, Y.P.; Pijnenborg, J.M.A.; Ham, M.A.P.C. van; Zomer, S.F.; Tilburg, J.M. van; Snijders, M.P.; Siebers, A.G.; Bulten, J.; Massuger, L.F.A.G.

    2013-01-01

    The aim of this study was to determine the frequency of abnormal cervical cytology in preoperative cervical cytology of patients diagnosed with uterine papillary serous carcinoma (UPSC) and endometrioid endometrial carcinoma (EEC). In addition, associations between abnormal cervical cytology and

  9. Leukemia inhibitory factor enhances endometrial stromal cell decidualization in humans and mice.

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    Lorraine Lin Shuya

    Full Text Available Adequate differentiation or decidualization of endometrial stromal cells (ESC is critical for successful pregnancy in humans and rodents. Here, we investigated the role of leukemia inhibitory factor (LIF in human and murine decidualization. Ex vivo human (H ESC decidualization was induced by estrogen (E, 10(-8 M plus medroxyprogesterone acetate (MPA, 10(-7 M. Exogenous LIF (≥50 ng/ml induced STAT3 phosphorylation in non-decidualized and decidualized HESC and enhanced E+MPA-induced decidualization (measured by PRL secretion, P100 pg/mg G-CSF, IL6, IL8, and MCP1. Decidualized HESC secreted IL6, IL8, IL15 and MCP1. LIF (50 ng/ml up-regulated IL6 and IL15 (P<0.05 secretion in decidualized HESC compared to 0.5 ng/ml LIF. In murine endometrium, LIF and LIFR immunolocalized to decidualized stromal cells on day 5 of gestation (day 0 = day of plug detection. Western blotting confirmed that LIF and the LIFR were up-regulated in intra-implantation sites compared to inter-implantation sites on Day 5 of gestation. To determine the role of LIF during in vivo murine decidualization, intra-peritoneal injections of a long-acting LIF antagonist (PEGLA; 900 or 1200 µg were given just post-attachment, during the initiation of decidualization on day 4. PEGLA treatment reduced implantation site decidual area (P<0.05 and desmin staining immuno-intensity (P<0.05 compared to control on day 6 of gestation. This study demonstrated that LIF was an important regulator of decidualization in humans and mice and data provides insight into the processes underlying decidualization, which are important for understanding implantation and placentation.

  10. Leukemia Inhibitory Factor Enhances Endometrial Stromal Cell Decidualization in Humans and Mice

    Science.gov (United States)

    Yap, Joanne; Li, Priscilla; Lane, Natalie; Dimitriadis, Evdokia

    2011-01-01

    Adequate differentiation or decidualization of endometrial stromal cells (ESC) is critical for successful pregnancy in humans and rodents. Here, we investigated the role of leukemia inhibitory factor (LIF) in human and murine decidualization. Ex vivo human (H) ESC decidualization was induced by estrogen (E, 10−8 M) plus medroxyprogesterone acetate (MPA, 10−7 M). Exogenous LIF (≥50 ng/ml) induced STAT3 phosphorylation in non-decidualized and decidualized HESC and enhanced E+MPA-induced decidualization (measured by PRL secretion, P100 pg/mg G-CSF, IL6, IL8, and MCP1. Decidualized HESC secreted IL6, IL8, IL15 and MCP1. LIF (50 ng/ml) up-regulated IL6 and IL15 (P<0.05) secretion in decidualized HESC compared to 0.5 ng/ml LIF. In murine endometrium, LIF and LIFR immunolocalized to decidualized stromal cells on day 5 of gestation (day 0 = day of plug detection). Western blotting confirmed that LIF and the LIFR were up-regulated in intra-implantation sites compared to inter-implantation sites on Day 5 of gestation. To determine the role of LIF during in vivo murine decidualization, intra-peritoneal injections of a long-acting LIF antagonist (PEGLA; 900 or 1200 µg) were given just post-attachment, during the initiation of decidualization on day 4. PEGLA treatment reduced implantation site decidual area (P<0.05) and desmin staining immuno-intensity (P<0.05) compared to control on day 6 of gestation. This study demonstrated that LIF was an important regulator of decidualization in humans and mice and data provides insight into the processes underlying decidualization, which are important for understanding implantation and placentation. PMID:21966484

  11. Human endometrial stromal stem cells differentiate into megakaryocytes with the ability to produce functional platelets.

    Science.gov (United States)

    Wang, Jinju; Chen, Shuzhen; Zhang, Cheng; Stegeman, Samantha; Pfaff-Amesse, Teresa; Zhang, Ying; Zhang, Wenfeng; Amesse, Lawrence; Chen, Yanfang

    2012-01-01

    Human endometrium is a high dynamic tissue that contains endometrial stromal stem cells (hESSCs). The hESSCs have been differentiated into a number of cell lineages. However, differentiation of hESSCs into megakaryocytes (MKs) has not yet been investigated. The aim of this study was to investigate the feasibility of MK generation from hESSCs and subsequent production of functional platelets (PLTs). In our study, hESSCs were cultured from endometrial stromal cells as confirmed by positive stromal cell specific markers (CD90 and CD29) and negative hematopoietic stem cell markers (CD45 and CD34) expression. Then, hESSCs were differentiated in a medium supplemented with thrombopoietin (TPO) for 18 days. The MK differentiation was analyzed by flow cytometry and confocal microscopy. The differentiation medium was collected for PLT production analysis by flow cytometry, transmission electron microscopy and functional measurements. Our results show: 1) MKs were successfully generated from hESSCs as identified by expression of specific markers (CD41a: 1 ± 0.09% and 39 ± 3.0%; CD42b: 1.2 ± 0.06% and 28 ± 2.0%, control vs. differentiation) accompanied with reduction of pluripotent transcription factors (Oct4 and Sox2) expression; 2) The level of PLTs in the differentiation medium was 16 ± 1 number/µl as determined by size (2-4 µm) and CD41a expression (CD41a: 1 ± 0.4% and 90±2.0%, control vs. differentiation); 3) Generated PLTs were functional as evidenced by the up-regulation of CD62p expression and fibrinogen binding following thrombin stimulation; 4) Released PLTs showed similar ultra-structure characteristics (alpha granules, vacuoles and dense tubular system) as PLTs from peripheral blood determined by electron microscopic analysis. Data demonstrate the feasibility of generating MKs from hESSCs, and that the generated MKs release functional PLTs. Therefore, hESSCs could be a potential new stem cell source for in vitro MK/PLT production.

  12. Human endometrial stromal stem cells differentiate into megakaryocytes with the ability to produce functional platelets.

    Directory of Open Access Journals (Sweden)

    Jinju Wang

    Full Text Available Human endometrium is a high dynamic tissue that contains endometrial stromal stem cells (hESSCs. The hESSCs have been differentiated into a number of cell lineages. However, differentiation of hESSCs into megakaryocytes (MKs has not yet been investigated. The aim of this study was to investigate the feasibility of MK generation from hESSCs and subsequent production of functional platelets (PLTs. In our study, hESSCs were cultured from endometrial stromal cells as confirmed by positive stromal cell specific markers (CD90 and CD29 and negative hematopoietic stem cell markers (CD45 and CD34 expression. Then, hESSCs were differentiated in a medium supplemented with thrombopoietin (TPO for 18 days. The MK differentiation was analyzed by flow cytometry and confocal microscopy. The differentiation medium was collected for PLT production analysis by flow cytometry, transmission electron microscopy and functional measurements. Our results show: 1 MKs were successfully generated from hESSCs as identified by expression of specific markers (CD41a: 1 ± 0.09% and 39 ± 3.0%; CD42b: 1.2 ± 0.06% and 28 ± 2.0%, control vs. differentiation accompanied with reduction of pluripotent transcription factors (Oct4 and Sox2 expression; 2 The level of PLTs in the differentiation medium was 16 ± 1 number/µl as determined by size (2-4 µm and CD41a expression (CD41a: 1 ± 0.4% and 90±2.0%, control vs. differentiation; 3 Generated PLTs were functional as evidenced by the up-regulation of CD62p expression and fibrinogen binding following thrombin stimulation; 4 Released PLTs showed similar ultra-structure characteristics (alpha granules, vacuoles and dense tubular system as PLTs from peripheral blood determined by electron microscopic analysis. Data demonstrate the feasibility of generating MKs from hESSCs, and that the generated MKs release functional PLTs. Therefore, hESSCs could be a potential new stem cell source for in vitro MK/PLT production.

  13. Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors.

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    Maren Schwenke

    Full Text Available Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF triggered chemotaxis (directed locomotion, whereas platelet-derived growth factor (PDGF-BB elicited both chemotaxis and chemokinesis (non-directed locomotion of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating

  14. Low molecular weight heparin and aspirin exacerbate human endometrial endothelial cell responses to antiphospholipid antibodies.

    Science.gov (United States)

    Quao, Zola Chihombori; Tong, Mancy; Bryce, Elena; Guller, Seth; Chamley, Lawrence W; Abrahams, Vikki M

    2018-01-01

    Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications despite treatment with low molecular weight heparin (LMWH) or aspirin (ASA). aPL recognizing beta2 glycoprotein I can target the uterine endothelium, however, little is known about its response to aPL. This study characterized the effect of aPL on human endometrial endothelial cells (HEECs), and the influence of LMWH and ASA. HEECs were exposed to aPL or control IgG, with or without low-dose LMWH and ASA, alone or in combination. Chemokine and angiogenic factor secretion were measured by ELISA. A tube formation assay was used to measure angiogenesis. aPL increased HEEC secretion of pro-angiogenic VEGF and PlGF; increased anti-angiogenic sFlt-1; inhibited basal secretion of the chemokines MCP-1, G-CSF, and GRO-α; and impaired angiogenesis. LMWH and ASA, alone and in combination, exacerbated the aPL-induced changes in the HEEC angiogenic factor and chemokine profile. There was no reversal of the aPL inhibition of HEEC angiogenesis by either single or combination therapy. By aPL inhibiting HEEC chemokine secretion and promoting sFlt-1 release, the uterine endothelium may contribute to impaired placentation and vascular transformation. LMWH and ASA may further contribute to endothelium dysfunction in women with obstetric APS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Molecular Genetic Analysis of Human Endometrial Mesenchymal Stem Cells That Survived Sublethal Heat Shock

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    A. E. Vinogradov

    2017-01-01

    Full Text Available High temperature is a critical environmental and personal factor. Although heat shock is a well-studied biological phenomenon, hyperthermia response of stem cells is poorly understood. Previously, we demonstrated that sublethal heat shock induced premature senescence in human endometrial mesenchymal stem cells (eMSC. This study aimed to investigate the fate of eMSC-survived sublethal heat shock (SHS with special emphasis on their genetic stability and possible malignant transformation using methods of classic and molecular karyotyping, next-generation sequencing, and transcriptome functional analysis. G-banding revealed random chromosome breakages and aneuploidy in the SHS-treated eMSC. Molecular karyotyping found no genomic imbalance in these cells. Gene module and protein interaction network analysis of mRNA sequencing data showed that compared to untreated cells, SHS-survived progeny revealed some difference in gene expression. However, no hallmarks of cancer were found. Our data identified downregulation of oncogenic signaling, upregulation of tumor-suppressing and prosenescence signaling, induction of mismatch, and excision DNA repair. The common feature of heated eMSC is the silence of MYC, AKT1/PKB oncogenes, and hTERT telomerase. Overall, our data indicate that despite genetic instability, SHS-survived eMSC do not undergo transformation. After long-term cultivation, these cells like their unheated counterparts enter replicative senescence and die.

  16. 21 CFR 884.1060 - Endometrial aspirator.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Endometrial aspirator. 884.1060 Section 884.1060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... § 884.1060 Endometrial aspirator. (a) Identification. An endometrial aspirator is a device designed to...

  17. Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, L.; Deppert, W.R. [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany); Pfeifer, D. [Department of Hematology and Oncology, University Hospital Freiburg (Germany); Stanzel, S.; Weimer, M. [Department of Biostatistics, German Cancer Research Center, Heidelberg (Germany); Hanjalic-Beck, A.; Stein, A.; Straßer, M.; Zahradnik, H.P. [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany); Schaefer, W.R., E-mail: wolfgang.schaefer@uniklinik-freiburg.de [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany)

    2012-05-01

    Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17β-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration–response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies. -- Highlights: ► We compare progesterone receptor-mediated endometrial effects of chemicals and drugs. ► 4-Nonylphenol, bisphenol A and apigenin exert weak

  18. [Uterine cervical carcinoma and human papillomaviruses].

    Science.gov (United States)

    Sugase, M

    1992-06-01

    For many years it has been thought that a significant proportion of cervical cancer could be attributed to sexually transmitted agents, such as sperm, smegma, Treponema pallidum, Gonococcus and herpes simplexvirus type 2. Recent advances of molecular biology, however, have revealed that human papillomavirus (HPV) might be the most causative virus of the disease. Since HPV type 16 DNA was found in a patient with cervical cancer in 1983, many HPV types have been cloned from cervical cancers, also from premalignant lesions (intraepithelial neoplasias). In Japan, we have found 6 new types of HPV (HPV 58, 59, 61, 62, 64, 67) in the female genital tract so far. Especially, HPV 58, which was cloned from a patient with cervical squamous cell carcinoma and was already fully sequenced, is thought to be an important agent for the development of cervical cancer as well as HPV 16. Now we are investigating extensively to clarify the real relationship between genital HPV infection and cervical cancer.

  19. Effects of a hyperandrogenaemic state on the proliferation and decidualization potential in human endometrial stromal cells.

    Science.gov (United States)

    Freis, Alexander; Renke, Tobias; Kämmerer, Ulrike; Jauckus, Julia; Strowitzki, Thomas; Germeyer, Ariane

    2017-04-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, involving hyperandrogenaemia and insulin resistance. Treatment options include dexamethasone, as well as the off-label use of metformin. To evaluate the impact of those drugs on cyclic changes in endometrial development, we tested possible effects of metformin and dexamethasone on endometrial stromal cells decidualisation, proliferation, and gene regulation in a hyperandrogenaemic microenvironment in vitro. Ten endometrial biopsies (of which five were decidualized in vitro) were used from regularly cycling women. Cells were treated with testosterone, dexamethasone, and metformin in different concentrations. Thereafter, cells were assessed for proliferation and decidualization capacity, as well as mTor and MMP-2 gene regulation. Metformin showed a dose-dependent negative effect on prolactin secretion, a known decidualization marker. This effect was stronger in a hyperandrogenaemic condition and could not be compensated by dexamethasone. Testosterone had a dose dependent negative effect on proliferation in decidualized endometrial stromal cells. Dexamethasone slightly compensated the negative proliferative effect only in low-dose testosterone. High-dose metformin also showed a dose-dependent reduction in endometrial stromal cell proliferation without a major impact by testosterone or dexamethasone in decidualized and non-decidualized cells. High-dose metformin significantly reduced the expression of matrix metalloproteinase-2 (MMP-2) and mechanistic Target of Rapamycin (mTor), regardless of the concentration of dexamethasone and testosterone. The strongest effect could be observed for the combination with high-dose dexamethasone. When therapies, such as metformin and dexamethasone, are used to normalize peripheral androgen levels in patients with PCOS, their effect on the endometrial microenvironment should be taken into consideration as well, especially metformin has to be used with

  20. Growth Hormone differentially modulates chemoresistance in human endometrial adenocarcinoma cell lines.

    Science.gov (United States)

    Gentilin, Erica; Minoia, Mariella; Bondanelli, Marta; Tagliati, Federico; Degli Uberti, Ettore C; Zatelli, Maria Chiara

    2017-06-01

    Growth Hormone may influence neoplastic development of endometrial epithelium towards endometrial adenocarcinoma, which is one of the most occurring tumors in acromegalic patients. Since chemoresistance often develops in advanced endometrial adenocarcinoma, we investigated whether Growth Hormone might influence the development of chemoresistance to drugs routinely employed in endometrial adenocarcinoma treatment, such as Doxorubicin, Cisplatin, and Paclitaxel. Growth Hormone and Growth Hormone receptor expression was assessed by immunofluorescence in two endometrial adenocarcinoma cell lines, AN3 CA and HEC-1-A cells. Growth Hormone effects were assessed investigating cell viability, caspase3/7 activation, ERK1/2, and protein kinase C delta protein expression. AN3 CA and HEC-1-A cells display Growth Hormone and Growth Hormone receptor. Growth Hormone does not influence cell viability in both cells lines, but significantly reduces caspase 3/7 activation in AN3 CA cells, an effect blocked by a Growth Hormone receptor antagonist. Growth Hormone rescues AN3 CA cells from the inhibitory effects of Doxorubicin and Cisplatin on cell viability, while it has no effect on Paclitaxel. Growth Hormone does not influence the pro-apoptotic effects of Doxorubicin, but is capable of rescuing AN3 CA cells from the pro-apoptotic effects of Cisplatin. On the other hand, Growth Hormone did not influence the effects of Doxorubicin and Paclitaxel on HEC-1A cell viability. The protective action of Growth Hormone towards the effects of Doxorubicin may be mediated by ERK1/2 activation, while the pro-apoptotic effects of Cisplatin may be mediated by protein kinase C delta inhibition. All together our results indicate that Growth Hormone may differentially contribute to endometrial adenocarcinoma chemoresistance. This may provide new insights on novel therapies against endometrial adenocarcinoma chemoresistant aggressive tumors.

  1. The association between polycystic ovary syndrome and endometrial cancer.

    OpenAIRE

    Chedumbarum Pillay, O. D.

    2010-01-01

    HYPOTHESIS: Women suffering from polycystic ovary syndrome have an increased risk of developing endometrial carcinoma. AIM: To determine whether people with polycystic ovary syndrome have an increased risk of developing endometrial carcinoma. BACKGROUND: Endometrial cancer is one of the commonest cancers to occur in women in the Western World and unopposed oestrogen stimulation of the uterus is amongst one of the aetiologies postulated for this condition. It is generally assumed that ...

  2. Biomarkers of endometrial cancer and related gynaecological malignancies

    NARCIS (Netherlands)

    Seeber, L.M.S.

    2010-01-01

    In the Western World, endometrial cancer is the most common malignancy of the female genital tract. Endometrioid endometrial carcinoma (EEC or Type I tumour), accounts for approximately 75% of cases. Type II tumours, of which uterine papillary serous carcinoma (UPSC) is the most common subtype, are

  3. Hypoxia and cell cycle deregulation in endometrial carcinogenesis

    NARCIS (Netherlands)

    Horrée, N.

    2007-01-01

    Because uterine endometrial carcinoma is the most common malignancy of the female genital tract and 1 of every 5 patients dies of this disease, understanding the mechanisms of carcinogenesis and progression of endometrial carcinoma is important. In general, this thesis can be summarized as a study

  4. Endometrial safety of ultra-low-dose estradiol vaginal tablets

    DEFF Research Database (Denmark)

    Simon, James; Nachtigall, Lila; Ulrich, Lian G

    2010-01-01

    To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17β-estradiol vaginal tablets in postmenopausal women with vaginal atrophy.......To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17β-estradiol vaginal tablets in postmenopausal women with vaginal atrophy....

  5. Endometrial safety of ultra-low-dose estradiol vaginal tablets

    DEFF Research Database (Denmark)

    Simon, James; Nachtigall, Lila; Ulrich, Lian G

    2010-01-01

    To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17ß-estradiol vaginal tablets in postmenopausal women with vaginal atrophy.......To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17ß-estradiol vaginal tablets in postmenopausal women with vaginal atrophy....

  6. Multivariate assessment of cervical invasion of endometrial carcinoma. Comparison of transvaginal ultrasonography, hysteroscopy, and magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Miyagi, Yasunari; Yamada, Shinako; Miyagi, Yuji [Okayama Univ. (Japan). School of Medicine] [and others

    1997-07-01

    From 1991 to 1995, 71 patients with endometrial cancer at Okayama University Medical School underwent transvaginal ultrasonography with a 6.5-MHz transducer, MRI at 1.5 T, and hysteroscopy using a rigid hysteroscope. The findings of these examinations were compared against pathologic results. The sensitivity/specificity/accuracy were 0.73/0.89/0.86 for transvaginal ultrasonography, 0.73/0.88/0.85 for MRI, and 0.73/0.80/0.79 for hysteroscopy. The coefficient values for transvaginal ultrasonography/MRI/hysteroscopy were 0.69/0.62/-0.21 and 1.99/1.89/0.79 in quantification theory second family analysis and logistic regression, respectively. Misdiagnosed cases had the following factors: large tumor volume; tumor near the internal os; tumor descending from the uterine cavity; polypoid tumor in the endocervix; artifacts due to the use of a cervix dilator made from stems of the seaweed Laminaria japonica; endocervical glandular involvement only; and atypical signals on MRI. For the preoperative assessment of cervical invasion, transvaginal ultrasonography and MRI were the most reliable. Hysteroscopy was least reliable, because of a large number of false-positive results. The use of these examinations in combination, especially transvaginal ultrasonography and MRI, would be of great value in surgical planning for endometrial cancer, considering the factors responsible for misdiagnosis. (K.H.)

  7. Evidence of inhibin/activin subunit betaC and betaE synthesis in normal human endometrial tissue

    Directory of Open Access Journals (Sweden)

    Shabani Naim

    2010-11-01

    Full Text Available Abstract Background Inhibins are important regulators of the female reproductive system. Recently, two new inhibin subunits betaC and betaE have been described, although it is unclear if they are synthesized in normal human endometrium. Methods Samples of human endometrium were obtained from 82 premenopausal, non-pregnant patients undergoing gynecological surgery for benign diseases. Endometrium samples were classified according to anamnestic and histological dating into proliferative (day 1-14, n = 46, early secretory (day 15-22, n = 18 and late secretory phase (day 23-28, n = 18. Immunohistochemical analyses were performed with specific antibodies against inhibin alpha (n = 81 as well as inhibin betaA (n = 82, betaB (n = 82, betaC (n = 74 and betaE (n = 76 subunits. RT-PCR was performed for all inhibin subunits. Correlation was assessed with the Spearman factor to assess the relationship of inhibin-subunits expression within the different endometrial samples. Results The novel inhibin betaC and betaE subunits were found in normal human endometrium by immunohistochemical and molecular techniques. Inhibin alpha, betaA, betaB and betaE subunits showed a circadian expression pattern, being more abundant during the late secretory phase than during the proliferative phase. Additionally, a significant correlation between inhibin alpha and all inhibin beta subunits was observed. Conclusions The differential expression pattern of the betaC- and betaE-subunits in normal human endometrial tissue suggests that they function in endometrial maturation and blastocyst implantation. However, the precise role of these novel inhibin/activin subunits in human endometrium is unclear and warrants further investigation.

  8. The Emerging Genomic Landscape of Endometrial Cancer

    Science.gov (United States)

    Le Gallo, Matthieu; Bell, Daphne W.

    2014-01-01

    BACKGROUND Endometrial cancer is responsible for ~74,000 deaths amongst women worldwide each year. It is a heterogeneous disease that consists of multiple different histological subtypes. In the United States, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterations that drive serous and endometrioid endometrial carcinomas lays the foundation for the identification of molecular markers that could improve the clinical management of patients presenting with these tumors. CONTENT Herein we review the current state of knowledge of the somatic genomic alterations that are present in serous and endometrioid endometrial tumors. We present this knowledge in a historical context – reviewing the genomic alterations that have been identified over the past two decades or more, from studies of individual genes and proteins, followed by a review of very recent studies that have conducted comprehensive, systematic surveys of genomic, exomic, transcriptomic, epigenomic, and proteomic alterations in serous and endometrioid endometrial carcinomas. SUMMARY The recent mapping of the genomic landscape of serous and endometrioid endometrial carcinomas has resulted in the first comprehensive molecular classification of these tumors and has distinguished four molecular subgroups: a POLE ultramutated subgroup, a hypermutated/microsatellite unstable subgroup, a copy number low/microsatellite stable subgroup, and a copy number high subgroup. This molecular classification may ultimately serve to refine the diagnosis and treatment of women with endometrioid and serous endometrial tumors. PMID:24170611

  9. The morbidity of treatment for patients with stage I endometrial cancer : Results from a randomized trial

    NARCIS (Netherlands)

    Creutzberg, CL; van Putten, WLJ; Koper, PC; Lybeert, MLM; Jobsen, JJ; Warlam-Rodenhuis, CC; De Winter, KAJ; Lutgens, LCHW; van den Bergh, ACM; van der Steen-Banasik, E; Beerman, H; van Lent, M

    2001-01-01

    Purpose: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. Methods and Materials: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial

  10. Profiles of cytokines secreted by isolated human endometrial cells under the influence of chorionic gonadotropin during the window of embryo implantation

    Science.gov (United States)

    2013-01-01

    Background Several studies have indicated that human pre-implantation embryo-derived chorionic gonadotropin (hCG) may influence the implantation process by its action on human endometrial epithelial and stromal cells. Despite reports indicating that hCG acts on these cells to affect the production of several cytokines and growth factors (e.g., MIF, IGF-I, VEGF, LIF, IL-11, GMCSF, CXL10 and FGF2), our understanding of the integral influence of hCG on paracrine interactions between endometrial stromal and epithelial cells during implantation is very limited. Methods In the present study, we examined the profile of 48 cytokines in the conditioned media of primary cell cultures of human implantation stage endometrium. Endometrial epithelial cells (group 1; n = 20), stromal cells (group 2; n = 20), and epithelial plus stromal cells (group 3; n = 20) obtained from mid-secretory stage endometrial samples (n = 60) were grown on collagen and exposed to different doses (0, 1, 10 and 100 IU/ml) of rhCG for 24 h in vitro. Immunochemical and qRT-PCR methods were used to determine cytokine profiles. Enrichment and process networks analyses were implemented using a list of cytokines showing differential secretion in response to hCG. Results Under basal conditions, endometrial epithelial and stromal cells exhibited cell type-specific profiles of secreted cytokines. Administration of hCG (100 IU) resulted in significantly (P endometrial epithelial and stromal cells. CG may also affect complex paracrine processes in the different endometrial cell types. PMID:24345207

  11. Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor.

    Science.gov (United States)

    Tierney, Brent J; McCann, Georgia A; Naidu, Shan; Rath, Kellie S; Saini, Uksha; Wanner, Ross; Kuppusamy, Periannan; Suarez, Adrian; Goodfellow, Paul J; Cohn, David E; Selvendiran, Karuppaiyah

    2014-10-01

    Constitutive activation of STAT3 is a hallmark of various human cancers, however an increased pSTAT3 expression in high grade human endometrial cancer has not been reported. In the present study, we examine the expression of STAT family of proteins in endometrial cancer cell lines and the efficacy of HO-3867, a novel STAT3 inhibitor designed in our lab. Expression of STAT family proteins was evaluated via Western blot. The cell viability, post-treatment with HO-3867, was assessed using MTT, cell-cycle profile and Annexin assay. In vivo efficacy of HO-3867 was evaluated using xenograft mice. Expression of activated STATs was inconsistent among the cell lines and 18 human endometrial cancer specimens tested. While pSTAT3 Tyr705 was not expressed in any of the cell lines, pSTAT3 Ser727 was highly expressed in endometrial cancer cell lines and tumor specimens. HO-3867 decreased the expression of pSTAT3 Ser727 while total STAT3 remained constant; cell viability decreased by 50-80% and induced G2/M arrest in 55% of Ishikawa cells at the G2/M cell cycle checkpoint. There was an increase in p53, a decrease in Bcl2 and Bcl-xL, and cleavage of caspase-3, caspase-7 and PARP. HO-3867 mediated a dosage-dependent inhibition of the growth of xenografted endometrial tumors. HO-3867 treatment decreases the high levels of pSTAT3 Ser727 in endometrial cancer cells by inducing cell cycle arrest and apoptosis. This suggests a specific role of serine-phosphorylated STAT3, independent of tyrosine phosphorylation in the oncogenesis of endometrial cancer. HO-3867 could potentially serve as an adjunctive targeted therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Effects of low doses of mifepristone on human embryo implantation process in a three-dimensional human endometrial in vitro co-culture system.

    Science.gov (United States)

    Boggavarapu, N R; Berger, C; von Grothusen, C; Menezes, J; Gemzell-Danielsson, K; Lalitkumar, P G L

    2016-08-01

    We wanted to explore the effects of two different low doses (0.5μM and 0.05μM) of mifepristone, exposed during the receptive period, on the human embryo implantation process, using a well-established three-dimensional in vitro cell culture model, specifically developed to study this process. An in vitro three-dimensional cell culture model was constructed using human endometrial cells isolated from the endometrium of proven fertile women, collected on cycle day LH+4. After 5 days of culture, supernumerary human embryos were added and cultured for another 5 days with mifepristone 0.5μM (n=8) or 0.05μM (n=10) or vehicle as control (n=10). The cultures were checked for embryo attachment and terminated. We studied the expression of 16 reported endometrial receptivity markers in the endometrial constructs using real-time polymerase chain reaction. None of the embryos in 0.5μM of mifepristone attached to the endometrial constructs (p=.004), whereas 4 out of 10 in 0.05μM (p=.3698) and 7 out of 10 embryos in the control group attached to the cultures. We found that most of the studied receptivity markers were significantly altered with mifepristone exposure in a similar direction in both treatment groups. Only IL6 was significantly differentially expressed between the treatment groups (p=.017). We report for the first time that exposure to a low concentration (0.5μM) of mifepristone during the receptive period successfully inhibits human embryo implantation process in vitro. Further, we observed a dose-dependent effect of mifepristone on endometrial receptivity at the functional level. This study contributes new knowledge that low dose of mifepristone during the short period of receptive phase can inhibit endometrial receptivity, which further promotes mifepristone as a contraceptive agent. This could give women a treatment choice to avoid unwanted pregnancy with high efficacy and minimal side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Imaging of human urothelial carcinoma samples using multimodal multiphoton microscopy

    Science.gov (United States)

    Baria, E.; Barone, A.; Nesi, G.; Pavone, F. S.; Cicchi, R.

    2017-07-01

    We combined Second Harmonic Generation and Two-Photon Fluorescence for imaging ex vivo tissue sections of human bladder affected by urothelial carcinoma. We studied different grades of the tumor, and compared them to healthy bladder mucosa.

  14. Evaluation of irofulven (MGI-114) in the treatment of recurrent or persistent endometrial carcinoma: A phase II study of the Gynecologic Oncology Group.

    Science.gov (United States)

    Schilder, Russell J; Blessing, John A; Pearl, Michael L; Rose, Peter G

    2004-08-01

    This multi-center phase II trial was conducted by the Gynecologic Oncology Group to evaluate the activity and toxicity of irofulven in patients with previously treated adenocarcinoma of the endometrium. Eligible patients had documented recurrent or persistent endometrial carcinoma after receiving definitive locoregional therapy, and were required to have measurable disease, performance status of 0-2, and adequate bone marrow, hepatic and renal functions prior to study entry. Patients were allowed one prior chemotherapy regimen. The initial dose of irofulven was 11 mg/m(2)/day for four days administered intravenously. Cycles were repeated every 28 days. Doses were escalated or reduced based on previous cycle toxicity. Twenty-five patients were enrolled onto the trial. There was one (4%) confirmed complete response. Seven (28%) patients had stable disease, with a median duration of 10.4 (range: 4.4-21.6) months. Patients received a median of one (range: 1-5) cycle of protocol treatment. There were three early treatment-related deaths due to renal failure and severe electrolyte disturbances. Two patients experienced grade 4 hematologic adverse effects. Irofulven administered at the dose and schedule used in this trial was minimally active and resulted in significant toxicity.

  15. Human papilloma virus prevalence in laryngeal squamous cell carcinoma.

    Science.gov (United States)

    Gungor, A; Cincik, H; Baloglu, H; Cekin, E; Dogru, S; Dursun, E

    2007-08-01

    To determine the prevalence and type of human papilloma virus deoxyribonucleic acid (DNA) in cases of laryngeal squamous cell carcinoma. We analysed the prevalence of human papilloma virus infection in archived paraffin block specimens taken from 99 cases of laryngeal squamous cell carcinoma between 1990 and 2005, using polymerase chain reaction techniques. Biopsy specimens from five proven verrucous skin lesions were used as positive controls, and peripheral blood samples from five healthy volunteers were used as negative controls. Four test samples were found to have inadequate deoxyribonucleic acid purity and were therefore excluded from the study. Human papilloma virus deoxyribonucleic acid was detected in seven of 95 cases of laryngeal squamous cell carcinoma (7.36 per cent). Human papilloma virus genotyping revealed double human papilloma virus infection in three cases and single human papilloma virus infection in the remaining four cases. The human papilloma virus genotypes detected were 6, 11 and 16 (the latter detected in only one case). In our series, a very low human papilloma virus prevalence was found among laryngeal squamous cell carcinoma cases. The human papilloma virus genotypes detected were mostly 6 and/or 11, and 16 in only one case. To the best of our knowledge, this is the first report of human papilloma virus prevalence in laryngeal squamous cell carcinoma, based on polymerase chain reaction genotyping in a Turkish population.

  16. Endometrial biopsy

    Science.gov (United States)

    Biopsy - endometrium ... The biopsy is normal if the cells in the sample are not abnormal. ... Risks of endometrial biopsy include: Infection Causing a hole in (perforating) the uterus or tearing the cervix (rarely occurs) Prolonged bleeding Slight spotting ...

  17. Endometrial metaplasias and reactive changes: a spectrum of altered differentiation.

    Science.gov (United States)

    Nicolae, Alina; Preda, Ovidiu; Nogales, Francisco F

    2011-02-01

    Endometrial metaplasias and changes (EMCs) are conditions frequently overlooked and misdiagnosed. The aim of this review is to update current issues and provide a classification with a practical clinicopathological approach. Hormonal or irritative stimuli are the main inducing factors of EMCs, although some metaplasias have a mutational origin. EMCs vary from reactive, degenerative lesions to those able to associate with malignancy or those having a preneoplastic potential. The most common types of EMCs are ciliated tubal metaplasia (CTM) and mucinous metaplasia (MM), which occur in simple and complex glands, and possibly these architectural changes hold the same prognostic significance as they do in hyperplastic endometrioid lesions. Immunohistochemically, CTM is positive for LhS28, bcl-2, PAX2 and p16(INK4A). Complex CTM is likely to be a precursor of ciliated endometrioid-type carcinomas. MMs should be evaluated architecturally, taking into account that their atypicality is minimal. The differentiation between complex MM and mucinous carcinoma may be extremely difficult. Surface complex, papillary MM in endometrial polyps can be considered as benign. Intestinal-type endometrial MM is rare and its presence should prompt further investigation of associated lesions in the endocervix. Endometrial squamous metaplasia (ESS) is often linked to chronic irritative situations. It should be differentiated from secondary involvement by a human papilomavirus-related cervical lesion. Morular metaplasia is a mutational phenomenon with a distinct phenotype that helps to differentiate it from ESS. Morules are benign, hormonally inert structures that are often markers of complex endometrioid glandular architecture, and they are associated with an attenuated malignancy. Endometrial reactive changes are commonly associated with desquamation or hormonal imbalance. The frequent, p16(INK4A) positive, benign surface papillary syncytial change may be misdiagnosed, in some cases, as

  18. Endometrial cancer with cervical extension mimicking dual concordant endometrial and cervical malignancy by F18 FDG PET and MRI

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Seok Nam [Kwandong Univ. College of Medicine, Seoul (Korea, Republic of)

    2012-09-15

    A 35 year old woman with endometrial cancer and cervical extension underwent F18 FDG PET CT and MRI studies after resection of a cervical mass presumed to be cervical myoma. The patient underwent cervical myomectomy and the histopathologic report revealed poorly differentiated invasive carcinoma. Cervical cancer was ruled out because the patient had no history of sexual intercourse and was negative for human papilloma virus infection. The patient underwent radical hysterectomy, bilateral salpingo oophorectomy, pelvic and para aortic lymph node dissection, and multiple biopsies. F18 FDG PET CT showed intense FDG uptake along the cervix wall. T2 weighted MRI also revealed a mass lesion with high SI involving the anterior and posterior lips of the uterine cervix. Another area of focal increased uptake above the endometrial lesion in the left pelvic cavity was observed on PET CT and MRI, possibly due to a functioning ovary. PET CT and MRI were interpreted as showing a dual concordant malignant lesion due to separated FDG uptakes and high SI without any connection between the cervical and endometrial lesions. F18 FDG PET CT showed intense FDG uptake along the endometrium. Given the patient's history and the fact that she was not menstruating at the time of imaging, this intense uptake was interpreted as another pathologic lesion, suggesting dual primary lesions. A suspected heterogeneous mass lesion along the endometrium suggesting concordant endometrial cancer was found on MRI. Endometrial cancer with cervical extension is sometimes difficult to differentiate from primary cervical cancer. The final histopathologic report showed poorly differentiated endometrial adenocarcinoma with cervical extension, although the FDG PET CT and MRI findings were suggestive of concordant cervical and endometrial cancer. Although histopathologic confirmation is necessary for final diagnosis, MRI and FDG PET CT studies may aid in the differential diagnosis. A metastatic cervical mass

  19. Apoptosis and necrosis induced by novel realgar quantum dots in human endometrial cancer cells via endoplasmic reticulum stress signaling pathway.

    Science.gov (United States)

    Wang, Huan; Liu, Zhengyun; Gou, Ying; Qin, Yu; Xu, Yaze; Liu, Jie; Wu, Jin-Zhu

    2015-01-01

    Realgar (AS4S4) has been used in traditional medicines for malignancy, but the poor water solubility is still a major hindrance to its clinical use. Realgar quantum dots (RQDs) were therefore synthesized with improved water solubility and bioavailability. Human endometrial cancer JEC cells were exposed to various concentrations of RQDs to evaluate their anticancer effects and to explore mechanisms by the MTT assay, transmission electron microscopy (TEM), flow cytometry, real-time reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. Results revealed that the highest photoluminescence quantum yield of the prepared RQDs was up to approximately 70%, with the average size of 5.48 nm. RQDs induced antipro-liferative activity against JEC cells in a concentration-dependent manner. In light microscopy and TEM examinations, RQDs induced vacuolization and endoplasmic reticulum (ER) dilation in JEC cells in a concentration-dependent manner. ER stress by RQDs were further confirmed by increased expression of GADD153 and GRP78 at both mRNA and protein levels. ER stress further led to JEC cell apoptosis and necrosis, as evidenced by flow cytometry and mitochondrial membrane potential detection. Our findings demonstrated that the newly synthesized RQDs were effective against human endometrial cancer cells. The underlying mechanism appears to be, at least partly, due to ER stress leading to apoptotic cell death and necrosis.

  20. Sonohysterographic findings of endometrial abnormalities in women with polycystic ovarian disease

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eun Ju [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2004-06-15

    To describe the sonohysterographic findings of endometrial abnormalities, and to determine the usefulness of sonohysterography (SH) for predicting endometrial abnormalities in women with polycystic ovarian disease(PCOD). 82 patients with PCOD who had vaginal bleeding or endometrial thickening and lesion mass on baseline transvaginal sonography were prospectively examined with SH. The SH findings were evaluated for endometrial thickness, the presence of endometrial thickening and lesion mass, echogenicity and surface contour, distensibility of the endometrial cavity, and disruption of endometrial-myometrial interface. These findings were compared with the pathologic findings and the diagnostic accuracy of SH for predicting endometrial abnormalities was assessed. Endometrial abnormalities were identified in 47 (57.3%) of 82 PCOD patients, and their pathologic diagnosis included endometrial carcinoma in 7 cases, hyperplasia in 19 cases (atypical hyperplasia, n=5), and polyp in 21 cases. Of the 35 patients who did not have endometrial abnormalities, there was disordered proliferative endometrium in 18 cases and normal proliferative or secretory endometrium in 17 cases. The SH findings of endometrial carcinoma were endometrial thickening in 5 cases, endometrial thickening and lesion mass in 2 cases, and the endometrial thickness ranged from 6 mm to 15 mm (mean 9.5 mm). They were characterized as a diffuse polyploid endometrial thickening or a sessile endometrial mass with irregular surface, homogeneous hyperechogenicity, and obliteration of the endometrial cavity. Endometrial hyperplasia appeared as endometrial thickening in 14 cases, endometrial lesion mass in 3 cases, and endometrial thickening and lesion mass in 2 cases, and the endometrial thickness was between 6.5-10.7 mm (mean 8.2 mm). They showed a diffuse uniform endometrial thickening or a polyploid endometrial lesion mass with homogeneous hyperechogenicity and a regular surface. Endometrial polyps appeared as

  1. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice

    Directory of Open Access Journals (Sweden)

    Shanzheng Lu

    2016-10-01

    Full Text Available Abstract Background The endometrial regenerative cell (ERC is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4–induced acute liver injury (ALI. Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT and aspartate aminotransferase (AST activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury

  2. mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium.

    Science.gov (United States)

    Karalok, Hakan Mete; Aydin, Ebru; Saglam, Ozlen; Torun, Aysenur; Guzeloglu-Kayisli, Ozlem; Lalioti, Maria D; Kristiansson, Helena; Duke, Cindy M P; Choe, Gina; Flannery, Clare; Kallen, Caleb B; Seli, Emre

    2014-12-01

    Cytokines and growth factors play important roles in endometrial function and the pathogenesis of endometriosis. mRNAs encoding cytokines and growth factors undergo rapid turnover; primarily mediated by adenosine- and uridine-rich elements (AREs) located in their 3'-untranslated regions. T-cell intracellular antigen (TIA-1), an mRNA-binding protein, binds to AREs in target transcripts, leading to decreased gene expression. The purpose of this article was to determine whether TIA-1 plays a role in the regulation of endometrial cytokine and growth factor expression during the normal menstrual cycle and whether TIA-1 expression is altered in women with endometriosis. Eutopic endometrial tissue obtained from women without endometriosis (n = 30) and eutopic and ectopic endometrial tissues from women with endometriosis (n = 17) were immunostained for TIA-1. Staining intensities were evaluated by histological scores (HSCOREs). The regulation of endometrial TIA-1 expression by immune factors and steroid hormones was studied by treating primary cultured human endometrial stromal cells (HESCs) with vehicle, lipopolysaccharide, TNF-α, IL-6, estradiol, or progesterone, followed by protein blot analyses. HESCs were engineered to over- or underexpress TIA-1 to test whether TIA-1 regulates IL-6 or TNF-α expression in these cells. We found that TIA-1 is expressed in endometrial stromal and glandular cells throughout the menstrual cycle and that this expression is significantly higher in the perimenstrual phase. In women with endometriosis, TIA-1 expression in eutopic and ectopic endometrium was reduced compared with TIA-1 expression in eutopic endometrium of unaffected control women. Lipopolysaccharide and TNF-α increased TIA-1 expression in HESCs in vitro, whereas IL-6 or steroid hormones had no effect. In HESCs, down-regulation of TIA-1 resulted in elevated IL-6 and TNF-α expression, whereas TIA-1 overexpression resulted in decreased IL-6 and TNF-α expression. Endometrial

  3. Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion.

    Directory of Open Access Journals (Sweden)

    Carlos Estella

    Full Text Available Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs to degrade extracellular matrix (ECM proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs. The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion.

  4. Inhibition of Histone Deacetylase Activity in Human Endometrial Stromal Cells Promotes Extracellular Matrix Remodelling and Limits Embryo Invasion

    Science.gov (United States)

    Atkinson, Stuart P.; Quiñonero, Alicia; Martínez, Sebastián; Pellicer, Antonio; Simón, Carlos

    2012-01-01

    Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion. PMID:22291969

  5. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

    DEFF Research Database (Denmark)

    Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M

    2007-01-01

    The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas...

  6. RNA interference-mediated targeting of DKK1 gene expression in Ishikawa endometrial carcinoma cells causes increased tumor cell invasion and migration.

    Science.gov (United States)

    Yi, Nuo; Liao, Qin-Ping; Li, Zhen-Hua; Xie, Bao-Jiang; Hu, Yu-Hong; Yi, Wei; Liu, Min

    2013-09-01

    The Wnt signaling pathway plays an essential role in tumor invasion and migration. DKK1 functions as an important inhibitor of the pathway and represents a promising target for cancer therapy. The aim of the present study was to determine the role of DKK1 in endometrial carcinoma (EC) cell invasion and migration using RNA interference (RNAi) technology. Ishikawa EC cells were transfected at high efficiency with specific DKK1 siRNA. RT-PCR and western blot analysis were used to determine the mRNA and protein levels of DKK1, β-catenin and metalloproteinase 14 (MMP14) in siRNA-treated and -untreated cells. In addition, the invasion and migration of the EC cells were detected by invasion and migration assays. Transient transfection of DKK1 siRNA significantly inhibited the mRNA and protein levels of DKK1. Markedly increased cell invasion and migration was observed following treatment with DKK1 siRNA when compared with the negative control siRNA-treated and siRNA-untreated cells. The knockdown of DKK1 also elevated the mRNA and protein levels of β-catenin and MMP14 involved in the Wnt signaling pathway, indicating that targeting this gene may promote intracellular Wnt signal transduction and thus, accelerate EC cell invasion and migration in vitro. The RNAi-mediated targeting of DKK1 gene expression in Ishikawa EC cells resulted in increased tumor cell invasion and migration. DKK1 was identified as an inhibitor of EC cell invasion and migration via its novel role in the Wnt signaling pathway. Targeting DKK1 may therefore represent an effective anti-invasion and -migration strategy for the treatment of EC.

  7. Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium.

    Science.gov (United States)

    Flannery, Clare A; Fleming, Andrew G; Choe, Gina H; Naqvi, Hanyia; Zhang, Margaret; Sharma, Anu; Taylor, Hugh S

    2016-10-01

    Endometrial cancer develops during exposure to estrogen unopposed by progesterone. Traditional formulations for menopausal hormone therapy include a progestin in women with a uterus. However, progestin exposure increases breast cancer risk in postmenopausal women. Alternatives to progestin include bazedoxifene (BZA), a selective estrogen receptor modulator, which prevents estrogen induced endometrial hyperplasia in clinical trials. Molecular mechanisms responsible for BZA's antiproliferative effect are not fully elucidated. We profiled endometrial adenocarcinoma, hyperplasia, and normal proliferative endometrium for differential expression in genes known to be regulated by estrogens or progesterone. Fibroblast growth factor (FGF)18, a paracrine growth factor promoting epithelial proliferation, was significantly increased in adenocarcinoma. Progesterone represses FGF18 by inducing heart and neural crest derivatives expressed transcript 2 (HAND2) in stromal cells. Notably, we confirmed lower HAND2 mRNA in adenocarcinoma, along with higher FGF tyrosine kinase receptor 2 and E74-like factor 5, collectively promoting FGF18 activity. We hypothesized BZA reduces epithelial proliferation by inhibiting FGF18 synthesis in stromal cells. To determine whether BZA regulates FGF18, we treated primary stromal cells with BZA or vehicle. In vitro, BZA reduced FGF18, but did not affect, HAND2. CD1 female mice received either BZA, conjugated estrogen (CE), or combined BZA/CE for 8 weeks. CE-treated mice had nearly 3-fold higher FGF18 expression. In contrast, BZA-treated mice, alone or with CE, had similar FGF18 as controls. Unexpectedly, BZA, alone or with CE, reduced HAND2 more than 80%, differing from progesterone regulation. Reduction of FGF18 is a potential mechanism by which BZA reduces endometrial proliferation and hyperplasia induced by estrogens. However, BZA works independently of HAND2, revealing a novel mechanism for progestin-free hormone therapy in postmenopausal women.

  8. Proteomic analysis of human oral verrucous carcinoma

    African Journals Online (AJOL)

    Jane

    2011-10-05

    Oct 5, 2011 ... from tumour and adjacent normal oral mucosa of patients with OVC and oral squamous cell carcinoma. (OSCC) were separated with two ... node and implant metastasis can be found in infiltrative type and cystoid type ..... according to circadian rhythms in mouse liver (Wei et al.,. 2006). In the latter study, ...

  9. Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model.

    Science.gov (United States)

    Li, Hang-Wun Raymond; Li, Ying-Xing; Li, Tian-Tian; Fan, Hongjie; Ng, Ernest Hung-Yu; Yeung, William Shu-Biu; Ho, Pak-Chung; Lee, Kai-Fai

    2017-12-01

    Do both ulipristal acetate (UPA) and mifepristone inhibit embryo-endometrial attachment at concentrations corresponding to the emergency contraception (EC) dose? Both UPA and mifepristone at concentrations corresponding to the EC dose do not have an inhibitory effect on embryo implantation, although mifepristone at a higher concentration appeared to have such an effect. Levonorgestrel is commonly used for EC, but it only acts through inhibition of ovulation. UPA and mifepristone have higher efficacy as EC compared to levonorgestrel; while there is some suggestion that mifepristone may interfere with implantation, whether UPA has post-ovulatory action in inhibiting implantation is yet to be confirmed. An in vitro experimental study using trophoblastic spheroids made from JAr cell line as the embryo surrogate, and the Ishikawa cell line and primary human endometrial cells cultured to monolayer as the endometrial surrogate. The primary endometrial cells were collected from nine volunteer women in the mid-luteal phase with consent. The study was conducted in a university gynaecology unit. The JAr and Ishikawa cell lines (or primary endometrial cells) were treated with graded concentrations of UPA (0, 0.04, 0.4 and 4 μM) or mifepristone (0, 0.1, 1 and 10 μM) for 24 h. Embryo-endometrial attachment was studied using an in vitro JAr spheroid-endometrial co-culture model. Expressions of progesterone receptor, β-catenin and glycogen synthase kinase 3 β (GSK-3β) were studied with real-time RT-PCR and Western blotting, respectively. In the Ishikawa experiments, there was no significant difference in the JAr spheroid attachment rate after treatment with UPA at 0 (93.0%), 0.04 (93.6%), 0.4 (93.4%) and 4 (91.4%) μM concentrations (P > 0.05); the attachment rate was reduced after treatment with mifepristone only at 10 μM (79.8%, P endometrial cell experiments, again no significant difference was observed in the JAr spheroid attachment rate after treatment with UPA 4

  10. miR-152 inhibits proliferation of human endometrial cancer cells via inducing G2/M phase arrest by suppressing CDC25B expression.

    Science.gov (United States)

    Xie, Dan; Liang, Yijuan; Su, Yuanyuan; An, Yan; Qu, Pengpeng

    2018-01-17

    microRNA-152 (miR-152) is a tumor suppressor that is down-regulated in many cancers including endometrial cancer (EC). However, the underlying mechanism of action of miR-152 in EC is unclear. The aim of the present study was to evaluate the role of miR-152 on proliferation of human endometrial cancer cells. Herein, we found that miR-152 overexpression and CDC25B knockdown inhibited proliferative ability and induced G2/M phase arrest in KLE and HEC-1B cells. CDC25B was a target of miR-152. In addition, CDC25B overexpression rescued miR-152-induced proliferation inhibition and G2/M phase arrest in human endometrial cancer cells. The results indicated that miR-152 was a tumor suppressor in EC that inhibited proliferation of human endometrial cancer cells via inducing G2/M phase arrest by suppressing CDC25B expression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  11. The association between human papillomavirus and oropharyngeal squamous cell Carcinoma

    DEFF Research Database (Denmark)

    Walvik, Lena; Svensson, Amanda Björk; Friborg, Jeppe

    2016-01-01

    There is emerging evidence of the association between human papillomavirus and a subset of head and neck cancers. However, the role of human papillomavirus as a causal factor is still debated. This review addresses the association between human papillomavirus and oropharyngeal squamous cell...... carcinoma using the Bradford Hill criteria. The strength of the association is supported by, detection of human papillomavirus infection and antibodies prior to oropharyngeal squamous cell carcinoma. This is furthermore reinforced by the absence of human papillomavirus DNA in healthy tonsils....... The association is geographically consistent throughout the economically developed world. The presence and integration of high-risk human papillomavirus genome in tonsillar tumours, and expression of viral oncogenes, are specific and plausible. Analogous to human papillomavirus in cervical cancer, the rising...

  12. CARCINOMA OF THE LARYNX AND HUMAN PAPILLOMA VIRUS INFECTION

    Directory of Open Access Journals (Sweden)

    Georgi N. Nikolov

    2016-03-01

    Full Text Available Background: Laryngeal carcinoma is one of the most common form of head and neck cancer. During the last two decades, it has been recognized that this cancer is causally related to human papillomavirus (HPV. Objective: We presented a study on prevalence of human papilloma viruses (HPV in patients with laryngeal carcinoma. Methods: This study consists of 43 patients with laryngeal carcinoma who were diagnosed and treated with surgical techniques in Department of Otorhinolaryngology, University Hospital, Pleven, Bulgaria. Immunohistochemistry of p16INK4a and Ki-67 were used to prove the relationship between high-risk-HPV (HR-HPV and carcinogenesis. Results: Papilloma virus infection with high-risk oncogenic types of HPV was determined in more than 39.5% of surgically treated patients with histologically proven laryngeal cancer. HPV-induced carcinogenesis was assumed in 17 (13.9% of all patients whose spouses were operated from cervical cancer. The patients with HPV-positive laryngeal carcinoma were younger than the others in the group (8 years on average. Risk factors for development of HPV-associated laryngeal carcinoma were related to higher number of sexual partners and the practice of oral sex. Frequently, in patients with HPV-associated laryngeal carcinoma we find data for so-called “family’s carcinogenesis”. The possibility of appearance (either preceding or following the treatment of a second carcinoma and/or tumour recurrence is higher in HPV-positive laryngeal carcinomas. Conclusion: It is recommended to extend the diagnostic methods for laryngeal and hypo pharyngeal cancer with a routine search for high-risk oncogenic HPV strains.

  13. Differentiation of human umbilical cord Wharton's jelly-derived mesenchymal stem cells into endometrial cells.

    Science.gov (United States)

    Shi, Qin; Gao, JingWei; Jiang, Yao; Sun, Baolan; Lu, Wei; Su, Min; Xu, Yunzhao; Yang, Xiaoqing; Zhang, Yuquan

    2017-11-02

    Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are a novel and promising strategy for tissue engineering because of their ability to differentiate into many cell types. We characterized the differentiation of WJ-MSCs into endometrial epithelial cell (EEC)-like and endometrial stromal cell (ESC)-like cells and assessed the effect of 17β-estradiol and 8-Br-cAMP on the differentiation system. WJ-MSCs were treated in two ways to differentiate into EEC-like and ESC-like cells respectively: cocultured with ESCs in control/differentiation medium (17β-estradiol, growth factors); and cultured in control/differentiation medium (8-Br-cAMP alone or 8-Br-cAMP plus 17β-estrogen and growth factors). Three signaling pathway inhibitors (SB203580, PD98059, H89) were used to investigate the mechanism of WJ-MSC differentiation into ESC-like cells. Immunofluorescence, western blot and flow cytometry analyses were used to analyze expression of epithelial markers and stromal cell markers. Enzyme-linked immunosorbent assays were used to test the production of secretory proteins associated with the differentiation of ESC-like cells. 17β-estradiol at 1 μM downregulated vimentin and CD13 and upregulated cytokeratin and CD9 proteins, promoting the differentiation of WJ-MSCs into EEC-like cells in the coculture system. 8-Br-cAMP at 0.5 mM upregulated vimentin and CD13 and downregulated CK and CD9, promoting the differentiation of WJ-MSCs into ESC-like cells. Prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1) were upregulated and the protein kinase A (PKA) signaling pathway was activated, whereas extracellular signal-regulated (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) were not affected. 17β-estradiol at 1 μM is a good inducer for facilitating the differentiation of WJ-MSCs into EEC-like cells. 8-Br-cAMP plus estrogen and growth factors can induce the differentiation of WJ-MSCs into ESC-like cells. During the differentiation of WJ

  14. Human Three-Dimensional Endometrial Epithelial Cell Model To Study Host Interactions with Vaginal Bacteria and Neisseria gonorrhoeae.

    Science.gov (United States)

    Łaniewski, Paweł; Gomez, Adriana; Hire, Geoffrey; So, Magdalene; Herbst-Kralovetz, Melissa M

    2017-03-01

    Colonization of the endometrium by pathogenic bacteria ascending from the lower female reproductive tract (FRT) is associated with many gynecologic and obstetric health complications. To study these host-microbe interactions in vitro, we developed a human three-dimensional (3-D) endometrial epithelial cell (EEC) model using the HEC-1A cell line and the rotating wall vessel (RWV) bioreactor technology. Our model, composed of 3-D EEC aggregates, recapitulates several functional/structural characteristics of human endometrial epithelial tissue, including cell differentiation, the presence of junctional complexes/desmosomes and microvilli, and the production of membrane-associated mucins and Toll-like receptors (TLRs). TLR function was evaluated by exposing the EEC aggregates to viral and bacterial products. Treatment with poly(I·C) and flagellin but not with synthetic lipoprotein (fibroblast-stimulating lipoprotein 1 [FSL-1]) or lipopolysaccharide (LPS) significantly induced proinflammatory mediators in a dose-dependent manner. To simulate ascending infection, we infected EEC aggregates with commensal and pathogenic bacteria: Lactobacillus crispatus, Gardnerella vaginalis, and Neisseria gonorrhoeae All vaginal microbiota and N. gonorrhoeae efficiently colonized the 3-D surface, localizing to crevices of the EEC model and interacting with multiple adjacent cells simultaneously. However, only infection with pathogenic N. gonorrhoeae and not infection with the other bacteria tested significantly induced proinflammatory mediators and significant ultrastructural changes to the host cells. The latter observation is consistent with clinical findings and illustrated the functional specificity of our system. Additionally, we highlighted the utility of the 3-D EEC model for the study of the pathogenesis of N. gonorrhoeae using a well-characterized ΔpilT mutant. Overall, this study demonstrates that the human 3-D EEC model is a robust tool for studying host

  15. Risks of Endometrial Cancer Screening

    Science.gov (United States)

    ... Treatment Endometrial Cancer Prevention Endometrial Cancer Screening Research Endometrial Cancer Screening (PDQ®)–Patient Version What is screening? ... These are called diagnostic tests . General Information About Endometrial Cancer Key Points Endometrial cancer is a disease ...

  16. Quantitative diffusion-weighted MRI parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma

    NARCIS (Netherlands)

    Schouten, C.S.; Graaf, P. de; Bloemena, E.; Witte, B.I.; Braakhuis, B.J.; Brakenhoff, R.H.; Leemans, C.R.; Castelijns, J.A.; Bree, R. de

    2015-01-01

    BACKGROUND AND PURPOSE: Patients with human papillomavirus-positive oropharyngeal squamous cell carcinomas have a better survival rate than those with human papillomavirus-negative oropharyngeal squamous cell carcinomas. DWI characterizes biologically relevant tumor features, and the generated ADC

  17. Endometrial Cancer

    Science.gov (United States)

    ... healthy lifestyle is recommended after cancer treatment. Several studies have found that obesity, high blood pressure, and diabetes can contribute to long-term health risks for women with type 1 endometrial cancer. A healthy diet and regular exercise can help ...

  18. Quantitative analysis of expression level of estrogen and progesterone receptors and VEGF genes in human endometrial stromal cells after treatment with nicotine.

    Science.gov (United States)

    Totonchi, Hamidreza; Miladpour, Behnoosh; Mostafavi-Pour, Zohreh; Khademi, Fatemeh; Kasraeian, Maryam; Zal, Fatemeh

    2016-10-01

    Cigarette smoke is a complex mixture of toxic chemicals, including nicotine, carbon monoxide, and several recognized carcinogens and mutagens. Nicotine has a direct disturbing influence on steroid hormones (estrogen and progesterone), which are essential components of the female reproductive system, but the effect of nicotine on the hormone receptors is not yet clear. The aim of this study was to elucidate the effect of nicotine on the expression of estrogen receptor (ER), progesterone receptor (PR), and vascular endothelial growth factor (VEGF) in endometrial stromal cells. Expression levels of PR, ER, and VEGF in human endometrial stromal primary cells treated with nicotine (0, 10 -11 , 10 -8 , and 10 -6  μM) for 24 h were measured by quantitative real-time PCR. MTT assay demonstrated that nicotine decreased cell viability in a dose-dependent manner. Real-time PCR data showed that despite decrease in ER expression in the nicotine-treated groups compared with the control, nicotine exerted an increased inhibitory effect on PR expression compared to that on ER expression. VEGF mRNA expression in nicotine-treated endometrial stromal cells was increased. The results from this study provide novel evidence for inhibitory effects of nicotine on steroid hormones receptor expression in human primary endometrial cells. Also, our data suggest that nicotine might have angiogenesis effects on these cells.

  19. Differentiation of human endometrial stem cells into endothelial-like cells on gelatin/chitosan/bioglass nanofibrous scaffolds.

    Science.gov (United States)

    Shamosi, Atefeh; Mehrabani, Davood; Azami, Mahmoud; Ebrahimi-Barough, Somayeh; Siavashi, Vahid; Ghanbari, Hossein; Sharifi, Esmaeel; Roozafzoon, Reza; Ai, Jafar

    2017-02-01

    The capacity of gelatin/chitosan/bioactive glass nanopowders (GEL/CS/BGNPs) scaffolds was investigated for increasing human endometrial stem cells (hEnSCs) differentiation into the endothelial cells in the presence of angiogenic factors. GEL/CS nanofibrous scaffold with different contents of BGNPs were fabricated and assessed. Expression of endothelial markers (CD31, vascular endothelial cadherin (VE-cadherin), and KDR) in differentiated cells was evaluated. Results showed the diameter of nanofiber increases with decreasing the BG content in GEL/CS scaffolds. Moreover, in vitro study indicated that the GEL/CS/BGNPs scaffold with 1.5% BGNPs content provided a suitable three-dimensional structure for endothelial cells differentiation. Thus, the GEL/CS/BGNPs scaffold can be recommended for blood vessels repair.

  20. Effects of ulipristal acetate on human embryo attachment and endometrial cell gene expression in an in vitro co-culture system.

    Science.gov (United States)

    Berger, C; Boggavarapu, N R; Menezes, J; Lalitkumar, P G L; Gemzell-Danielsson, K

    2015-04-01

    Does ulipristal acetate (UPA) used for emergency contraception (EC) interfere with the human embryo implantation process? UPA, at the dosage used for EC, does not affect human embryo implantation process, in vitro. A single pre-ovulatory dose of UPA (30 mg) acts by delaying or inhibiting ovulation and is recommended as first choice among emergency contraceptive pills due to its efficacy. The compound has also been demonstrated to have a dose-dependent effect on the endometrium, which theoretically could impair endometrial receptivity but its direct action on human embryo implantation has not yet been studied. Effect of UPA on embryo implantation process was studied in an in vitro endometrial construct. Human embryos were randomly added to the cultures and cultured for 5 more days with UPA (n = 10) or with vehicle alone (n = 10) to record the attachment of embryos. Endometrial biopsies were obtained from healthy, fertile women on cycle day LH+4 and stromal and epithelial cells were isolated. A three-dimensional in vitro endometrial co-culture system was constructed by mixing stromal cells with collagen covered with a layer of epithelial cells and cultured in progesterone containing medium until confluence. The treatment group received 200 ng/ml of UPA. Healthy, viable human embryos were placed on both control and treatment cultures. Five days later the cultures were tested for the attachment of embryos and the 3D endometrial constructs were analysed for endometrial receptivity markers by real-time PCR. There was no significant difference in the embryo attachment rate between the UPA treated group and the control group as 5 out of 10 human embryos exposed to UPA and 7 out of 10 embryos in the control group attached to the endometrial cell surface (P = 0.650). Out of 17 known receptivity genes studied here, only 2 genes, HBEGF (P = 0.009) and IL6 (P = 0.025) had a significant up-regulation and 4 genes, namely HAND2 (P = 0.003), OPN (P = 0.003), CALCR (P = 0.016) and

  1. Is human papillomavirus involved in laryngeal neuroendocrine carcinoma?

    NARCIS (Netherlands)

    Halmos, Gyorgy B; van der Laan, Tom P; van Hemel, Bettien M; Dikkers, Frederik G; Slagter-Menkema, Lorian; van der Laan, Bernard F A M; Schuuring, Ed

    The purpose of this study was to detect human papillomavirus (HPV) infection in laryngeal neuroendocrine carcinoma (LNEC) and to explore the possible relationship between HPV-induced malignant transformation and prognosis in LNEC. Ten cases of LNEC from a tertiary referral hospital were

  2. Complement C3 and decay-accelerating factor expression levels are modulated by human chorionic gonadotropin in endometrial compartments during the implantation window.

    Science.gov (United States)

    Palomino, Wilder Alberto; Argandoña, Felipe; Azúa, Rodrigo; Kohen, Paulina; Devoto, Luigi

    2013-09-01

    The control of complement activation in the embryo-maternal environment has been demonstrated to be critical for embryo survival. Complement proteins are expressed in the human endometrium; however, the modulation of this expression by embryo signals has not been explored. To assess the expression of complement proteins in response to human chorionic gonadotropin (hCG), we designed an experimental study using in vivo and in vitro models. Twelve fertile women were treated with hCG or left untreated during the mid-luteal phase, and an endometrial biopsy was performed 24 hours later. The localizations of C3, membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55), and protectin (CD59) were assessed by immunohistochemistry, and the messenger RNA (mRNA) levels of these proteins were quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in cells harvested from endometrial compartments using laser capture microdissection. Endometrial explants were cultured with or without hCG for 24 hours, and the C3 and DAF protein levels were measured by Western blotting. Elevated C3 mRNA levels in stromal cells and elevated DAF levels in epithelial luminal cells were detected after hCG treatment. In the endometrial explant model, the progesterone receptor antagonist RU486 inhibited the increases in the levels of C3 and DAF in response to hCG. The findings of this study indicate that hCG plays a role in embryo-endometrium communication and affects the expression of complement proteins in endometrial compartments during the implantation window.

  3. Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK dependent pathway in human endometrial cancer cells.

    Directory of Open Access Journals (Sweden)

    Chunxiao Zhou

    Full Text Available Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2 induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs, and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.

  4. Identification of differences in gene expression in primary cell cultures of human endometrial epithelial cells and trophoblast cells following their interaction

    DEFF Research Database (Denmark)

    Høgh, Mette; Islin, Henrik; Møller, Charlotte

    2006-01-01

    The interaction between the cell types was simulated in vitro by growing primary cell cultures of human endometrial epithelial cells and trophoblast cells together (co-culture) and separately (control cultures). Gene expression in the cell cultures was compared using the Differential Display method and confirmed...... using a modified Northern Blot method. Results Twelve transcripts were identified as being differentially expressed following the interaction between trophoblast and endometrial cells. Some of these sequences show homology to known human genes while other sequences are coding for potential novel genes......: (1) one sequence was homologous to the to Homer 1 gene, (2) one identical to the mRNA for XP-G factor, (3) one similar to a hypothetical protein, (4) transcripts showing homologies to a mRNA coding for a cellular proapoptotic protein, and (5) sequences homologous to regions on human chromosomes 5...

  5. Rapid induction of senescence in human cervical carcinoma cells

    Science.gov (United States)

    Goodwin, Edward C.; Yang, Eva; Lee, Chan-Jae; Lee, Han-Woong; Dimaio, Daniel; Hwang, Eun-Seong

    2000-09-01

    Expression of the bovine papillomavirus E2 regulatory protein in human cervical carcinoma cell lines repressed expression of the resident human papillomavirus E6 and E7 oncogenes and within a few days caused essentially all of the cells to synchronously display numerous phenotypic markers characteristic of cells undergoing replicative senescence. This process was accompanied by marked but in some cases transient alterations in the expression of cell cycle regulatory proteins and by decreased telomerase activity. We propose that the human papillomavirus E6 and E7 proteins actively prevent senescence from occurring in cervical carcinoma cells, and that once viral oncogene expression is extinguished, the senescence program is rapidly executed. Activation of endogenous senescence pathways in cancer cells may represent an alternative approach to treat human cancers.

  6. Biomarkers of endometrial cancer and related gynaecological malignancies

    OpenAIRE

    Seeber, L.M.S.

    2010-01-01

    In the Western World, endometrial cancer is the most common malignancy of the female genital tract. Endometrioid endometrial carcinoma (EEC or Type I tumour), accounts for approximately 75% of cases. Type II tumours, of which uterine papillary serous carcinoma (UPSC) is the most common subtype, are less common. Since classification as EEC or UPSC has therapeutic and prognostic implications, it is important to make the proper diagnosis. UPSC share their aggressive clinical behaviour and their ...

  7. 21 CFR 884.1175 - Endometrial suction curette and accessories.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Endometrial suction curette and accessories. 884.1175 Section 884.1175 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Diagnostic Devices § 884.1175 Endometrial suction curette and accessories. (a) Identification. An endometrial...

  8. Outcome of endometrial cancer stage IIIA with adnexa or serosal involvement only

    NARCIS (Netherlands)

    Jobsen, Jan J.; Naudin ten Cate, Lambert; Lybeert, Marnix L.M.; Scholten, Astrid; van der Steen-Banasik, Elzbieta M.; van der Palen, Jacobus Adrianus Maria; Stenfert Kroese, Marika C.; Slot, Annerie; Schutter, Eltjo M.; Siesling, Sabine

    2011-01-01

    Objective. The aim of this study is to look at possible differences in outcome between serosa and adnexal involvement stage IIIA endometrial carcinoma. Methods. 67 patients with stage IIIA endometrial carcinoma were included, 46 with adnexal involvement and 21 with serosa. A central

  9. Telomerase Activity in Human Ovarian Carcinoma

    Science.gov (United States)

    Counter, Christopher M.; Hirte, Hal W.; Bacchetti, Silvia; Harley, Calvin B.

    1994-04-01

    Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes telomeric DNA, is not detected in normal somatic cells and that telomeres shorten with replicative age. In cells immortalized in vitro, activation of telomerase apparently stabilizes telomere length, preventing a critical destabilization of chromosomes, and cell proliferation continues even when telomeres are short. In vivo, telomeres of most tumors are shorter than telomeres of control tissues, suggesting an analogous role for the enzyme. To assess the relevance of telomerase and telomere stability in the development and progression of tumors, we have measured enzyme activity and telomere length in metastatic cells of epithelial ovarian carcinoma. We report that extremely short telomeres are maintained in these cells and that tumor cells, but not isogenic nonmalignant cells, express telomerase. Our findings suggest that progression of malignancy is ultimately dependent upon activation of telomerase and that telomerase inhibitors may be effective antitumor drugs.

  10. Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

    Science.gov (United States)

    2015-10-01

    deficient endometrial cancer, and colorectal carcinoma.19 Unanswered Questions At present, it remains unclear how to best identify patients who will... endometrial can- cer123 and in combination with paclitaxel in gastric cancer with ATM deficiency.124 Studies including PALB2-mutated OC and pancreatic cancer...abstr TPS5619) 15. Lehmann BD, Bauer JA, Chen X, et al: Iden- tification of human triple-negative breast cancer subtypes and preclinical models for

  11. Syndecan-1 Acts as an Important Regulator of CXCL1 Expression and Cellular Interaction of Human Endometrial Stromal and Trophoblast Cells

    Directory of Open Access Journals (Sweden)

    Dunja Maria Baston-Buest

    2017-01-01

    Full Text Available Successful implantation of the embryo into the human receptive endometrium is substantial for the establishment of a healthy pregnancy. This study focusses on the role of Syndecan-1 at the embryo-maternal interface, the multitasking coreceptor influencing ligand concentration, release and receptor presentation, and cellular morphology. CXC motif ligand 1, being involved in chemotaxis and angiogenesis during implantation, is of special interest as a ligand of Syndecan-1. Human endometrial stromal cells with and without Syndecan-1 knock-down were decidualized and treated with specific inhibitors to evaluate signaling pathways regulating CXC ligand 1 expression. Western blot analyses of MAPK and Wnt members were performed, followed by analysis of spheroid interactions between human endometrial cells and extravillous trophoblast cells. By mimicking embryo contact using IL-1β, we showed less ERK and c-Jun activation by depletion of Syndecan-1 and less Frizzled 4 production as part of the canonical Wnt pathway. Additionally, more beta-catenin was phosphorylated and therefore degraded after depletion of Syndecan-1. Secretion of CXC motif ligand 1 depends on MEK-1 with respect to Syndecan-1. Regarding the interaction of endometrial and trophoblast cells, the spheroid center-to-center distances were smaller after depletion of Syndecan-1. Therefore, Syndecan-1 seems to affect signaling processes relevant to signaling and intercellular interaction at the trophoblast-decidual interface.

  12. Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.

    Science.gov (United States)

    Borodkina, Aleksandra V; Shatrova, Alla N; Deryabin, Pavel I; Grukova, Anastasiya A; Nikolsky, Nikolay N; Burova, Elena B

    2016-01-01

    Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-α, we confirmed implication of both ATM and p53 in H(2)O(2)-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs. ATM inhibition allowed H(2)O(2)-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H(2)O(2)-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy.

  13. Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos.

    Directory of Open Access Journals (Sweden)

    Charlotte H E Weimar

    Full Text Available BACKGROUND: The aetiology of recurrent miscarriage (RM remains largely unexplained. Women with RM have a shorter time to pregnancy interval than normally fertile women, which may be due to more frequent implantation of non-viable embryos. We hypothesized that human endometrial stromal cells (H-EnSCs of women with RM discriminate less effectively between high-and low-quality human embryos and migrate more readily towards trophoblast spheroids than H-EnSCs of normally fertile women. METHODOLOGY/PRINCIPAL FINDINGS: Monolayers of decidualized H-EnSCs were generated from endometrial biopsies of 6 women with RM and 6 fertile controls. Cell-free migration zones were created and the effect of the presence of a high-quality (day 5 blastocyst, n = 13, a low-quality (day 5 blastocyst with three pronuclei or underdeveloped embryo, n = 12 or AC-1M88 trophoblast cell line spheroid on H-ESC migratory activity was analyzed after 18 hours. In the absence of a spheroid or embryo, migration of H-EnSCs from fertile or RM women was similar. In the presence of a low-quality embryo in the zone, the migration of H-EnSCs of control women was inhibited compared to the basal migration in the absence of an embryo (P<0.05 and compared to the migration in the presence of high-quality embryo (p<0.01. Interestingly, the migratory response H-EnSCs of women with RM did not differ between high- and low-quality embryos. Furthermore, in the presence of a spheroid their migration was enhanced compared to the H-EnSCs of controls (p<0.001. CONCLUSIONS: H-EnSCs of fertile women discriminate between high- and low-quality embryos whereas H-EnSCs of women with RM fail to do so. H-EnSCs of RM women have a higher migratory response to trophoblast spheroids. Future studies will focus on the mechanisms by which low-quality embryos inhibit the migration of H-EnSCs and how this is deregulated in women with RM.

  14. Growth regulation by estrogen in breast cancer 1 (GREB1) is a novel progesterone-responsive gene required for human endometrial stromal decidualization.

    Science.gov (United States)

    Camden, Alison J; Szwarc, Maria M; Chadchan, Sangappa B; DeMayo, Francesco J; O'Malley, Bert W; Lydon, John P; Kommagani, Ramakrishna

    2017-09-01

    Is Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) required for progesterone-driven endometrial stromal cell decidualization? GREB1 is a novel progesterone-responsive gene required for progesterone-driven human endometrial stromal cell (HESC) decidualization. Successful establishment of pregnancy requires HESCs to transform from fibroblastic to epithelioid cells in a process called decidualization. This process depends on the hormone progesterone, but the molecular mechanisms by which it occurs have not been determined. Primary and transformed HESCs in which GREB1 expression was knocked down were decidualized in culture for up to 6 days. Wild-type and progesterone receptor (PR) knockout mice were treated with progesterone, and their uteri were assessed for levels of GREB1 expression. Analysis of previous data included data mining of expression profile data sets and in silico transcription factor-binding analysis. Endometrial biopsies obtained from healthy women of reproductive age during the proliferative phase (Days 8-12) of their menstrual cycle were used for isolating HESCs. Experiments were carried out with early passage (no more than four passages) HESCs isolated from at least three subjects. Transcript levels of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were detected by quantitative RT-PCR as readouts for HESC decidualization. Cells were also imaged by phase-contrast microscopy. To assess the requirement for GREB1, PR and SRC-2, cells were transfected with specifically targeted small interfering RNAs. Results are shown as mean and SE from three replicates of one representative patient-derived primary endometrial cell line. Experiments were also conducted with transformed HESCs. Progesterone treatment of mice and transformed HESCs led to an ~5-fold (5.6 ± 0.81, P endometrial function and dysfunction should be assessed by using knock-out mouse models. Identification and functional analysis of

  15. Selective assembly of laminin variants by human carcinoma cells

    DEFF Research Database (Denmark)

    Wewer, U M; Wayner, E A; Hoffstrom, B G

    1994-01-01

    BACKGROUND: The laminins are heterotrimeric basement membrane glycoproteins. Eight subunits that can be assembled into laminins have been characterized and are known as: A, B1, B2, S, M, K, B2t, B1k laminin chains. Although many neoplastic cells secrete laminins and some of them even assemble...... basement membranes, the pattern of production of various laminin subunits remains to be explored. EXPERIMENTAL DESIGN: The expression of laminin was examined in several human carcinoma cells using a panel of specific cDNA probes as well as polyclonal and chain specific monoclonal antibodies....... For this purpose a human laminin S chain 2 kb cDNA was isolated and characterized and used together with existing probes for laminin chains. RESULTS: All carcinoma cell lines had a high level of expression of three light chains (B1, S and B2) mRNA. In contrast, the heavy chains of laminin, A and M, were expressed...

  16. Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients

    Science.gov (United States)

    Berg, Anna; Hoivik, Erling A.; Mjøs, Siv; Holst, Frederik; Werner, Henrica M. J.; Tangen, Ingvild L.; Taylor-Weiner, Amaro; Gibson, William J.; Kusonmano, Kanthida; Wik, Elisabeth; Trovik, Jone; Halle, Mari K.; Øyan, Anne M.; Kalland, Karl-Henning; Cherniack, Andrew D.; Beroukhim, Rameen; Stefansson, Ingunn; Mills, Gordon B.; Krakstad, Camilla; Salvesen, Helga B.

    2015-01-01

    Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions. PMID:25415225

  17. The regulation and function of the Forkhead transcription factor, Forkhead box O1, is dependent on the progesterone receptor in endometrial carcinoma

    NARCIS (Netherlands)

    E.C. Ward (Erin); A.V. Hoekstra (Anna); L.J. Blok (Leen); P. Hanifi-Moghaddam (Payman); J.R. Lurain (John); D.K. Singh (Diljeet); B.M. Buttin (Barbara); J.C. Schink (Julian); J.J. Kim (Julie)

    2008-01-01

    textabstractIn many type I endometrial cancers, the PTEN gene is inactivated, which ultimately leads to constitutively active Akt and the inhibition of Forkhead box O1 (FOXO1), a member of the FOXO subfamily of Forkhead/winged helix family of transcription factors. The expression, regulation, and

  18. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition

    NARCIS (Netherlands)

    Eggink, Florine A.; Van Gool, Inge C.; Leary, Alexandra; Pollock, Pamela M.; Crosbie, Emma J.; Mileshkin, Linda; Jordanova, Ekaterina S.; Adam, Julien; Freeman-Mills, Luke; Church, David N.; Creutzberg, Carien L.; De Bruyn, Marco; Nijman, Hans W.; Bosse, Tjalling

    2017-01-01

    High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs

  19. Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors.

    Science.gov (United States)

    Merritt, Melissa A; Strickler, Howard D; Einstein, Mark H; Yang, Hannah P; Sherman, Mark E; Wentzensen, Nicolas; Brouwer-Visser, Jurriaan; Cossio, Maria Jose; Whitney, Kathleen D; Yu, Herbert; Gunter, Marc J; Huang, Gloria S

    2016-06-01

    Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology. We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively. In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01). These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.

  20. Type I Versus Type II Endometrial Cancer

    DEFF Research Database (Denmark)

    Noer, Mette Calundann; Antonsen, Sofie Leisby; Ottesen, Bent

    2018-01-01

    OBJECTIVE: Two distinct types of endometrial carcinoma (EC) with different etiology, tumor characteristics, and prognosis are recognized. We investigated if the prognostic impact of comorbidity varies between these 2 types of EC. Furthermore, we studied if the recently developed ovarian cancer...

  1. Endometrial cysteine-rich secretory protein 3 is inhibited by human chorionic gonadotrophin, and is increased in the decidua of tubal ectopic pregnancy

    DEFF Research Database (Denmark)

    Horne, A W; Duncan, W C; King, A E

    2009-01-01

    gestation-matched women undergoing surgical termination of pregnancy (n = 8), evacuation of uterus for miscarriage (n = 6) and surgery for EP (n = 11) was subjected to quantitative RT-PCR, morphological assessment, immunohistochemistry and western blot analysis. Sera were analysed for progesterone and human...... chorionic gonadotrophin (hCG) levels. Immortalized endometrial epithelial cells were cultured with physiological concentrations of hCG. CRISP-3 mRNA and protein expression were greater in endometrium from ectopic when compared with intrauterine pregnancies (P ... to epithelium and granulocytes of endometrium. CRISP-3 serum concentrations were not different in women with ectopic compared with intrauterine pregnancies. CRISP-3 expression in endometrium was not related to the degree of decidualization or to serum progesterone levels. Endometrial CRISP-3 expression...

  2. α-Terthienylmethanol, isolated from Eclipta prostrata, induces apoptosis by generating reactive oxygen species via NADPH oxidase in human endometrial cancer cells.

    Science.gov (United States)

    Lee, Jae-Seung; Ahn, Ji-Hye; Cho, Yoon-Jin; Kim, Ha-Yeong; Yang, Yeong-In; Lee, Kyung-Tae; Jang, Dae-Sik; Choi, Jung-Hye

    2015-07-01

    Eclipta prostrate L. (syn. E. alba Hassk), commonly known as False Daisy, has been used in traditional medicine in Asia to treat a variety of diseases, including cancer. Although an anti-tumor effect has been suggested for E. prostrata, the exact anti-tumor effects and underlying molecular mechanisms of its bioactive compounds are poorly understood. The aim of this study was to identify compounds with anti-cancer activity from E. prostrata and to investigate their mechanism of action. To assess cell viability, cell cycle progression, and apoptosis, we performed MTT assays and FACS analysis using Annexin and PI staining. We also investigated reactive oxygen species (ROS) production and caspase activation using flow cytometry and Western blot analysis, respectively. Cytosolic translocation of cytochrome c was measured using an ELISA kit. Antioxidants, MAPK signaling inhibitors, NADPH oxidase inhibitors, and siRNA were used to elucidate the molecular mechanism of action of the compound. We isolated five terthiophenes from the n-hexane fraction of E. prostrata; of these, α-terthienylmethanol possessed potent cytotoxic activity against human endometrial cancer cells (Hec1A and Ishikawa) (IC50endometrial cancer cells. Overall, these results suggest that α-terthienylmethanol, a naturally occurring terthiophene isolated from E. prostrata, induces apoptosis in human endometrial cancer cells by ROS production, partially via NADPH oxidase. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo

    Science.gov (United States)

    Almomen, Aliyah; Jarboe, Elke A.; Dodson, Mark K.; Peterson, C. Matthew; Owen, Shawn C.; Janát-Amsbury, Margit M.

    2016-01-01

    Purpose The increasing incidence of endometrial cancer (EC), in younger age at diagnosis, calls for new tissue-sparing treatment options. This work aims to evaluate the potential of imiquimod (IQ) in the treatment of low-grade EC. Methods Effects of IQ on the viabilities of Ishikawa and HEC-1A cells were evaluated using MTT assay. The ability of IQ to induce apoptosis was evaluated by testing changes in caspase 3/7 levels and expression of cleaved caspase-3, using luminescence assay and western blot. Apoptosis was confirmed by flow cytometry and the expression of cleaved PARP. Western blot was used to evaluate the effect of IQ on expression levels of Bcl-2, Bcl-xL, and BAX. Finally, the in vivo efficacy of IQ was tested in an EC mouse model. Results There was a decrease in EC cell viability following IQ treatment as well as increased caspase 3/7 activities, cleaved caspase-3 expression, and Annexin-V/ 7AAD positive cell population. Western blot results showed the ability of IQ in cleaving PARP, decreasing Bcl-2 and Bcl-xL expressions, but not affecting BAX expression. In vivo study demonstrated IQ’s ability to inhibit EC tumor growth and progression without significant toxicity. Conclusions IQ induces apoptosis in low-grade EC cells in vitro, probably through its direct effect on Bcl-2 family protein expression. In, vivo, IQ attenuates EC tumor growth and progression, without an obvious toxicity. Our study provides the first building block for the potential role of IQ in the non-surgical management of low-grades EC and encouraging further investigations. PMID:27245465

  4. [Regulation of [12Asp]K-ras4B on transcriptional activity of estrogen receptor in endometrial carcinoma HEC-1A cell lines].

    Science.gov (United States)

    Gui, Li-ming; Wei, Li-hui; Xu, Ming-xu; Wang, Jian-liu; Zhong, Ying-cheng; Li, Xiao-ping; Tu, Zheng; Sun, Peng-ming; Ma, Da-long

    2004-01-01

    To investigate the effect of mutant-type [(12)Asp]K-ras4B gene on the expression of estrogen receptor (ER) alpha and beta and their transcriptional activity as a transcription factor in endometrial carcinoma HEC-1A cell line. (1) Effect of [(12)Asp]K-ras4B on the expression of ER alpha and beta were determined using Western blot assay. (2) Eukaryotic expression plasmid pGL3-luciferase-ERE containing luciferase report gene and estrogen receptor element (ERE) was constructed, and co-transfected into NIH3T3 and HEC-1A cell lines with pEGFP-N1 to examine the effect of [(12)Asp]K-ras4B on ER transcription that is regulated by estradiol. In addition, they were transfected into pSV5-HER0 (containing full length wide type ERalpha cDNA) and pCMV-rafS621A (inhibiting raf kinase) plasmids to test the effect of [(12)Asp]K-ras4B/raf signal pathway on transcriptional activity of ER proteins. (1) Protein level of ERs expressed in pcDI transfected control cells was low while it was increased for 3.6-fold (97 +/- 25, 349 +/- 67, P ras4B NIH3T3 cells after transfection. (2) In pcDI-[(12)Asp]K-ras4B NIH3T3 cells, the ratios for ERalpha and and ERbeta levels before transfection of rafS621A plasmids to that after the transfection, were 2.4:1 (724 +/- 45, 310 +/- 46, P HEC-1A cells, these ratios were 2.1:1 (566 +/- 22, 279 +/- 30, P ras4B NIH3T3 cells, 19-fold (141 +/- 39, 2644 +/- 331, P HEC-1A cells, respectively, when compared with those in the absence of E(2). (4) In pSV5-HER0 transfected pcDI-[(12)Asp] K-ras4B NIH3T3 cells and HEC-1A cells, compared to the untransfected cells, the ER transcriptional activity in the transfected cells increased markedly. The luciferase activity was increased for 8-fold (1048 +/- 91, 8099 +/- 452, P HEC-1A cells and pcDI-[(12)Asp]K-ras4B NIH3T3 cells. The ratio of luciferase activities in pcDI-[(12)Asp]K-ras4B NIH3T3 and HEC-1A cells, before and after transfection was 7.8:1 (1184 +/- 168, 152 +/- 27, P ras4B can enhance the expression of ERalpha and

  5. Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b

    Directory of Open Access Journals (Sweden)

    Brosens Jan J

    2009-07-01

    Full Text Available Abstract Background Coordinated differentiation of the endometrial compartments in the second half of the menstrual cycle is a prerequisite for the establishment of pregnancy. Endometrial stromal cells (ESC decidualize under the influence of ovarian progesterone to accommodate implantation of the blastocyst and support establishment of the placenta. Studies into the mechanisms of decidualization are often hampered by the lack of primary ESC. Here we describe a novel immortalized human ESC line. Methods Primary ESC were immortalized by the transduction of telomerase. The resultant cell line, termed St-T1b, was characterized for its morphological and biochemical properties by immunocytochemistry, RT-PCR and immunoblotting. Its progestational response was tested using progesterone and medroxyprogesterone acetate with and without 8-Br-cAMP, an established inducer of decidualization in vitro. Results St-T1b were positive for the fibroblast markers vimentin and CD90 and negative for the epithelial marker cytokeratin-7. They acquired a decidual phenotype indistinguishable from primary ESC in response to cAMP stimulation. The decidual response was characterized by transcriptional activation of marker genes, such as PRL, IGFBP1, and FOXO1, and enhanced protein levels of the tumor suppressor p53 and the metastasis suppressor KAI1 (CD82. Progestins alone had no effect on St-T1b cells, but medroxyprogesterone acetate greatly enhanced the cAMP-stimulated expression of IGFBP-1 after 3 and 7 days. Progesterone, albeit more weakly, also augmented the cAMP-induced IGFBP-1 production but only after 7 days of treatment. The cell line remained stable in continuous culture for more than 150 passages. Conclusion St-T1b express the appropriate phenotypic ESC markers and their decidual response closely mimics that of primary cultures. Decidualization is efficiently induced by cAMP analog and enhanced by medroxyprogesterone acetate, and, to a lesser extent, by natural

  6. Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding.

    Directory of Open Access Journals (Sweden)

    Ozlem Guzeloglu Kayisli

    Full Text Available Use of long-acting progestin only contraceptives (LAPCs offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s in human endometrial stromal cells (HESCs. Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2 or E2+ medroxyprogesterone acetate (MPA or E2+ etonogestrel (ETO or E2+ progesterone (P4 were analyzed by quantitative Real-time (q-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA treated women and ovariectomized guinea pigs (GPs treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR

  7. Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer.

    Science.gov (United States)

    Cai, Dongge; Sun, Hongli; Qi, Yanhua; Zhao, Xiaogui; Feng, Minjuan; Wu, Xiaoling

    2016-11-01

    Metformin is a well-tolerated biguanide drug used for decades to treat type 2 diabetes mellitus. In recent years, long-term administration of metformin has been found to reduce carcinogenic risk for cancers derived from various tissues. However, its cellular and molecular mechanisms of anticancer action in the endometrial cancer (EC) have not yet been fully elucidated. Sixty patients diagnosed as endometrial carcinoma were grouped into (n = 30) and non-treatment mixed (n = 30) for analysis. Thirty healthy donors are control groups. We attempt to investigate the interaction of metformin, insulin-like growth factor 1 (IGF-1) expression, and phosphorylated mammalian target of rapamycin (p-mTOR) and AMP-activated protein kinase (p-AMPK). We found that high IGF-1 plasma concentrations in women with EC were reversed by conventional antidiabetic doses of metformin in the present work. In parallel, the activation of AMPK and suppression of mTOR seemed to play an important role for the effect of metformin in patients with EC. This pilot trial presents biological evidence consistent with antiproliferative effects of metformin in women with EC in the clinical setting.

  8. Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial.

    Science.gov (United States)

    Strug, Michael R; Su, Renwei; Young, James E; Dodds, William G; Shavell, Valerie I; Díaz-Gimeno, Patricia; Ruíz-Alonso, Maria; Simón, Carlos; Lessey, Bruce A; Leach, Richard E; Fazleabas, Asgerally T

    2016-07-01

    Does a single intrauterine infusion of human chorionic gonadotropin (hCG) at the time corresponding to a Day 3 embryo transfer in oocyte donors induce favorable molecular changes in the endometrium for embryo implantation? Intrauterine hCG was associated with endometrial synchronization between endometrial glands and stroma following ovarian stimulation and the induction of early decidual markers associated with stromal cell survival. The clinical potential for increasing IVF success rates using an intrauterine hCG infusion prior to embryo transfer remains unclear based on previously reported positive and non-significant findings. However, infusion of CG in the non-human primate increases the expression of pro-survival early decidual markers important for endometrial receptivity, including α-smooth muscle actin (α-SMA) and NOTCH1. Oocyte donors (n=15) were randomly assigned to receive an intrauterine infusion of 500 IU hCG (n=7) or embryo culture media vehicle (n=8) 3 days following oocyte retrieval during their donor stimulation cycle. Endometrial biopsies were performed 2 days later, followed by either RNA isolation or tissue fixation in formalin and paraffin embedding. Reverse transcription of total RNA from endometrial biopsies generated cDNA, which was used for analysis in the endometrial receptivity array (ERA; n = 5/group) or quantitative RT-PCR to determine relative expression of ESR1, PGR, C3 and NOTCH1. Tissue sections were stained with hematoxylin and eosin followed by blinded staging analysis for dating of endometrial glands and stroma. Immunostaining for ESR1, PGR, α-SMA, C3 and NOTCH1 was performed to determine their tissue localization. Intrauterine hCG infusion was associated with endometrial synchrony and reprograming of stromal development following ovarian stimulation. ESR1 and PGR were significantly elevated in the endometrium of hCG-treated patients, consistent with earlier staging. The ERA did not predict an overall positive impact of

  9. LeftyA sensitive cytosolic pH regulation and glycolytic flux in Ishikawa human endometrial cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Salker, Madhuri S.; Zhou, Yuetao; Singh, Yogesh [Department of Physiology, University of Tuebingen, 72076 Tuebingen (Germany); Brosens, Jan [Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry CV2 2DX (United Kingdom); Lang, Florian, E-mail: florian.lang@uni-tuebingen.de [Department of Physiology, University of Tuebingen, 72076 Tuebingen (Germany)

    2015-05-08

    Objective: LeftyA, a powerful regulator of stemness, embryonic differentiation, and reprogramming of cancer cells, counteracts cell proliferation and tumor growth. Key properties of tumor cells include enhanced glycolytic flux, which is highly sensitive to cytosolic pH and thus requires export of H{sup +} and lactate. H{sup +} extrusion is in part accomplished by Na{sup +}/H{sup +} exchangers, such as NHE1. An effect of LeftyA on transport processes has, however, never been reported. The present study thus explored whether LeftyA modifies regulation of cytosolic pH (pHi) in Ishikawa cells, a well differentiated endometrial carcinoma cell model. Methods: NHE1 transcript levels were determined by qRT-PCR, NHE1 protein abundance quantified by Western blotting, pH{sub i} estimated utilizing (2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein [BCECF] fluorescence, Na{sup +}/H{sup +} exchanger activity from Na{sup +} dependent realkalinization after an ammonium pulse, and lactate concentration in the supernatant utilizing an enzymatic assay and subsequent colorimetry. Results: A 2 h treatment with LeftyA (8 ng/ml) significantly decreased NHE1 transcript levels (by 99.6%), NHE1 protein abundance (by 71%), Na{sup +}/H{sup +} exchanger activity (by 55%), pHi (from 7.22 ± 0.02 to 7.05 ± 0.02), and lactate release (by 41%). Conclusions: LeftyA markedly down-regulates NHE1 expression, Na{sup +}/H{sup +} exchanger activity, pHi, and lactate release in Ishikawa cells. Those effects presumably contribute to cellular reprogramming and growth inhibition. - Highlights: • LeftyA, an inhibitor of tumor growth, reduces Na{sup +}/H{sup +}-exchanger activity by 55%. • LeftyA decreases NHE1 transcripts by 99.6% and NHE1 protein by 71%. • LeftyA decreases cytosolic pH from 7.22 ± 0.02 to 7.05 ± 0.02. • Cytosolic acidification by Lefty A decreases glycolysis by 41%. • Cytosolic acidification by Lefty A compromises energy production of tumor cells.

  10. The roles of tricellular tight junction protein lipolysis-stimulated lipoprotein receptor in malignancy of human endometrial cancer cells.

    Science.gov (United States)

    Shimada, Hiroshi; Satohisa, Seiro; Kohno, Takayuki; Takahashi, Syunta; Hatakeyama, Tsubasa; Konno, Takumi; Tsujiwaki, Mitsuhiro; Saito, Tsuyoshi; Kojima, Takashi

    2016-05-10

    Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a novel molecular constituent of tricellular contacts that have a barrier function for the cellular sheet. LSR recruits tricellulin (TRIC), which is the first molecular component of tricellular tight junctions. Knockdown of LSR increases cell motility and invasion of certain cancer cells. However, the behavior and the roles of LSR in endometrial cancer remain unknown. In the present study, we investigated the behavior and roles of LSR in normal and endometrial cancer cells in vivo and in vitro. In endometriosis and endometrial cancer, LSR was observed not only in the subapical region but also throughout the lateral region as well as in normal endometrial epithelial cells in the secretory phase, and LSR in the cancer was reduced in correlation with the malignancy. Knockdown of LSR by the siRNA in cells of the endometrial cancer cell line Sawano, induced cell migration, invasion and proliferation, while TRIC relocalized from the tricellular region to the bicellular region at the membrane. In Sawano cells and normal HEEs, a decrease of LSR induced by leptin and an increase of LSR induced by adiponectin and the drugs for type 2 diabetes metformin and berberine were observed via distinct signaling pathways including JAK2/STAT. In Sawano cells, metformin and berberine prevented cell migration and invasion induced by downregulation of LSR by the siRNA and leptin treatment. The dissection of the mechanism in the downregulation of endometrial LSR during obesity is important in developing new diagnostic and therapy for endometrial cancer.

  11. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha increased apoptosis of human endometrial cancer HEC-1A cells

    Directory of Open Access Journals (Sweden)

    Yang H

    2016-08-01

    Full Text Available Hui Yang, Rui Yang, Hao Liu, Zhongqian Ren, Cuicui Wang, Da Li, Xiaoxin Ma Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China Background: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α coactivates multiple transcription factors and regulates several metabolic processes. In this study, we focused on the roles of PGC-1α in the apoptosis of endometrial cancer HEC-1A cells. Materials and methods: PGC-1α expression in the HEC-1A cells was detected with real-time polymerase chain reaction and Western blot. Small interfering RNA directed against PGC-1α was designed and synthesized, and RNA interference technology was used to knock down PGC-1α mRNA and protein expression. Cell apoptosis, cell cycle, and mitochondrial membrane potential were then analyzed using flow cytometry. The expression of apoptotic proteins, Bcl-2 and Bax, was detected with Western blot. Results: The specific downregulation of PGC-1α expression in the HEC-1A cells increased their apoptosis through the mitochondrial apoptotic pathway by reducing the expression of Bcl-2 and increasing the expression of Bax. Conclusion: These results suggest that PGC-1α influences the apoptosis of HEC-1A cells and also provides a molecular basis for further investigation of the apoptotic mechanism in human endometrial cancer. Keywords: endometrial cancer, PGC-1α, apoptosis, Bcl-2, Bax

  12. Deep Infiltrating Endometriosis and Endometrial Adenocarcinoma Express High Levels of Myostatin and Its Receptors Messenger RNAs.

    Science.gov (United States)

    Carrarelli, Patrizia; Funghi, Lucia; Ciarmela, Pasquapina; Centini, Gabriele; Reis, Fernando M; Dela Cruz, Cynthia; Mattei, Alberto; Vannuccini, Silvia; Petraglia, Felice

    2017-12-01

    Myostatin is a growth factor member of the transforming growth factor β superfamily, which is known to play major roles in cell proliferation and differentiation. The present study investigated the messenger RNA (mRNA) expression of myostatin and myostatin receptors (activin receptor-like kinase 4 [ALK4], transforming growth factor (TGF)-β type I receptor kinase [ALK5] and activin receptor type IIB [ActRIIB]) in endometrium of healthy women during menstrual cycle as well as in benign (endometriosis, polyps) and malignant (endometrial adenocarcinoma) conditions. Endometrial specimens were collected by hysteroscopy, whereas endometriotic lesions were collected by laparoscopy, and adenocarcinomas were sampled after hysterectomy. Total RNA was extracted from tissue homogenates, and gene expression was assessed by quantitative real-time polymerase chain reaction. Myostatin and myostatin receptors mRNAs were expressed by healthy endometrium throughout the menstrual cycle, with no differences between the proliferative and secretory phase. The highest myostatin mRNA expression was found in patients with deep infiltrating endometriosis (DIE) and in endometrial carcinoma; expression was also found in ovarian endometrioma (OMA ) and endometrial polyps. Myostatin receptors mRNA expression was higher in DIE and adenocarcinomas compared to control endometrium. The expression of ALK5 and ActRIIB in OMA was higher than in controls, whereas polyps had an increased expression of ALK5 mRNA. In conclusion, the present data showed for the first time the expression of myostatin in healthy endometrium and a higher expression in endometriosis and endometrial cancer, suggesting myostatin involvement in human endometrial physiology and related pathologies.

  13. The association of the microcystic, elongated and fragmented (MELF) invasion pattern in endometrial carcinomas with deep myometrial invasion, lymphovascular space invasion and lymph node metastasis.

    Science.gov (United States)

    Dogan Altunpulluk, M; Kir, G; Topal, C S; Cetiner, H; Gocmen, A

    2015-05-01

    The purpose of this study was to investigate the frequency of microcystic, elongated and fragmented (MELF) pattern of invasion in endometrioid endometrial adenocarcinomas (EA) and its association with prognostic factors. Stained tissue sections from 121 cases of EA (total hysterectomy and pelvic, with or without para-aortic, lymphadenectomy specimens) were reviewed to identify cases showing MELF-type invasion. The prognostic factors of low tumour grade, deep myometrial invasion (MI), cervical stromal involvement, lymphovascular space invasion (LVSI), lymph node (LN) metastasis and advanced clinical stage were more frequently observed in MELF-positive cases (p deep MI, cervical stroma involvement and LVSI were significantly related to LN metastasis (p < 0.05). However, in multivariate analysis, only MELF pattern invasion and cervical stroma involvement were independent factors for LN metastasis. Nevertheless, further studies are needed to evaluate the clinical significance of MELF pattern of invasion in endometrial adenocarcinoma.

  14. Cytokine profiling in endometrial secretions : a non-invasive window on endometrial receptivity

    NARCIS (Netherlands)

    Boomsma, C. M.; Kavelaars, A.; Eijkemans, M. J. C.; Amarouchi, K.; Teklenburg, G.; Gutknecht, D.; Fauser, B. J. C. M.; Heijnen, C. J.; Macklon, N. S.

    Investigation of human embryo implantation requires a non-disruptive means of studying the endometrium during the window of implantation. This stud), describes a novel approach of cytokine profiling in endometrial secretions. Endometrial secretions aspirated prior to embryo transfer from 210 women

  15. Expression of leptin receptor in endometrial biopsies of endometrial and ovarian cancer patients.

    Science.gov (United States)

    Méndez-López, Luis Fernando; Dávila-Rodríguez, Martha Imelda; Zavala-Pompa, Angel; Torres-López, Ernesto; González-Martínez, Blanca Edelia; López-Cabanillas-Lomelí, Manuel

    2013-07-01

    The adipokine leptin plays a critical role in the regulation of reproductive function and there has been growing interest in its potential role in the development of cancers in which obesity is an established risk factor. Serum leptin levels were found to be higher in patients diagnosed with endometrial and ovarian cancer compared to those observed in healthy individuals. This study was conducted to determine the expression of the leptin receptor (Ob-R) in endometrial biopsies of patients diagnosed with endometrial and ovarian cancer. In this preliminary study, immunohistochemistry (IHC) and the color deconvolution method were used to assess the expression levels of the Ob-R protein in three groups of endometrial tissue: one from patients diagnosed with endometrioid endometrial carcinoma, one from patients diagnosed with ovarian cancer and one from individuals without any diagnosed gynecologic disease (control group). Our results demonstrated that the highest expression of Ob-R protein in endometrial biopsies was detected in the ovarian cancer group (P=0.000). This finding suggests that changes in Ob-R expression may be assessed through the measurement of the optical density of endometrial biopsies and may become a useful tool in preventive screening, particularly for ovarian cancer.

  16. Endometrial pathology by endometrial curettage in menorrhagia in premenopausal age group.

    Science.gov (United States)

    Riaz, Shazia; Ibrar, Faiza; Dawood, Nasira Sabiha; Jabeen, Alia

    2010-01-01

    Menorrhagia is objectively defined as blood loss greater than 80 ml or menstrual period lasting longer than 7 days. Dysfunctional uterine bleeding is responsible for 80% cases of Menorrhagia. Objective of this study was to find out the endometrial pathology and usefulness of hysterocopic directed endomentrial sampling in patient having menorrhagia in premenopausal age group. This prospective descriptive study was conducted at Unit 1 of the Department of Obstetrics and Gynaecology, Fauji Foundation Hospital Rawalpindi, Pakistan from January to December 2007. During the study period, 100 patients with menorrhagia in age group 35-50 years were selected after fulfilling the inclusion criteria. These patients were selected from Gynaecology out patient department. After detailed history, examination and ultra sonography, they were admitted and hysteroscopic directed endometrial sampling was done endometrial samples were sent for histopathology to find out the endometrial pathology. The selected patients of my study with menorrhagia were scattered over all premenopusal age groups > 35 years. It was observed that 67 patient were above the age of 40 years. The analysis of histopathology reports of endometrial curettage revealed proliferative endomentrium in 33%, cystic hyperplasia's in 25% and carcinoma endometrium in one case. Cystichyperplasia and proliferative endometrium were found in menorrhagic women over 40 years of age. Adenoicarcinoma was found in a single premenopausal women of 48 years. All patients having menorrhagia above 40 years should be screened for any endometrial pathology. Accurate analysis of endometrial sampling is the key to effective therapy and optimal out come.

  17. The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells.

    Science.gov (United States)

    Fatima, I; Saxena, R; Kharkwal, G; Hussain, M K; Yadav, N; Hajela, K; Sankhwar, P L; Dwivedi, A

    2013-11-01

    In an effort to develop novel therapeutic agents for endometrial cancer, benzopyran derivatives synthesized at our institute display significant inhibitory activity on cellular growth in uterine cancer cells. The current study was undertaken to demonstrate and explore the estrogen receptor (ER) subtype mediated mechanism of action of benzopyran derivative 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran (K-1) in human endometrial cancer cells. K-1 competitively inhibited the estradiol binding to human ERα and ERβ and showed growth inhibitory activity in human endometrial Ishikawa, HEC1B and primary endometrial adenocarcinoma cells. Transient transactivation assays carried out in COS-1 cells have demonstrated the diminished ERα-ERE mediated- and induced the ERβ-ERE mediated-transactivation triggered by compound. It also induced ER-mediated transactivation of the cyclin-dependent kinase inhibitor (CDKI) p21(WAF-1) in both COS-1 cells and in Ishikawa cells. ERβ inducing effects of compound were blocked by ICI182,780. In endometrial adenocarcinoma cells, it induced ERβ and p21 expression significantly whereas the expression of fos, jun and ERα were significantly reduced. In addition, compound promoted ERα-β heterodimerization as observed in Ishikawa cells. These results demonstrate that the benzopyran compound suppressed the cellular growth via ERβ agonism, induction of p21 and via promoting the ERα-β heterodimerization, in addition to its antagonistic effects exerted on ERα, in human endometrial cancer cells. The study suggests that the dual action of benzopyran molecule may be of significant therapeutic value in ERα/β-positive cases of endometrial cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Pathologies of the uterine endometrial cavity: usual and unusual manifestations and pitfalls on magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Takeuchi, Mayumi; Matsuzaki, Kenji; Yoshida, Shusaku; Nishitani, Hiromu [University of Tokushima, Department of Radiology, Tokushima (Japan); Uehara, Hisanori [University of Tokushima, Department of Molecular and Environmental Pathology, Tokushima (Japan); Shimazu, Hideki [Oe Kyoudo Hospital, Department of Radiology (Japan)

    2005-11-01

    The endometrial cavity may demonstrate various imaging manifestations such as normal, reactive, inflammatory, and benign and malignant neoplasms. We evaluated usual and unusual magnetic resonance imaging (MRI) findings of the uterine endometrial cavity, and described the diagnostic clues to differential diagnoses. Surgically proven pathologies of the uterine endometrial cavity were evaluated retrospectively with pathologic correlation. The pathologies included benign endometrial neoplasms such as endometrial hyperplasia and polyp, malignant endometrial neoplasms such as endometrial carcinoma and carcinosarcoma, endometrial-myometrial neoplasm such as endometrial stromal sarcoma, pregnancy-related lesions in the endometrial cavity such as gestational trophoblastic diseases (hydatidiform mole, invasive mole and choriocarcinoma) and placental polyp, myometrial lesions simulating endometrial lesions such as submucosal leiomyoma and some adenomyosis, endometrial neoplasms simulating myometrial lesions such as adenomyomatous polyp and endometrial lesions arising in the hemicavity of a septate/bicornate uterus, and fluid collections in the uterine cavity (hydro/hemato/pyometra). It is important to recognize various imaging findings in these diseases, in order to make a correct preoperative diagnosis. (orig.)

  19. Endometrial Cancer Prevention

    Science.gov (United States)

    ... following protective factors decrease the risk of endometrial cancer: Pregnancy and breast-feeding Estrogen levels are lower during pregnancy and when breast-feeding. The risk of endometrial cancer is lower in women who have had children. ...

  20. The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors.

    Science.gov (United States)

    Hillion, Joelle; Roy, Sujayita; Heydarian, Mohammad; Cope, Leslie; Xian, Lingling; Koo, Michael; Luo, Li Z; Kellyn, Kathleen; Ronnett, Brigitte M; Huso, Tait; Armstrong, Deborah; Reddy, Karen; Huso, David L; Resar, L M S

    2016-06-01

    Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1a transgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing MatrixMetalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer. To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors). Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background. In human tumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human carcinosarcoma cells. Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of human carcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Micronuclei with kinetochores in human melanoma cells and rectal carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Weissenborn, U.; Streffer, C. (Essen Univ. (Gesamthochschule) (Germany, F.R.). Inst. fuer Medizinische Strahlenbiologie)

    1991-02-01

    Micronucleus frequencies were analysed in an X-irradiated human melanoma cell line and in untreated rectal carcinoma cells. As a special aspect of the micronucleus formation, micronuclei-containing kinetochores were analysed by the method of indirect immunofluorescence. The incidence of kinetochore-positive micronuclei was taken as a measure of chromosome loss. The authors have attempted to summarize the data by means of a numerical expression which takes into account the relation between lost chromosomes, visible as kinetochore-positive micronuclei, and the total sum of micronuclei. (author).

  2. Trappin-2/elafin modulate innate immune responses of human endometrial epithelial cells to PolyI:C.

    Directory of Open Access Journals (Sweden)

    Anna G Drannik

    Full Text Available BACKGROUND: Upon viral recognition, innate and adaptive antiviral immune responses are initiated by genital epithelial cells (ECs to eradicate or contain viral infection. Such responses, however, are often accompanied by inflammation that contributes to acquisition and progression of sexually transmitted infections (STIs. Hence, interventions/factors enhancing antiviral protection while reducing inflammation may prove beneficial in controlling the spread of STIs. Serine antiprotease trappin-2 (Tr and its cleaved form, elafin (E, are alarm antimicrobials secreted by multiple cells, including genital epithelia. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated whether and how each Tr and E (Tr/E contribute to antiviral defenses against a synthetic mimic of viral dsRNA, polyinosine-polycytidylic acid (polyI:C and vesicular stomatitis virus. We show that delivery of a replication-deficient adenovector expressing Tr gene (Ad/Tr to human endometrial epithelial cells, HEC-1A, resulted in secretion of functional Tr, whereas both Tr/E were detected in response to polyI:C. Moreover, Tr/E were found to significantly reduce viral replication by either acting directly on virus or through enhancing polyI:C-driven antiviral protection. The latter was associated with reduced levels of pro-inflammatory factors IL-8, IL-6, TNFα, lowered expression of RIG-I, MDA5 and attenuated NF-κB activation. Interestingly, enhanced polyI:C-driven antiviral protection of HEC-Ad/Tr cells was partially mediated through IRF3 activation, but not associated with higher induction of IFNβ, suggesting multiple antiviral mechanisms of Tr/E and the involvement of alternative factors or pathways. CONCLUSIONS AND SIGNIFICANCE: This is the first evidence of both Tr/E altering viral binding/entry, innate recognition and mounting of antiviral and inflammatory responses in genital ECs that could have significant implications for homeostasis of the female genital tract.

  3. Elevated expression of squamous cell carcinoma antigen (SCCA is associated with human breast carcinoma.

    Directory of Open Access Journals (Sweden)

    Joseph M Catanzaro

    Full Text Available Squamous cell carcinoma antigen (SCCA belongs to the serine protease inhibitor (Serpin family of proteins. Elevated expression of SCCA has been used as a biomarker for aggressive squamous cell carcinoma (SCC in cancers of the cervix, lung, head and neck, and liver. However, SCCA expression in breast cancer has not been investigated. Immunohistochemical analysis of SCCA expression was performed on tissue microarrays containing breast tumor tissues (n = 1,360 and normal breast epithelium (n = 124. SCCA expression was scored on a tiered scale (0-3 independently by two evaluators blind to the patient's clinical status. SCCA expression was observed in Grade I (0.3%, Grade II (2.5%, and Grade III (9.4% breast cancers (p<0.0001. Comparing tissues categorized into the three non-metastatic TNM stages, I-III, SCCA positivity was seen in 2.4% of Stage I cancers, 3.1% of Stage II cancers, and 8.6% of Stage III breast cancers (p = 0.0005. No positive staining was observed in normal/non-neoplastic breast tissue (0 out of 124. SCCA expression also correlated to estrogen receptor/progesterone receptor (ER/PR double-negative tumors (p = 0.0009. Compared to SCCA-negative patients, SCCA-positive patients had both a worse overall survival and recurrence-free survival (p<0.0001 and p<0.0001, respectively. This study shows that SCCA is associated with both advanced stage and high grade human breast carcinoma, and suggests the necessity to further explore the role of SCCA in breast cancer development and treatment.

  4. Laminin production by human endometrial stromal cells relates to the cyclic and pathologic state of the endometrium

    DEFF Research Database (Denmark)

    Faber, M; Wewer, U M; Berthelsen, J G

    1986-01-01

    The cyclic changes in the presence of the basement membrane glycoprotein laminin in endometrial stromal cells was studied by immunohistochemistry. The interstitial matrix around the stromal cells of the proliferative phase of the normal menstrual cycle was unreactive with antibodies to laminin. H...

  5. Are gestational age and endometrial thickness alternatives for serum human chorionic gonadotropin as criteria for the diagnosis of ectopic pregnancy?

    NARCIS (Netherlands)

    Mol, B. W.; Hajenius, P. J.; Engelsbel, S.; Ankum, W. M.; van der Veen, F.; Hemrika, D. J.; Bossuyt, P. M.

    1999-01-01

    OBJECTIVE: To compare gestational age and endometrial stripe thickness measurement with serum hCG measurement as criteria for the diagnosis of ectopic pregnancy (EP). DESIGN: Prospective study. SETTING: Two large teaching hospitals in Amsterdam, The Netherlands. PATIENT(S): Three hundred fifty-four

  6. Interferon-γ differentially modulates the impact of tumor necrosis factor-α on human endometrial stromal cells.

    Science.gov (United States)

    Spratte, Julia; Oemus, Anne; Zygmunt, Marek; Fluhr, Herbert

    2015-09-01

    The pro-inflammatory T helper (Th)-1 cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), are immunological factors relevant at the feto-maternal interface and involved in the pathophysiology of implantation disorders. The synergistic action of the two cytokines has been described with regard to apoptotic cell death and inflammatory responses in different cell types, but little is known regarding the human endometrium. Therefore, we examined the interaction of TNF-α and IFN-γ in human endometrial stromal cells (ESCs). ESCs were isolated from specimens obtained during hysterectomy and decidualized in vitro. Cells were incubated with TNF-α, IFN-γ or signaling-inhibitor. Insulin-like growth factor binding protein (IGFBP)-1, prolactin (PRL), leukemia inhibitory factor (LIF), interleukin (IL)-6, IL-8, regulated on activation normal T-cell expressed and secreted protein (RANTES) and monocyte chemotactic protein (MCP)-1 were measured using ELISA and real-time RT-PCR. Nuclear factor of transcription (NF)-κB and its inhibitor (IκBα) were analyzed by in-cell western assay and transcription factor assay. TNF-α inhibited and IFN-γ did not affect the decidualization of ESCs. In contrast, IFN-gamma differentially modulated the stimulating effect of TNF-alpha on cytokines by enhancing IL-6, RANTES and MCP-1 and attenuating LIF mRNA expression. These effects were time- and dose-dependent. IFN-γ had no impact on the initial activation of NF-κB signaling. Histone-deacetylase activity was involved in the modulating effect of IFN-γ on RANTES secretion. These observations showed a distinct pattern of interaction of the Th-1 cytokines, TNF-α and IFN-γ in the human endometrium, which could play an important role in the pathophysiology of implantation disorders. Copyright © 2015 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z

  7. The Krüppel-like factor 9 (KLF9 network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression

    Directory of Open Access Journals (Sweden)

    Zeng Zhaoyang

    2008-09-01

    Full Text Available Abstract Background Krüppel-like factor 9 (KLF9 is a transcriptional regulator of uterine endometrial cell proliferation, adhesion and differentiation; processes essential for pregnancy success and which are subverted during tumorigenesis. The network of endometrial genes controlled by KLF9 is largely unknown. Over-expression of KLF9 in the human endometrial cancer cell line HEC-1-A alters cell morphology, proliferative indices, and differentiation, when compared to KLF9 under-expressing HEC-1-A cells. This cell line provides a unique model for identifying KLF9 downstream gene targets and signaling pathways. Methods HEC-1-A sub-lines differing in relative levels of KLF9 were subjected to microarray analysis to identify differentially-regulated RNAs. Results KLF9 under-expression induced twenty four genes. The KLF9-suppressed mRNAs encode protein participants in: aldehyde metabolism (AKR7A2, ALDH1A1; regulation of the actin cytoskeleton and cell motility (e.g., ANK3, ITGB8; cellular detoxification (SULT1A1, ABCC4; cellular signaling (e.g., ACBD3, FZD5, RAB25, CALB1; and transcriptional regulation (PAX2, STAT1. Sixty mRNAs were more abundant in KLF9 over-expressing sub-lines. The KLF9-induced mRNAs encode proteins which participate in: regulation and function of the actin cytoskeleton (COTL1, FSCN1, FXYD5, MYO10; cell adhesion, extracellular matrix and basement membrane formation (e.g., AMIGO2, COL4A1, COL4A2, LAMC2, NID2; transport (CLIC4; cellular signaling (e.g., BCAR3, MAPKAPK3; transcriptional regulation [e.g., KLF4, NR3C1 (glucocorticoid receptor, RXRα], growth factor/cytokine actions (SLPI, BDNF; and membrane-associated proteins and receptors (e.g., CXCR4, PTCH1. In addition, the abundance of mRNAs that encode hypothetical proteins (KLF9-inhibited: C12orf29 and C1orf186; KLF9-induced: C10orf38 and C9orf167 were altered by KLF9 expression. Human endometrial tumors of high tumor grade had decreased KLF9 mRNA abundance. Conclusion KLF9

  8. Membrane Drug Transporters and Chemoresistance in Human Pancreatic Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hagmann, Wolfgang, E-mail: w.hagmann@dkfz.de; Faissner, Ralf [Clinical Cooperation Unit of Molecular Gastroenterology, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Schnolzer, Martina [Functional Proteome Analysis, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Lohr, Matthias [Clinical Cooperation Unit of Molecular Gastroenterology, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Department of Surgical Gastroenterology, CLINTEC, K53, Karolinska Institute, SE-14186 Stockholm (Sweden); Jesnowski, Ralf [Clinical Cooperation Unit of Molecular Gastroenterology, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Department of Medicine II, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim (Germany)

    2010-12-30

    Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by in vivo and in vitro data. Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.

  9. Biomarkers as prognostic factors in endometrial cancer.

    Directory of Open Access Journals (Sweden)

    Sławomir J Terlikowski

    2010-11-01

    Full Text Available Endometrial cancer is the most common gynecologic malignancy in more developed countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis and endometrioid histology and type II, associated with a poor prognosis and non-endometrioid histology. This review will focus primarily on the molecular biomarkers that have supported the dualistic model of endometrial carcinoma and help determine which patients would benefit from either adjuvant therapy or more aggressive primary treatment.

  10. p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma.

    Science.gov (United States)

    Alexander, Riley E; Hu, Yingchuan; Kum, Jennifer B; Montironi, Rodolfo; Lopez-Beltran, Antonio; Maclennan, Gregory T; Idrees, Muhammad T; Emerson, Robert E; Ulbright, Thomas M; Grignon, David G; Eble, John N; Cheng, Liang

    2012-11-01

    Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.

  11. Bisphenol A Alters β-hCG and MIF Release by Human Placenta: An In Vitro Study to Understand the Role of Endometrial Cells

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    C. Mannelli

    2014-01-01

    Full Text Available A proper fetomaternal immune-endocrine cross-talk in pregnancy is fundamental for reproductive success. This might be unbalanced by exposure to environmental chemicals, such as bisphenol A (BPA. As fetoplacental contamination with BPA originates from the maternal compartment, this study investigated the role of the endometrium in BPA effects on the placenta. To this end, in vitro decidualized stromal cells were exposed to BPA 1 nM, and their conditioned medium (diluted 1 : 2 was used on chorionic villous explants from human placenta. Parallel cultures of placental explants were directly exposed to 0.5 nM BPA while, control cultures were exposed to the vehicle (EtOH 0.1%. After 24–48 h, culture medium from BPA-treated and control cultures was assayed for concentration of hormone human Chorionic Gonadotropin (β-hCG and cytokine Macrophage Migration Inhibitory Factor (MIF. The results showed that direct exposure to BPA stimulated the release of both MIF and β-hCG. These effects were abolished/diminished in placental cultures exposed to endometrial cell-conditioned medium. GM-MS analysis revealed that endometrial cells retain BPA, thus reducing the availability of this chemical for the placenta. The data obtained highlight the importance of in vitro models including the maternal component in reproducing the effects of environmental chemicals on human fetus/placenta.

  12. Metformin for endometrial hyperplasia: a Cochrane protocol

    Science.gov (United States)

    Clement, Naomi S; Oliver, Thomas R W; Shiwani, Hunain; Saner, Juliane R F; Mulvaney, Caroline A; Atiomo, William

    2016-01-01

    Introduction Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. Methods and analysis We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. Ethics and dissemination

  13. A Phase II Study of Intensity Modulated Radiation Therapy to the Pelvis for Postoperative Patients With Endometrial Carcinoma: Radiation Therapy Oncology Group Trial 0418

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    Jhingran, Anuja, E-mail: ajhingra@mdanderson.org [University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Winter, Kathryn [RTOG Statistical Center, Philadelphia, Pennsylvania (United States); Portelance, Lorraine [University of Miami, Miami, Florida (United States); Miller, Brigitte [Carolinas Medical Center North East, Concord, North Carolina (United States); Salehpour, Mohammad [University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gaur, Rakesh [St. Luke' s Hospital, Kansas City, Missouri (United States); Souhami, Luis [McGill University Health Centre, Montreal, Quebec (Canada); Small, William [Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illionis (United States); Berk, Lawrence [H. Lee Moffitt Cancer Center, Tampa, Florida (United States); Gaffney, David [Huntsman Cancer Hospital, Salt Lake City, Utah (United States)

    2012-09-01

    Purpose: To determine the feasibility of pelvic intensity modulated radiation therapy (IMRT) for patients with endometrial cancer in a multi-institutional setting and to determine whether this treatment is associated with fewer short-term bowel adverse events than standard radiation therapy. Methods: Patients with adenocarcinoma of the endometrium treated with pelvic radiation therapy alone were eligible. Guidelines for target definition and delineation, dose prescription, and dose-volume constraints for the targets and critical normal structures were detailed in the study protocol and a web-based atlas. Results: Fifty-eight patients were accrued by 25 institutions; 43 were eligible for analysis. Forty-two patients (98%) had an acceptable IMRT plan; 1 had an unacceptable variation from the prescribed dose to the nodal planning target volume. The proportions of cases in which doses to critical normal structures exceeded protocol criteria were as follows: bladder, 67%; rectum, 76%; bowel, 17%; and femoral heads, 33%. Twelve patients (28%) developed grade {>=}2 short-term bowel adverse events. Conclusions: Pelvic IMRT for endometrial cancer is feasible across multiple institutions with use of a detailed protocol and centralized quality assurance (QA). For future trials, contouring of vaginal and nodal tissue will need continued monitoring with good QA and better definitions will be needed for organs at risk.

  14. Obesity and Endometrial Cancer.

    Science.gov (United States)

    Shaw, Eileen; Farris, Megan; McNeil, Jessica; Friedenreich, Christine

    Endometrial cancer is the sixth most common cancer in women worldwide and the most common gynecologic malignancy in the developed world. This chapter explores the current epidemiologic evidence on the association between obesity and endometrial cancer risk and mortality. Using body mass index (BMI) as a measure of obesity, we found that obesity (defined as BMI > 30 and endometrial cancer risk, while severe obesity (BMI > 35 kg/m(2)) was associated with a 4.7-fold increase compared to normal-weight women (BMI endometrial cancer risk by 1.5- to twofold. Among both healthy and endometrial cancer patient populations, obesity was associated with a roughly twofold increase in endometrial cancer-specific mortality. This risk reduction was also observed for obesity and all-cause mortality among endometrial cancer patients. In the few studies that assessed risk associated with weight change, an increased endometrial cancer risk with weight gain and weight cycling was observed, whereas some evidence for a protective effect of weight loss was found. Furthermore, early-life obesity was associated with a moderately increased risk of endometrial cancer later in life. There are several mechanisms whereby obesity is hypothesized to increase endometrial cancer risk, including increased endogenous sex steroid hormones, insulin resistance, chronic inflammation and adipokines. Further research should focus on histological subtypes or molecular phenotypes of endometrial tumors and population subgroups that could be at an increased risk of obesity-associated endometrial cancer. Additionally, studies on weight gain, loss or cycling and weight loss interventions can provide mechanistic insight into the obesity-endometrial cancer association. Sufficient evidence exists to recommend avoiding obesity to reduce endometrial cancer risk.

  15. Expression of PTEN in endometrial liquid-based cytology.

    Science.gov (United States)

    Di Lorito, Alessia; Zappacosta, Roberta; Capanna, Serena; Gatta, Daniela Mariapia; Rosini, Sandra; Schmitt, Fernando Carlos

    2014-01-01

    Endometrial cytology offers a reliable alternative to biopsy in endometrial cancer detection and it may be useful in obtaining material to study prognostic and predictive markers. Over the years, new sampling devices have been developed. Molecular alterations in endometrial cancers were previously described using formalin-fixed paraffin-embedded tissues with particular attention, in endometrioid carcinomas, to the PTEN-PI3K pathway. PTEN evaluation could be useful in endometrial carcinomas for selecting patients for target therapies. We studied 51 endometrial samples collected using the Endogyn device and 71 obtained with the Endoflower dispositive device, and processed using liquid-based cytology. Most of the cases were matched with a corresponding histological biopsy. The overall accuracy of Endoflower was 100%. Immunohistochemistry (IHC) and immunocytochemistry (ICC) for PTEN were performed using monoclonal antibody 6H2.1 from DAKO. The IHC showed PTEN-null glands in 4 cases. The same cancers were negative in ICC. Among the 10 carcinomas on cytology, PTEN-null glands were found in 1 case. All the normal endometrium control cases were positive in cytology and histology. Our results suggest that endometrial devices provide useful material for the diagnosis and evaluation of PTEN expression. © 2014 S. Karger AG, Basel.

  16. p16 is Consistently Expressed in Endometrial Tubal Metaplasia

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    N. Horree

    2007-01-01

    Full Text Available Background: Cell cycle proteins and HIF-1α with downstream factors are often abberrantly expressed in (preneoplastic tissue. Methods: Paraffin-embedded specimens of inactive endometrium with TM (n=15, ovarian inclusion cysts (n=6, cervix with TM (tubal metaplasia (n=3, Fallopian tubes (n=7, cycling endometrium (n=9 and a ciliated cell tumor of the ovary were stained for p16 and LhS28. 39 Endometrioid endometrial carcinomas and 5 serous endometrial carcinomas were stained for p16. Additionally, inactive endometrium (n=15 was immunohistochemically stained for p21, p27, p53, cyclin A, cyclin D1, cyclin E, HIF-1α, CAIX, Glut-1 and MIB-1. Results: A mosaic pattern of expression of p16 was seen throughout in all cases of endometrial TM (15/15, in 2/6 of the ovarian inclusion cysts with TM, in all (3/3 cervical TM and focal in 5/7 of Fallopian tube cases. Mosaic expression was also seen in a ciliated cell tumor of the ovary and in 18/39 of endometrioid endometrial carcinomas, and diffuse p16 expression was seen in 5/5 serous carcinomas. In comparison with normal endometrium, TM areas in the endometrium showed significantly increased expression of HIF-1α, cyclin E, p21 and cyclin A, and decreased expression of p27. Membranous expression of CAIX and Glut-1 was only seen in TM areas, pointing to functional HIF-1α. Conclusion: As p16 is consistently expressed in TM, less and only patchy expressed in the normal Fallopian tube, is paralleled by aberrant expression of cell cycle proteins, HIF-1α, CAIX and Glut-1 and resembles the pattern of p16 expression frequently seen in endometrial carcinomas, we propose endometrial TM to be a potential premalignant endometrial lesion.

  17. Intraoperative lymphatic mapping techniques for endometrial cancer.

    Science.gov (United States)

    Mais, Valerio; Cirronis, Maria Giuseppina; Piras, Bruno; Silvetti, Enrico; Cossu, Ester; Melis, Gian Benedetto

    2011-01-01

    Endometrial cancer is the most common malignancy of the female genital tract in developed countries. The primary treatment for women with endometrial cancer is surgical, as well as the staging of the pathological spread pattern of this carcinoma outside of the uterus. A complete surgical staging should include both pelvic and para-aortic lymphadenectomy. The vast majority of endometrial cancers are diagnosed at a very early stage owing to the early presentation as abnormal uterine bleeding. In women with early-stage endometrial cancer the systematic pelvic and para-aortic lymphadenectomy may produce additional morbidity without the benefit of appropriate surgical staging. The procedure of sentinel lymph node (SLN) biopsy after lymphatic mapping has been introduced for patients with cancers of various organs in an effort to avoid complete systematic lymphadenectomy whenever possible. In the case of gynecological malignancies, the reliability of the SLN detection procedure has been extensively investigated in vulvar and cervical cancer. This article focuses on the peculiar aspects of intraoperative lymphatic mapping techniques and SLN procedures in endometrial cancer.

  18. Human Papillomavirus in Oral Leukoplakia, Verrucous Carcinoma, Squamous Cell Carcinoma, and Normal Mucous Membrane.

    Science.gov (United States)

    Saghravanian, Nasrollah; Ghazi, Narges; Meshkat, Zahra; Mohtasham, Nooshin

    2015-11-01

    Squamous cell carcinoma (SCC) is the most common oral malignancy, and verrucous carcinoma (VC) is a less invasive type of SCC. Leukoplakia (LP) is the most frequent premalignant lesion in the oral cavity. The human papillomavirus (HPV) has been recognized as one of the etiologic factors of these conditions. The association of anogenital and cervical cancers with HPV particularly its high-risk subtypes (HPV HR) has been demonstrated. The purpose of our study was to investigate the hypothetical association between HPV and the mentioned oral cavity lesions. One hundred and seventy-three samples (114 SCCs, 21 VCs, 20 LPs) and 18 normal mucosa samples (as a control group) were retrieved from the Department of Oral and Maxillofacial Pathology of Mashhad Dental School, Iran. The association of HPV genotypes in LP, VC, and SCC was compared to normal oral mucosa using the polymerase chain reaction. The results showed the absence of HPV in normal mucosa and LP lesions. In three samples of VC (14.3%), we observed the presence of HPV HR (types 16 and 18). All VCs were present in the mandibular ridge of females aged over 65 years old. No statistically significant correlation between HPV and VC was observed (p=0.230). Additionally, 15 (13.1%) SCCs showed HPV positivity, but this was not significant (p=0.830). The prevalence of SCC was higher on the tongue with the dominant presence of less carcinogenic species of HPV (types 6 and 11). A statistically significant association was not observed between HPV and SCC or VC in the oral cavity. More studies are necessary to better understand the relationship between HPV and malignant/premalignant oral cavity lesions.

  19. Human Papillomavirus in Oral Leukoplakia, Verrucous Carcinoma, Squamous Cell Carcinoma, and Normal Mucous Membrane

    Directory of Open Access Journals (Sweden)

    Nasrollah Saghravanian

    2015-11-01

    Full Text Available Objectives: Squamous cell carcinoma (SCC is the most common oral malignancy, and verrucous carcinoma (VC is a less invasive type of SCC. Leukoplakia (LP is the most frequent premalignant lesion in the oral cavity. The human papillomavirus (HPV has been recognized as one of the etiologic factors of these conditions. The association of anogenital and cervical cancers with HPV particularly its high-risk subtypes (HPV HR has been demonstrated. The purpose of our study was to investigate the hypothetical association between HPV and the mentioned oral cavity lesions.  Methods: One hundred and seventy-three samples (114 SCCs, 21 VCs, 20 LPs and 18 normal mucosa samples (as a control group were retrieved from the Department of Oral and Maxillofacial Pathology of Mashhad Dental School, Iran. The association of HPV genotypes in LP, VC, and SCC was compared to normal oral mucosa using the polymerase chain reaction.  Results: The results showed the absence of HPV in normal mucosa and LP lesions. In three samples of VC (14.3%, we observed the presence of HPV HR (types 16 and 18. All VCs were present in the mandibular ridge of females aged over 65 years old. No statistically significant correlation between HPV and VC was observed (p=0.230. Additionally, 15 (13.1% SCCs showed HPV positivity, but this was not significant (p=0.830. The prevalence of SCC was higher on the tongue with the dominant presence of less carcinogenic species of HPV (types 6 and 11. A statistically significant association was not observed between HPV and SCC or VC in the oral cavity.  Conclusions: More studies are necessary to better understand the relationship between HPV and malignant/premalignant oral cavity lesions.

  20. The Anticancer Effects of Radachlorin-mediated Photodynamic Therapy in the Human Endometrial Adenocarcinoma Cell Line HEC-1-A.

    Science.gov (United States)

    Kim, Su-Mi; Rhee, Yun-Hee; Kim, Jong-Soo

    2017-11-01

    We investigated the effect of photodynamic therapy (PDT) using radachlorin on invasion, vascular formation and apoptosis by targeting epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways in the HEC-1-A endometrial adenocarcinoma cell line. To investigate the apoptotic pathway, we performed the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and western blot analysis. We also evaluated the effects of PDT on tubular capillary formation in and invasion by HEC-1-A cells with a tube formation assay, invasion assay, prostaglandin E2 (PGE2) assay, and western blot analysis. PDT had anticancer effects on HEC-1-A through activation of the intrinsic pathway of apoptosis via caspase-9 and poly-(ADP-ribose) polymerase (PARP). PDT also inhibited tubular capillary formation in and invasion by HEC-1-A under VEGF pretreatment, that resulted from down-regulation of VEGFR2, EGFR, Ras homolog gene family/ member A (RhoA) and PGE2. These results are indicative of the specificity of radachlorin-mediated PDT to VEGF. The major advantage of radachlorin-mediated PDT is its selectivity for cancer tissue while maintaining adjacent normal endometrial tissue. Therefore, radachlorin-mediated PDT might offer high anticancer efficacy for endometrial adenocarcinoma and an especially useful modality for preserving fertility. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  1. Human endometrial milk fat globule-epidermal growth factor 8 (MFGE8) is up regulated by estradiol at the transcriptional level, and its secretion via microvesicles is stimulated by human chorionic gonadotropin (hCG)

    KAUST Repository

    Sarhan, Abbaa

    2013-10-17

    Objective: We have recently showed that MFGE8, a novel epithelial cell protein in the human endometrium, upregulated during the window of implantation. We hypothesized that MFGE8 may act as a key modulator of endometrial remodeling and trophoblast invasion. The aims of this study were (i) to investigate the in vitro regulation of human endometrial epithelial cells MFGE8 transcription, translation, and secretion by sex steroids and hCG; and (ii) to examine the possibility of MFGE8 secretion via microvesicles. Design: Experimental in vitro study using Ishikawa cells. Setting: University center. Interventions: Treatment with estradiol (E2), progesterone (P4), and human chorionic gonatropin (hCG). Main outcome measures: MFGE8 mRNA and protein expression, and identification of secreted microvesicles by mass spectrometry (MS) and immunoblotting. Results: E2, but not P4 or hCG, significantly upregulated MFGE8 mRNA expression. hCG significantly increased MFGE8 secretion. Microvesicels obtained after ultracentrifugation were visualized with atomic force microscopy ranging from ~100 to 200 nm. In addition to the expected 46 kD protein, the microvesicles contained a second form of secreted MFGE8 measuring ~30 kD which was confirmed by MS. Conclusions: We demonstrated (i) dual effects of E2 and hCG on the regulation of MFGE8, and (ii) MFGE8 protein secretion in association with microvesicles. MFGE8 has the potential to modulate endometrial function and implantation via exocrine and/ or paracrine-autocrine effects. To the best of our knowledge, this is the first demonstration of microvesicular secretion of any regulatory protein by endometrial epithelial cells, providing initial evidence suggestive of microvesicular participation in cellular trafficking information in the non-pregnant and pregnant endometrium.

  2. Development of a xeno-free non-contact co-culture system for derivation and maintenance of embryonic stem cells using a novel human endometrial cell line.

    Science.gov (United States)

    Desai, Nina; Ludgin, Jennifer; Goldberg, Jeffrey; Falcone, Tommaso

    2013-06-01

    Mouse embryonic fibroblast feeder layers (MEF) have conventionally been used to culture and maintain the pluripotency of embryonic stem cells (ESC). This study explores the potential of using a novel human endometrial cell line to develop a non-xeno, non-contact co-culture system for ESC propagation and derivation. Such xeno-free systems may prove essential for the establishment of clinical grade human ESC lines suitable for therapeutic application. A novel line of human endometrial cells were seeded in a 6-well dish. Filter inserts containing mouse ESCs were placed on these wells and passaged 2-3 times per week. Inner cell masses derived from mouse blastocysts were also cultured on transwells in the presence of the feeder layer. In both cases, staining for SSEA-1, SOX-2, OCT-4 and alkaline phosphatase were used to monitor the retention of stem cells. ESC colonies retained their stem cell morphology and attributes for over 120 days in culture and 44 passages to date. Inner cell mass derived ESC cultures were maintained in a pluripotent state for 45 days, through 6 passages with retention of all stem cell characteristics. The stem cell colonies expressed stem cell specific markers SSEA-1, Sox 2, Oct-4 and alkaline phosphatase. Upon removal of the human feeder layer, there was a distinct change in cell morphology within the colonies and evidence of ESC differentiation. Human feeder layers offer a simple path away from the use of MEF feeder cells or MEF conditioned medium for ESC culture. Furthermore, indirect co-culture using porous membranes to separate the two cell types can prevent contamination of stem cell preparations with feeder cells during passaging.

  3. Stem cell-like properties of the endometrial side population: implication in endometrial regeneration.

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    Hirotaka Masuda

    Full Text Available BACKGROUND: The human endometrium undergoes cyclical regeneration throughout a woman's reproductive life. Ectopic implantation of endometrial cells through retrograde menstruation gives rise to endometriotic lesions which affect approximately 10% of reproductive-aged women. The high regenerative capacity of the human endometrium at eutopic and ectopic sites suggests the existence of stem/progenitor cells and a unique angiogenic system. The objective of this study was to isolate and characterize putative endometrial stem/progenitor cells and to address how they might be involved in the physiology of endometrium. METHODOLOGY/PRINCIPAL FINDINGS: We found that approximately 2% of the total cells obtained from human endometrium displayed a side population (SP phenotype, as determined by flow cytometric analysis of Hoechst-stained cells. The endometrial SP (ESP cells exhibited preferential expression of several endothelial cell markers compared to endometrial main population (EMP cells. A medium specific for endothelial cell culture enabled ESP cells to proliferate and differentiate into various types of endometrial cells, including glandular epithelial, stromal and endothelial cells in vitro, whereas in the same medium, EMP cells differentiated only into stromal cells. Furthermore, ESP cells, but not EMP cells, reconstituted organized endometrial tissue with well-delineated glandular structures when transplanted under the kidney capsule of severely immunodeficient mice. Notably, ESP cells generated endothelial cells that migrated into the mouse kidney parenchyma and formed mature blood vessels. This potential for in vivo angiogenesis and endometrial cell regeneration was more prominent in the ESP fraction than in the EMP fraction, as the latter mainly gave rise to stromal cells in vivo. CONCLUSIONS/SIGNIFICANCE: These results indicate that putative endometrial stem cells are highly enriched in the ESP cells. These unique characteristics suggest that

  4. Endometrial infusion of human chorionic gonadotropin at the time of blastocyst embryo transfer does not impact clinical outcomes: a randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Hong, Kathleen H; Forman, Eric J; Werner, Marie D; Upham, Kathleen M; Gumeny, Christina L; Winslow, Ayesha D; Kim, Thomas J; Scott, Richard T

    2014-12-01

    To determine whether endometrial hCG infusion at the time of human blastocyst transfer impacts implantation rates. Randomized double-blinded placebo-controlled trial. Academic. Infertile couples with the female partner less than 43 years old (n = 300) undergoing fresh or frozen ET of one or two blastocysts. Patients undergoing ET were randomized into either a treatment or a control group. The treatment group received an infusion of 500 IU of hCG diluted in ET media. The control group received a sham infusion of ET media. Infusions were done using a separate catheter less than 3 minutes before actual ET. Sustained implantation rate: ongoing viable gestation (primary outcome) and ongoing pregnancy rate (secondary outcome). A total of 473 blastocysts were transferred into 300 patients. There were no differences between the two groups in sustained implantation rate (48.1% in the hCG group, 44.2% in the control group) or ongoing pregnancy rate (58.8% in the hCG group, 52.0% in the control group). Endometrial infusion of hCG at the time of blastocyst ET does not improve sustained implantation rates. NCT01643993. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Human papillomavirus detection in moroccan patients with nasopharyngeal carcinoma

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    Belghmi Khalid

    2011-02-01

    Full Text Available Abstract Background Nasopharyngeal carcinoma (NPC is a malignant tumor which arises in surface epithelium of the posterior wall of the nasopharynx. There's is evidence that Epstein Barr virus (EBV is associated to NPC development. However, many epidemiologic studies point to a connection between viral infections by the human papillomavirus (HPV and NPC. Method Seventy Moroccan patients with NPC were screened for EBV and HPV. EBV detection was performed by PCR amplification of BZLF1 gene, encoding the ZEBRA (Z Epstein-Barr Virus Replication Activator protein, and HPV infection was screened by PCR amplification with subsequent typing by hybridization with specific oligonucleotides for HPV types 16, 18, 31, 33, 35, 45 and 59. Results The age distribution of our patients revealed a bimodal pattern. Sixty two cases (88.9% were classified as type 3 (undifferentiated carcinoma, 6 (8.6% as type 2 (non keratinizing NPC and only 2 (2.9% cases were classified as type 1 (keratinizing NPC. EBV was detected in all NPC tumors, whereas HPV DNA was revealed in 34% of cases (24/70. Molecular analysis showed that 20.8% (5/24 were infected with HPV31, and the remaining were infected with other oncogenic types (i.e., HPV59, 16, 18, 33, 35 and 45. In addition, statistical analysis showed that there's no association between sex or age and HPV infection (P > 0.1. Conclusion Our data indicated that EBV is commonly associated with NPC in Moroccan patients and show for the first time that NPC tumours from Moroccan patients harbour high risk HPV genotypes.

  6. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

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    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  7. Is the endometrial evaluation routinely required in patients with adult granulosa cell tumors of the ovary?

    Science.gov (United States)

    Ottolina, Jessica; Ferrandina, Gabriella; Gadducci, Angiolo; Scollo, Paolo; Lorusso, Domenica; Giorda, Giorgio; Breda, Enrico; Savarese, Antonella; Candiani, Massimo; Zullo, Fulvio; Mangili, Giorgia

    2015-02-01

    Granulosa cell tumors (GCTs) are the most common estrogen-secreting ovarian tumors; perhaps due to the persistent hyperestrogenism, a wide spectrum of associated endometrial pathologies ranging from endometrial hyperplasia to carcinoma has been documented in patients with GCTs. The aim of this study is to evaluate the incidence of endometrial pathologies in a large series of GCT patients treated in MITO centers. A retrospective multi-institutional review of patients with granulosa cell tumors of the ovary treated or referred to MITO centers was conducted. Descriptive statistics were used to characterize the patient population and to assess the association of GCT and endometrial abnormalities at the time of diagnosis; multivariate regression analysis was also performed to identify independent predictors of endometrial abnormalities. A total of 150 patients with primary adult GCT was identified. During the preoperative assessment, endometrial pathology was found in 35.9% of symptomatic patients and in 90.9% of asymptomatic women with endometrial thickening at transvaginal ultrasound. At the time of surgery, hyperplasia was documented in 29.2% of patients, whereas endometrial cancer occurred in 7.5% of patients. Almost all of the patients (97.6%) with endometrial hyperplasia were older than 40years. All patients with endometrial cancer were older than 40years and postmenopausal. Endometrial carcinoma/atypical hyperplasia were commonly observed in GCT patients >40years; based on these data, endometrial sampling should be performed in symptomatic women at least 40years of age. In asymptomatic women <40years, endometrial sampling is of low yield. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Endometrial adenocarcinoma after endometrial ablation. A case report

    OpenAIRE

    Areia, AL; Branco, M; Frutuoso, C; Oliveira, CF

    2006-01-01

    The authors present a case of endometrial adenocarcinoma after endometrial ablation, emphasizing the importance of close surveillance of these patients, patient selection and education. Even patients with none of the risk factors for endometrial cancer or contraindications to endometrial ablation should be checked carefully.

  9. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: A morphological and immunohistochemical study

    Directory of Open Access Journals (Sweden)

    Jauniaux Eric

    2004-07-01

    Full Text Available Abstract Background The maternal circulation to the human placenta is not fully established until 10–12 weeks of pregnancy. During the first trimester the intervillous space is filled by a clear fluid, in part derived from secretions from the endometrial glands via openings in the basal plate. The aim was to determine the activity of the glands throughout the first trimester, and to identify components of the secretions. Methods Samples of human decidua basalis from 5–14 weeks gestational age were examined by transmission electron microscopy and immunohistochemically. An archival collection of placenta-in-situ samples was also reviewed. Results The thickness of the endometrium beneath the implantation site reduced from approximately 5 mm at 6 weeks to 1 mm at 14 weeks of gestation. The glandular epithelium also transformed from tall columnar cells, packed with secretory organelles, to a low cuboidal layer over this period. The lumens of the glands were always filled with precipitated secretions, and communications with the intervillous space could be traced until at least 10 weeks. The glandular epithelium reacted strongly for leukaemia inhibitory factor, vascular endothelial growth factor, epidermal growth factor, transforming growth factor beta, alpha tocopherol transfer protein, MUC-1 and glycodelin, and weakly for lactoferrin. As gestation advanced uterine natural killer cells became closely approximated to the basal surface of the epithelium. These cells were also immunopositive for epidermal growth factor. Conclusions Morphologically the endometrial glands are best developed and most active during early human pregnancy. The glands gradually regress over the first trimester, but still communicate with the intervillous space until at least 10 weeks. Hence, they could provide an important source of nutrients, growth factors and cytokines for the feto-placental unit. The endometrium may therefore play a greater role in regulating placental

  10. Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection.

    Science.gov (United States)

    Qing, Song; Tulake, Wuniqiemu; Ru, Mingfang; Li, Xiaohong; Yuemaier, Reziwanguli; Lidifu, Dilare; Rouzibilali, Aierken; Hasimu, Axiangu; Yang, Yun; Rouziahong, Reziya; Upur, Halmurat; Abudula, Abulizi

    2017-04-01

    It is known that high-risk human papillomavirus infection is the main etiological factor in cervical carcinogenesis. However, human papillomavirus screening is not sufficient for early diagnosis. In this study, we aimed to identify potential biomarkers common to cervical carcinoma and human papillomavirus infection by proteomics for human papillomavirus-based early diagnosis and prognosis. To this end, we collected 76 cases of fresh cervical tissues and 116 cases of paraffin-embedded tissue slices, diagnosed as cervical squamous cell carcinoma, cervical intraepithelial neoplasia II-III, or normal cervix from ethnic Uighur and Han women. Human papillomavirus infection by eight oncogenic human papillomavirus types was detected in tissue DNA samples using a quantitative polymerase chain reaction. The protein profile of cervical specimens from human papillomavirus 16-positive squamous cell carcinoma and human papillomavirus-negative normal controls was analyzed by proteomics and bioinformatics. The expression of candidate proteins was further determined by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. We identified 67 proteins that were differentially expressed in human papillomavirus 16-positive squamous cell carcinoma compared to normal cervix. The quantitative reverse transcriptase-polymerase chain reaction analysis verified the upregulation of ASAH1, PCBP2, DDX5, MCM5, TAGLN2, hnRNPA1, ENO1, TYPH, CYC, and MCM4 in squamous cell carcinoma compared to normal cervix ( p potentially associated with human papillomavirus infection. Further validation studies of the profile will contribute to establishing auxiliary diagnostic markers for human papillomavirus-based cancer prognosis.

  11. Cadmium Chloride Induces DNA Damage and Apoptosis of Human Liver Carcinoma Cells via Oxidative Stress

    National Research Council Canada - National Science Library

    Skipper, Anthony; Sims, Jennifer N; Yedjou, Clement G; Tchounwou, Paul B

    2016-01-01

    ... mechanisms of action are not fully elucidated. In this research, we hypothesized that oxidative stress plays a key role in cadmium chloride-induced toxicity, DNA damage, and apoptosis of human liver carcinoma (HepG₂) cells...

  12. Human papillomavirus (HPV) in vulvar dysplasia and carcinoma in situ

    DEFF Research Database (Denmark)

    Junge, Jette; Poulsen, H; Horn, T

    1995-01-01

    Surgical specimens from 62 patients with vulvar dysplasia and carcinoma in situ were morphologically investigated. Lesions were classified according to WHO (mild, moderate, severe dysplasia and carcinoma in situ) and according to Toki et al. (1991) (warty, basaloid, combined warty/basaloid or bas...

  13. hCG activates Epac-Erk1/2 signaling regulating Progesterone Receptor expression and function in human endometrial stromal cells.

    Science.gov (United States)

    Tapia-Pizarro, Alejandro; Archiles, Sebastián; Argandoña, Felipe; Valencia, Cecilia; Zavaleta, Keyla; Cecilia Johnson, M; González-Ramos, Reinaldo; Devoto, Luigi

    2017-06-01

    How does hCG signal in human endometrial stromal cells (ESCs) and what is its role in regulating ESC function? hCG signaling in ESCs activates the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) pathway through exchange protein activated by cyclic AMP (cAMP) (Epac) and transiently increases progesterone receptor (PR) transcript and protein expression and its transcriptional function. hCG is one of the earliest embryo-derived secreted signals in the endometrium, which abundantly expresses LH/hCG receptors. hCG signals through cAMP/protein kinase A (PKA) in gonadal cells, but in endometrial epithelial cells, hCG induces Erk1/2 activation independent of the cAMP/PKA pathway. Few data exist concerning the signal transduction pathways triggered by hCG in ESCs and their role in regulation of ESC function. This is an in vitro study comprising patients undergoing benign gynecological surgery (n = 46). Endometrial samples were collected from normal cycling women during the mid-secretory phase for ESCs isolation. The study conducted in an academic research laboratory within a tertiary-care hospital. The activation of the Erk1/2 signal transduction pathway elicited by hCG was evaluated in ESC. Signaling pathway inhibitors were used to examine the roles of PKA, PI3K, PKC, adenylyl cyclase and Epac on the hCG-stimulated up-regulation of phospho-Erk1/2 (pErk1/2). Erk1/2 phosphorylation was determined by immunoblot. siRNA targeting Epac was used to investigate the molecular mechanisms. To assess the role of Erk1/2 signaling induced by hCG on ESC function, gene expression regulation was examined by immunofluorescence and real-time quantitative PCR. The role of PR on the regulation of transcript levels was studied using progesterone and the PR antagonist RU486. All experiments were conducted using at least three different cell culture preparations in triplicate. Addition of hCG to ESCs in vitro induced the phosphorylation of Erk1/2 through cAMP accumulation. Such

  14. Lobaplatin arrests cell cycle progression in human hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Chen Chang-Jie

    2010-10-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC still is a big burden for China. In recent years, the third-generation platinum compounds have been proposed as potential active agents for HCC. However, more experimental and clinical data are warranted to support the proposal. In the present study, the effect of lobaplatin was assessed in five HCC cell lines and the underlying molecular mechanisms in terms of cell cycle kinetics were explored. Methods Cytotoxicity of lobaplatin to human HCC cell lines was examined using MTT cell proliferation assay. Cell cycle distribution was determined by flow cytometry. Expression of cell cycle-regulated genes was examined at both the mRNA (RT-PCR and protein (Western blot levels. The phosphorylation status of cyclin-dependent kinases (CDKs and retinoblastoma (Rb protein was also examined using Western blot analysis. Results Lobaplatin inhibited proliferation of human HCC cells in a dose-dependent manner. For the most sensitive SMMC-7721 cells, lobaplatin arrested cell cycle progression in G1 and G2/M phases time-dependently which might be associated with the down-regulation of cyclin B, CDK1, CDC25C, phosphorylated CDK1 (pCDK1, pCDK4, Rb, E2F, and pRb, and the up-regulation of p53, p21, and p27. Conclusion Cytotoxicity of lobaplatin in human HCC cells might be due to its ability to arrest cell cycle progression which would contribute to the potential use of lobaplatin for the management of HCC.

  15. Prognostic Value of Focal Adhesion Kinase (FAK in Human Solid Carcinomas: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Xiao-Qing Zeng

    Full Text Available Recently, the number of reports on focal adhesion kinase (FAK as a vital therapeutic target in solid carcinomas has increased; however, the prognostic role of FAK status remains poorly understood. This study aims to evaluate the prognostic effect of FAK by means of a meta-analysis.We performed a systematic literature search in order to examine the correlation between expression of FAK and overall survival(OS. The hazard ratio (HR of OS was used to measure survival. A random-effects model was used to pool study statistics. Sensitivity and publication bias analyses were also conducted.Thirty eligible studies involving 4702 patients were included. The median expression rate of FAK was 54%. Meta-analysis of the HRs demonstrated that high FAK expression was associated with worse OS (average HR = 2.073, 95%confidence interval[CI]:1.712-2.510, p = 0.000. Regarding cancer type, FAK was associated with worse OS in gastric cancer (HR = 2.646,95% CI:1.743-4.017, p = 0.000, hepatocellular carcinoma (HR = 1.788,95% CI:1.228-2.602, p = 0.002, ovarian cancer (HR = 1.815, 95% CI: 1.193-2.762, p = 0.005, endometrial cancer (HR = 4.149, 95% CI:2.832-6.079, p = 0.000, gliomas (HR = 2.650, 95% CI: 1.205-5.829, p = 0.015, and squamous cell carcinoma (HR = 1,696, 95% CI: 1.030-2.793, p = 0.038. No association was found between HR and disease staging according to our meta-regression analysis.Our study shows that high expression of FAK is associated with a worse OS in patients with carcinomas, but the association between FAK and prognosis varies according to cancer type. The value of FAK status in clinical prognosis in cancer needs further research.

  16. [OBESITY AND ENDOMETRIAL CARCINOGENESIS].

    Science.gov (United States)

    Uchikova, E; Uchikov, P; Parahuleva, P

    2015-01-01

    Endometrial cancer is one of the main cancers occurring in industrialized countries. According to the National Cancer Registry in Bulgaria, cancer of the uterine body occupies 8.6% from all cancers in women and ranks second in frequency. It is found that over weight and obesity are a major risk factor for the development of endometrial cancer and the mortality associated with it. Adipose tissue is seen as endocrine organ, synthesizing so called adipocytokine - leptin, adiponectin, vistafin, that play a key role in the carcinogenesis of endometrial cancer and can be used as new markers for establishing the potential risk of this disease. The link between obesity, insulin resistance and endometrial cancer that has been proven, determines it as a socially significant disease. All this makes it necessary to clarify and specify the role of obesity in endometrial carcinogenesis and the development of strategies for the prevention and early diagnosis.

  17. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation

    OpenAIRE

    Magaldi, Thomas G.; Almstead, Laura L.; Bellone, Stefania; Prevatt, Edward G.; Santin, Alessandro D.; DiMaio, Daniel

    2012-01-01

    Repression of human papillomavirus (HPV) E6 and E7 oncogenes in established cervical carcinoma cell lines causes senescence due to reactivation of cellular tumor suppressor pathways. Here, we determined whether ongoing expression of HPV16 or HPV18 oncogenes is required for the proliferation of primary human cervical carcinoma cells in serum-free conditions at low passage number after isolation from patients. We used an SV40 viral vector expressing the bovine papillomavirus E2 protein to repre...

  18. Local Anesthetics Inhibit the Growth of Human Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Le Gac, Grégoire; Angenard, Gaëlle; Clément, Bruno; Laviolle, Bruno; Coulouarn, Cédric; Beloeil, Hélène

    2017-11-01

    Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapeutic options. Retrospective studies have shown that the administration of local anesthetics (LAs) during cancer surgery could reduce cancer recurrence. Besides, experimental studies reported that LAs could inhibit the growth of cancer cells. Thus, the purpose of this study was to investigate the effects of LAs on human HCC cells. The effects of 2 LAs (lidocaine and ropivacaine) (10 to 10 M) were studied after an incubation of 48 hours on 2 HCC cell lines, namely HuH7 and HepaRG. Cell viability, cell cycle analysis, and apoptosis and senescence tests were performed together with unsupervised genome-wide expression profiling and quantitative real-time polymerase chain reaction for relevant genes. We showed that LAs decreased viability and proliferation of HuH7 cells (from 92% [P lidocaine) and HepaRG progenitor cells (from 58% at 5 × 10 M [P lidocaine and 59% [P Lidocaine had no specific effect on cell cycle but increased by 10× the mRNA level of adenomatous polyposis coli (P < .01), which acts as an antagonist of the Wnt/β-catenin pathway. Both LAs increased apoptosis in Huh7 and HepaRG progenitor cells (P < .01). The data demonstrate that LAs induced profound modifications in gene expression profiles of tumor cells, including modulations in the expression of cell cycle-related genes that result in a cytostatic effect and induction of apoptosis.

  19. The influence of human papillomavirus on nasopharyngeal carcinoma in Japan.

    Science.gov (United States)

    Kano, Makoto; Kondo, Satoru; Wakisaka, Naohiro; Moriyama-Kita, Makiko; Nakanishi, Yosuke; Endo, Kazuhira; Murono, Shigeyuki; Nakamura, Hiroyuki; Yoshizaki, Tomokazu

    2017-06-01

    Although Japan is a non-endemic area with nasopharyngeal carcinoma (NPC), the proportion of WHO type I NPC in Japan are different from that in non-endemic areas such as North America and Europe. Recently, it is said that not only Epstein-Barr virus (EBV) but also human papillomavirus (HPV) has an influence on NPC in non-endemic areas. The aim of this study is to clarify the influence of HPV on NPC in Japan. Paraffin-embedded tumor specimens were available for 59 patients with NPC diagnosed between 1996 and 2015. We detected the virus status by p16 immunohistochemistry, HPV PCR, and in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA. Kaplan-Meier curves were used to compare the overall survival by viral status. Among the 59 patients, 49 (83%) were EBV-positive/HPV-negative, 2 (3%) were EBV-positive/HPV-positive, and 8 (16%) were EBV-negative/HPV-negative. All HPV-positive NPCs were co-infected with EBV. There were no significant differences between the overall survival in the three groups (p=0.111). In Japan, HPV was detected in a few patients with NPC, and we suggest that HPV has no influence on NPC carcinogenesis in this population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. GAGE12 mediates human gastric carcinoma growth and metastasis.

    Science.gov (United States)

    Lee, Eun Kyung; Song, Kyung-A; Chae, Ji-Hye; Kim, Kyoung-Mee; Kim, Seok-Hyung; Kang, Myung-Soo

    2015-05-15

    The spontaneous metastasis from human gastric carcinoma (GC) remains poorly reproduced in animal models. Here, we established an experimental mouse model in which GC progressively developed in the orthotopic stomach wall and metastasized to multiple organs; the tumors colonized in the ovary exhibited typical characteristics of Krukenberg tumor. The expression of mesenchymal markers was low in primary tumors and high in those in intravasating and extravasating veins. However, the expression of epithelial markers did not differ, indicating that the acquisition of mesenchymal markers without a concordant loss of typical epithelial markers was associated with metastasis. We identified 35 differentially expressed genes (DEGs) in GC cells metastasized to ovary, among which overexpression of GAGE12 family genes, the top-ranked DEGs, were validated. In addition, knockdown of the GAGE12 gene family affected transcription of many of the aforementioned 35 DEGs and inhibited trans-well migration, tumor sphere formation in vitro and tumor growth in vivo. In accordance, GAGE12 overexpression augmented migration, tumor sphere formation and sustained in vivo tumor growth. Taken together, the GAGE12 gene family promotes GC growth and metastasis by modulating the expression of GC metastasis-related genes. © 2014 UICC.

  1. Silymarin nanoemulsion against human hepatocellular carcinoma: development and optimization.

    Science.gov (United States)

    Ahmad, Usama; Akhtar, Juber; Singh, Satya Prakash; Ahmad, Farhan Jalees; Siddiqui, Sahabjada

    2018-03-01

    Nanoemulsion of silymarin was developed and optimized. Nanoemulsion was made by aqueous titration method. Sefsol 218 (5.8% v/v), Kolliphor RH40 and polyethylene glycol 400 (Smix; 2:1; 28.99% v/v) were used as oil phase, surfactant and co-surfactant while distilled water (65.22% v/v) acted as an aqueous phase. Nanoemulsion was characterized on the basis of particle size, viscosity, electrical conductivity and refractive index. Further, in vitro release, in vivo pharmacokinetic study, stability study and cancer cell line studies were also performed. The optimized formulation (NE9) with mean particle size of 21.24 nm showed a minimum viscosity of 9.59 cps, maximum drug release (97.75%) in 24 h. The NE9 formulation also showed higher AUC (p  .05). The cancer cell line studies also confirmed that silymarin nanoemulsion reduced the cell viability and increased ROS intensity and chromatin condensation (p nanoemulsion may be an efficient carrier for oral delivery of silymarin against human hepatocellular carcinoma without damaging normal cells.

  2. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas.

    Science.gov (United States)

    Nault, Jean-Charles; Datta, Shalini; Imbeaud, Sandrine; Franconi, Andrea; Mallet, Maxime; Couchy, Gabrielle; Letouzé, Eric; Pilati, Camilla; Verret, Benjamin; Blanc, Jean-Frédéric; Balabaud, Charles; Calderaro, Julien; Laurent, Alexis; Letexier, Mélanie; Bioulac-Sage, Paulette; Calvo, Fabien; Zucman-Rossi, Jessica

    2015-10-01

    Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

  3. Induction of retinoic acid receptor β mediates growth inhibition in retinoid resistant human colon carcinoma cells

    OpenAIRE

    Nicke, B; Riecken, E; Rosewicz, S

    1999-01-01

    BACKGROUND—The molecular mechanisms underlying the differential sensitivity of human colon carcinoma cells to retinoid mediated growth inhibition are poorly understood.
AIM—To identify the intracellular mechanisms responsible for resistance against retinoid mediated growth inhibition in human colon carcinoma cells.
METHODS—Anchorage independent growth of the human colon carcinoma cell lines HT29 and LoVo was determined by a human tumour clonogenic assay. Retinoid receptor expression was evalu...

  4. 7,12-Dimethylbenzanthracene induces apoptosis in RL95-2 human endometrial cancer cells: Ligand-selective activation of cytochrome P450 1B1

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ji Young [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Lee, Seung Gee [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Chung, Jin-Yong [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Kim, Yoon-Jae [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Park, Ji-Eun [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); Oh, Seunghoon [Department of Physiology, College of Medicine, Dankook University, Cheonan 330-714 (Korea, Republic of); Lee, Se Yong [Department of Obstetrics and Gynecology, Busan Medical Center, Busan 611-072 (Korea, Republic of); Choi, Hong Jo [Department of General Surgery, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Yoo, Young Hyun, E-mail: yhyoo@dau.ac.kr [Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Medical Research Science Center, Dong-A University, Busan 602-714 (Korea, Republic of); and others

    2012-04-15

    7,12-Dimethylbenzanthracene (DMBA), a polycyclic aromatic hydrocarbon, exhibits mutagenic, carcinogenic, immunosuppressive, and apoptogenic properties in various cell types. To achieve these functions effectively, DMBA is modified to its active form by cytochrome P450 1 (CYP1). Exposure to DMBA causes cytotoxicity-mediated apoptosis in bone marrow B cells and ovarian cells. Although uterine endometrium constitutively expresses CYP1A1 and CYP1B1, their apoptotic role after exposure to DMBA remains to be elucidated. Therefore, we chose RL95-2 endometrial cancer cells as a model system for studying DMBA-induced cytotoxicity and cell death and hypothesized that exposure to DMBA causes apoptosis in this cell type following CYP1A1 and/or CYP1B1 activation. We showed that DMBA-induced apoptosis in RL95-2 cells is associated with activation of caspases. In addition, mitochondrial changes, including decrease in mitochondrial potential and release of mitochondrial cytochrome c into the cytosol, support the hypothesis that a mitochondrial pathway is involved in DMBA-induced apoptosis. Exposure to DMBA upregulated the expression of AhR, Arnt, CYP1A1, and CYP1B1 significantly; this may be necessary for the conversion of DMBA to DMBA-3,4-diol-1,2-epoxide (DMBA-DE). Although both CYP1A1 and CYP1B1 were significantly upregulated by DMBA, only CYP1B1 exhibited activity. Moreover, knockdown of CYP1B1 abolished DMBA-induced apoptosis in RL95-2 cells. Our data show that RL95-2 cells are susceptible to apoptosis by exposure to DMBA and that CYP1B1 plays a pivotal role in DMBA-induced apoptosis in this system. -- Highlights: ► Cytotoxicity-mediated apoptogenic action of DMBA in human endometrial cancer cells. ► Mitochondrial pathway in DMBA-induced apoptosis of RL95-2 endometrial cancer cells. ► Requirement of ligand-selective activation of CYP1B1 in DMBA-induced apoptosis.

  5. Arsenic trioxide-mediated oxidative stress and genotoxicity in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Alarifi, Saud; Ali, Daoud; Alkahtani, Saad; Siddiqui, Maqsood A; Ali, Bahy A

    2013-01-01

    Arsenic is a ubiquitous environmental toxicant, and abnormalities of the skin, lung, kidney, and liver are the most common outcomes of long-term arsenic exposure. This study was designed to investigate the possible mechanisms of genotoxicity induced by arsenic trioxide in human hepatocellular carcinoma cells. A mild cytotoxic response of arsenic trioxide was observed in human hepatocellular carcinoma cells, as evident by (3-(4,5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) and lactate dehydrogenase assays after 24 and 48 hours of exposure. Arsenic trioxide elicited a significant (P hepatocellular carcinoma cells exposed to arsenic trioxide. The results demonstrate that arsenic trioxide induces apoptosis and genotoxicity in human hepatocellular carcinoma cells through reactive oxygen species and oxidative stress.

  6. High-risk human papillomavirus in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Antonsson, Annika; Nancarrow, Derek J; Brown, Ian S; Green, Adele C; Drew, Paul A; Watson, David I; Hayward, Nicholas K; Whiteman, David C

    2010-08-01

    Although most cases of esophageal squamous cell carcinoma (ESCC) in western populations have been attributed to high levels of exposure to tobacco and alcohol, infectious agents have been postulated as possible causes, particularly human papillomavirus (HPV). To explore this issue, we analyzed HPV DNA prevalence and HPV types together with lifestyle factors, in relation to tumor stage and survival in a low-incidence population. Archived tumor samples from a nationwide cohort of 222 ESCC patients were tested for the presence of HPV DNA by PCR; positive samples were sequenced to determine HPV type, and p16(INK4a) status was assessed by immunohistochemistry. Of 222 ESCC patients, 8 tested HPV positive (prevalence, 3.6%; 95% confidence interval, 1.1-6.1%), of which 6 were HPV-16 positive and 2 were HPV-35 positive. Four of the eight HPV-positive tumors overexpressed p16(INK4a). None of 55 normal esophageal tissue samples from healthy participants had any detectable HPV. Although the numbers were low, it seemed that patients with HPV-positive ESCC tumors were younger than those with HPV-negative tumors (mean age, 60.8 versus 65.3 years, P = 0.18) and had higher body mass index (BMI) throughout life (mean current BMI of 25.1 for HPV positive, 22.2 for HPV negative, P = 0.08; mean BMI at 20 years of 25.8 for HPV positive, 22.1 for HPV negative, P = 0.003). We found no difference between patients with HPV-positive and HPV-negative tumors with respect to other lifestyle factors. These findings suggest a very low prevalence of HPV DNA in human ESCC. HPV is very unlikely to be a common cause of ESCC in Australia. (c)2010 AACR.

  7. Human papillomavirus-related basaloid squamous cell carcinoma of the bladder associated with genital tract human papillomavirus infection.

    Science.gov (United States)

    Ginori, Alessandro; Barone, Aurora; Santopietro, Rosa; Barbanti, Gabriele; Cecconi, Filippo; Tripodi, Sergio Antonio

    2015-02-01

    Basaloid squamous cell carcinoma is a biologically aggressive neoplasm mainly found in the head and neck region. Recently, four cases of basaloid squamous cell carcinoma of the bladder have been reported, and three of them occurred in patients with neurogenic bladder, repeated catheterizations and human papillomavirus infection of the urinary tract. To the best of our knowledge, none of the patients affected by basaloid squamous cell carcinoma of the bladder described in the literature had documented genital involvement by human papillomavirus. Herein, we describe the case of a woman with neurogenic bladder affected by basaloid squamous cell carcinoma of the bladder and by a concomitant genital tract human papillomavirus infection. © 2014 The Japanese Urological Association.

  8. Dynamic protein interaction modules in human hepatocellular carcinoma progression.

    Science.gov (United States)

    Yu, Hui; Lin, Chen-Ching; Li, Yuan-Yuan; Zhao, Zhongming

    2013-01-01

    Gene expression profiles have been frequently integrated with the human protein interactome to uncover functional modules under specific conditions like disease state. Beyond traditional differential expression analysis, differential co-expression analysis has emerged as a robust approach to reveal condition-specific network modules, with successful applications in a few human disease studies. Hepatocellular carcinoma (HCC), which is often interrelated with the Hepatitis C virus, typically develops through multiple stages. A comprehensive investigation of HCC progression-specific differential co-expression modules may advance our understanding of HCC's pathophysiological mechanisms. Compared with differentially expressed genes, differentially co-expressed genes were found more likely enriched with Hepatitis C virus binding proteins and cancer-mutated genes, and they were clustered more densely in the human reference protein interaction network. These observations indicated that a differential co-expression approach could outperform the standard differential expression network analysis in searching for disease-related modules. We then proposed a differential co-expression network approach to uncover network modules involved in HCC development. Specifically, we discovered subnetworks that enriched differentially co-expressed gene pairs in each HCC transition stage, and further resolved modules with coherent co-expression change patterns over all HCC developmental stages. Our identified network modules were enriched with HCC-related genes and implicated in cancer-related biological functions. In particular, APC and YWHAZ were highlighted as two most remarkable genes in the network modules, and their dynamic interaction partnership was resolved in HCC development. We demonstrated that integration of differential co-expression with the protein interactome could outperform the traditional differential expression approach in discovering network modules of human diseases

  9. The prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is dependent on concurrent overexpression of Human Leucocyte Antigen-E in the tumour microenvironment.

    Science.gov (United States)

    Versluis, M A C; Marchal, S; Plat, A; de Bock, G H; van Hall, T; de Bruyn, M; Hollema, H; Nijman, H W

    2017-11-01

    Human Leucocyte Antigen- E (HLA-E) has been reported as both a positive and negative prognostic marker in cancer. This apparent discrepancy may be due to opposing actions of HLA-E on tumour-infiltrating immune cells. Therefore, we evaluated HLA-E expression and survival in relation to the presence of intratumoural natural killer (NK) cells and cytotoxic T cells (CTLs). Tissue microarrays (TMAs) of endometrial tumours were used for immunohistochemical staining of parameters of interest. The combined impact of clinical, pathological and immune parameters on survival was analysed using log rank testing and Cox regression analyses. Upregulation of HLA-E was associated with an improved disease-free and disease-specific survival in univariate analysis (HR 0.58 95% CI 0.37-0.89; HR 0.42 95% CI 0.25-0.73, respectively). In multivariate analysis, the presence of NK cells predicts survival with a hazard ratio (HR) 0.28 (95% confidence interval (CI) 0.09-0.91) when HLA-E expression is upregulated; but it is associated with a worse prognosis when HLA-E expression is normal (HR 13.43, 95% CI 1.70-106.14). By contrast, the prognostic benefit of T cells was not modulated by HLA-E expression. Taken together, we demonstrate that the prognostic benefit of NK cells, but not T-cells, is influenced by HLA-E expression in endometrial cancer (EC) and propose a model to explain our observations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis.

    Science.gov (United States)

    Ma, Xianyong; Wang, Jinglan; Wang, Jianhui; Ma, Charles X; Gao, Xiaobin; Patriub, Vytas; Sklar, Jeffrey L

    2017-01-17

    The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17). Co-transient transfection assay indicated JAZF1-SUZ12 destabilized PRC2 components EZH2 and EED, resulting in decreased histone methyl transferase (HMT) activity, which was confirmed by in vitro studies using reconstituted PRC2 and nucleosome array substrates. We also demonstrated the PRC2 containing the fusion protein decreased the binding affinity to target chromatin loci. In addition, we found that trimethylation of H3K27 was decreased in ESS samples with the t(7;17), but there was no detectable change in H3K9 in these tissues. Moreover, re-expression of SUZ12 in Suz12 (-/-) ES cells rescued the neuronal differentiation while the fusion protein failed to restore this function and enhanced cell proliferation. In summary, our studies reveal that JAZF1-SUZ12 fusion protein disrupts the PRC2 complex, abolishes HMT activity and subsequently activates chromatin/genes normally repressed by PRC2. Such dyesfunction of PRC2 inhibits normal neural differentiation of ES cell and increases cell proliferation. Related changes induced by the JAZF-SUZ12 protein in endometrial stromal cells may explain the oncogenic effect of the t(7;17) in ESS.

  11. The Impact of Endometrial Thickness on the Day of Human Chorionic Gonadotrophin (hCG) Administration on Ongoing Pregnancy Rate in Patients with Different Ovarian Response.

    Science.gov (United States)

    Bu, Zhiqin; Sun, Yingpu

    2015-01-01

    In order to explore the impact of endometrial thickness on hCG administration day on ongoing pregnancy rate (OPR) in IVF-ET cycles, we retrospectively analyzed data from 10,406 patients undergoing their first IVF cycles with standard gonadotropin releasing hormone analogue (GnRH-a) long protocol. Firstly, patients were divided into poor (≤ 5 oocytes), medium (6-14 oocytes), and high (≥ 15 oocytes) ovarian responders based on the number of oocytes retrieved. In each group, patients were sub-divided into three groups according to the endometrial thickness on the day of hCG administration: Group A, thin endometrial thickness (≤ 7 mm); Group B, medium endometrial thickness (8-13 mm); Group C, thick endometrial thickness (≥ 14 mm). (1) For poor responders, OPRs were significantly different in the three endometrial thickness groups (28.57%, 44.25%, and 51.34%; P = 0.008). The association between thin endometrial thickness and OPR was significant after controlling for age, number of embryos transferred by multivariate logistic regression analysis (adjusted OR: 0.408; 95% CI: 0.186-0.898; P = 0.026. Reference = thick endometrial thickness). (2) For medium responders, OPRs were 31.58%, 55.56%, and 63.01% (P = 0.000) in the three groups. Adjusted OR for thin endometrial thickness was 0.284 (95% CI: 0.182-0.444; P = 0.000). (3) For high responders, OPRs were also significantly different in the three groups (28.13%, 52.63%, and 63.18; P = 0.000). Adjusted OR for thin endometrial thickness was 0.233 (95% CI: 0.105-0.514; P = 0.000). For patients undergoing IVF with different ovarian response, a thin endometrium on the day of hCG administration adversely affects ongoing pregnancy rate.

  12. Automated quantification of aligned collagen for human breast carcinoma prognosis

    Directory of Open Access Journals (Sweden)

    Jeremy S Bredfeldt

    2014-01-01

    Full Text Available Background: Mortality in cancer patients is directly attributable to the ability of cancer cells to metastasize to distant sites from the primary tumor. This migration of tumor cells begins with a remodeling of the local tumor microenvironment, including changes to the extracellular matrix and the recruitment of stromal cells, both of which facilitate invasion of tumor cells into the bloodstream. In breast cancer, it has been proposed that the alignment of collagen fibers surrounding tumor epithelial cells can serve as a quantitative image-based biomarker for survival of invasive ductal carcinoma patients. Specific types of collagen alignment have been identified for their prognostic value and now these tumor associated collagen signatures (TACS are central to several clinical specimen imaging trials. Here, we implement the semi-automated acquisition and analysis of this TACS candidate biomarker and demonstrate a protocol that will allow consistent scoring to be performed throughout large patient cohorts. Methods: Using large field of view high resolution microscopy techniques, image processing and supervised learning methods, we are able to quantify and score features of collagen fiber alignment with respect to adjacent tumor-stromal boundaries. Results: Our semi-automated technique produced scores that have statistically significant correlation with scores generated by a panel of three human observers. In addition, our system generated classification scores that accurately predicted survival in a cohort of 196 breast cancer patients. Feature rank analysis reveals that TACS positive fibers are more well-aligned with each other, are of generally lower density, and terminate within or near groups of epithelial cells at larger angles of interaction. Conclusion: These results demonstrate the utility of a supervised learning protocol for streamlining the analysis of collagen alignment with respect to tumor stromal boundaries.

  13. ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma

    DEFF Research Database (Denmark)

    Porter, Sarah; Span, Paul N; Sweep, Fred C G J

    2006-01-01

    We recently undertook expression profiling of all 19 human ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin motifs) in malignant and non-neoplastic breast tissue and showed that 11 of the ADAMTS genes are dysregulated in breast carcinoma. We identified a subgroup...... of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma. Further RNA expression analysis by real-time PCR on a different cohort of 229 patients with breast cancer has identified ADAMTS8 as a predictor of poor overall...... breast carcinoma, fitted the expectation that relatively high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 seen in human breast carcinoma are associated with a poor clinical outcome. In summary, ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients...

  14. Griffonia simplicifolia agglutinin-2-binding glycoprotein as a novel carbohydrate antigen of human colonic carcinoma.

    Science.gov (United States)

    Nakayama, J; Okano, A; Maeda, H; Miyachi, M; Ota, H; Katsuyama, T; Kanai, M

    1990-04-01

    Griffonia simplicifolia agglutinin-2-binding glycoprotein (GBG) in human colonic carcinoma was examined immunochemically and histochemically, GBG was extracted from colonic carcinoma as a serum-type glycoprotein of 160 kilodaltons. GBG was not identical with carcinoembryonic antigen (CEA), since its molecular weight and localization in tissue sections were different from those of CEA. The non-reducing terminals of GBG probably carry N-acetylglucosamine, but not blood group determinants. Furthermore, GBG was released by phosphatidylinositol-specific phospholipase C from cell membrane. GBG was suggested to be anchored to the membrane via linkage to a glycosyl-phosphatidylinositol molecule. Among colonic carcinoma-associated antigens, serum-type glycoproteins having N-acetylglucosamine at non-reducing terminals have not previously been reported. GBG is a novel carbohydrate antigen of human colonic carcinoma.

  15. Long-term survival outcomes of laparoscopic staging surgery in treating endometrial cancer: 20 years of follow-up

    Directory of Open Access Journals (Sweden)

    Chyi-Long Lee

    2016-08-01

    Conclusions: Patients with endometrial carcinoma treated by LSS had compatible or even better long-term survival outcomes and less complication in comparison with the published data, in addition to the benefits of its minimally invasive characteristics. LSS should be the treatment of choice for endometrial cancer.

  16. Human papillomavirus-driven neck lymph node metastases from oropharyngeal or unknown primary squamous cell carcinoma

    OpenAIRE

    Schroeder, Lea

    2017-01-01

    Patients with neck squamous cell carcinoma from unknown primary tumor (NSCCUP) present with lymph node metastases without evidence for a primary tumor. Most patients undergo an aggressive multimodal treatment, which induces severe toxicity. Primary tumors of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers f...

  17. ATX‑LPA axis facilitates estrogen‑induced endometrial cancer cell proliferation via MAPK/ERK signaling pathway.

    Science.gov (United States)

    Zhang, Guo; Cheng, Yuan; Zhang, Qi; Li, Xiaoping; Zhou, Jingwei; Wang, Jianliu; Wei, Lihui

    2018-03-01

    Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX is a crucial factor that facilitates cancer progression; however, the effect of ATX on endometrial cancer has not been explored. The aim of the present study was to investigate the role of ATX in the progression of endometrial cancer. The immunohistochemical results revealed higher protein expression levels of ATX and LPA receptors (LPA 1, 2 and 3) in human endometrial cancer tissue than in non‑carcinoma tissue. In addition, reverse transcription‑quantitative polymerase chain reaction and western blotting analysis demonstrated that ATX and LPA receptor mRNA and protein expression was greater in Ishikawa cells, which are positive for estrogen receptor (ER), than in Hec‑1A cells that exhibit low ER expression. Short interfering RNA knockdown of ATX in Ishikawa cells led to decreased cell proliferation and cell colony number, as determined by Cell Counting kit‑8 and colony formation assays. Estrogen stimulated ATX mRNA expression. Inhibition of ATX decreased estrogen and LPA‑induced cell proliferation. High LPA levels markedly elevated the phosphorylation levels of extracellular signal‑regulated kinase (ERK). ATX downregulation moderately decreased estrogen‑ and LPA‑induced phosphorylation of ERK. In addition, the ERK inhibitor, PD98059, reduced cell proliferation with estrogen, ATX and LPA treatment. The present study suggested that the ATX‑LPA axis may facilitate estrogen‑induced cell proliferation in endometrial cancer via the mitogen‑activated protein kinase/ERK signaling pathway. The present study may provide ideas and an experimental basis for clinicians to identify new molecular targeted drugs for the treatment of endometrial cancer.

  18. Establishment of human patient-derived endometrial cancer xenografts in NOD scid gamma mice for the study of invasion and metastasis.

    Directory of Open Access Journals (Sweden)

    Kenji Unno

    Full Text Available Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis.Endometrial tumor tissue fragments (1.5 mm × 1.5 mm from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6-8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers.Four cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor α, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor.Endometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer.

  19. Albumin Suppresses Human Hepatocellular Carcinoma Proliferation and the Cell Cycle

    Directory of Open Access Journals (Sweden)

    Shunsuke Nojiri

    2014-03-01

    Full Text Available Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of HCC has not yet been elucidated, so we investigated the effect of serum albumin on HCC cell proliferation. Hep3B was cultured in MEM with no serum or containing 5 g/dL human albumin. As control samples, Prionex was added to generate the same osmotic pressure as albumin. After 24-h incubation, the expressions of α-fetoprotein (AFP, p53, p21, and p57 were evaluated with real-time PCR using total RNA extracted from the liver. Protein expressions and the phosphorylation of Rb (retinoblastoma were determined by Western blot analysis using total protein extracted from the liver. For flow cytometric analysis of the cell cycle, FACS analysis was performed. The percentages of cell cycle distribution were evaluated by PI staining, and all samples were analyzed employing FACScalibur (BD with appropriate software (ModFit LT; BD. The cell proliferation assay was performed by counting cells with using a Scepter handy automated cell counter (Millipore. The mRNA levels of AFP relative to Alb(−: Alb(−, Alb(+, and Prionex, were 1, 0.7 ± 0.2 (p < 0.001 for Alb(−, and 1 ± 0.3, respectively. The mRNA levels of p21 were 1, 1.58 ± 0.4 (p = 0.007 for Alb(− and p = 0.004 for Prionex, and 0.8 ± 0.2, respectively. The mRNA levels of p57 were 1, 4.4 ± 1.4 (p = 0.002 for Alb(− and Prionex, and 1.0 ± 0.1, respectively. The protein expression levels of Rb were similar in all culture media. The phosphorylation of P807/811 and P780 of Rb protein was reduced in Alb(+. More cells in the G0/G1 phase and fewer cells in S and G2/M phases were obtained in Alb(+ than in Alb(− (G0/G1: 60.9%, 67.7%, 61.5%; G2/M: 16.5%, 13.1%, 15.6%; S: 22.6%, 19.2%, 23.0%, Alb(−, Alb

  20. MicroRNA-212 Regulates the Expression of Olfactomedin 1 and C-Terminal Binding Protein 1 in Human Endometrial Epithelial Cells to Enhance Spheroid Attachment In Vitro.

    Science.gov (United States)

    Kottawatta, Kottawattage S A; So, Kam-Hei; Kodithuwakku, Suranga P; Ng, Ernest H Y; Yeung, William S B; Lee, Kai-Fai

    2015-11-01

    Successful embryo implantation requires a synchronized dialogue between a competent blastocyst and the receptive endometrium, which occurs in a limited time period known as the "window of implantation." Recent studies suggested that down-regulation of olfactomedin 1 (OLFM1) in the endometrium and fallopian tube is associated with receptive endometrium and tubal ectopic pregnancy in humans. Interestingly, the human chorionic gonadotropin (hCG) induces miR-212 expression, which modulates OLFM1 and C-terminal binding protein 1 (CTBP1) expressions in mouse granulosa cells. Therefore, we hypothesized that embryo-derived hCG would increase miR-212 expression and down-regulate OLFM1 and CTBP1 expressions to favor embryo attachment onto the female reproductive tract. We found that hCG stimulated the expression of miR-212 and down-regulated OLFM1 but not CTBP1 mRNA in both human endometrial (Ishikawa) and fallopian (OE-E6/E7) epithelial cells. However, hCG suppressed the expression of OLFM1 and CTBP1 proteins in both cell lines. The 3'UTR of both OLFM1 and CTBP1 contained binding sites for miR-212. The miR-212 precursor suppressed luciferase expression, whereas the miR-212 inhibitor stimulated luciferase expression of the wild-type (WT)-OLFM1 and WT-CTBP1 reporter constructs. Furthermore, hCG (25 IU/ml) treatments stimulated trophoblastic (Jeg-3) spheroid (blastocyst surrogate) attachment onto Ishikawa and OE-E6/E7 cells. Transfection of miR-212 precursor increased Jeg-3 spheroid attachment onto Ishikawa cells and decreased OLFM1 and CTBP1 protein expressions, whereas the opposite occurred with miR-212 inhibitor. Taken together, hCG stimulated miR-212, which in turn down-regulated OLFM1 and CTBP1 expression in fallopian and endometrial epithelial cells to favor spheroid attachment. © 2015 by the Society for the Study of Reproduction, Inc.

  1. Influence of human papillomavirus on the clinical presentation of oropharyngeal carcinoma in the United States.

    Science.gov (United States)

    Stenmark, Matthew H; Shumway, Dean; Guo, Cui; Vainshtein, Jeffrey; Mierzwa, Michelle; Jagsi, Reshma; Griggs, Jennifer J; Banerjee, Mousumi

    2017-10-01

    Much of what is known about the significance of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is derived from single-institution retrospective studies, post hoc analyses of tissue specimens from clinical trials, and tissue bank studies with a small sample size. The objective of this study is to investigate the impact of HPV on the frequency and clinical presentation of oropharyngeal carcinoma in a large, national sample with information from patients who underwent HPV testing. Retrospective, cross-sectional study. We identified a comprehensive national sample of 8,359 patients with oropharyngeal carcinoma and known HPV status diagnosed between 2010 and 2011 within the National Cancer Database. Multivariable logistic regression was used to assess correlates of patient and tumor characteristics on HPV status. Among patients with oropharyngeal carcinoma, the frequency of HPV-related squamous cell carcinoma in the United States was 65.4%. HPV-related oropharyngeal carcinoma was associated with younger age, male sex, and white race (P carcinoma in the United States and is associated with a distinct clinical profile, supporting efforts to re-evaluate the staging and treatment paradigm for HPV-associated oropharyngeal cancer. 4. Laryngoscope, 127:2270-2278, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  2. Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives.

    Science.gov (United States)

    Ventriglia, Jole; Paciolla, Immacolata; Pisano, Carmela; Cecere, Sabrina Chiara; Di Napoli, Marilena; Tambaro, Rosa; Califano, Daniela; Losito, Simona; Scognamiglio, Giosuè; Setola, Sergio Venanzio; Arenare, Laura; Pignata, Sandro; Della Pepa, Chiara

    2017-09-01

    The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro.

    Directory of Open Access Journals (Sweden)

    Yanmei Sun

    Full Text Available Angiogenesis is a prerequisite for the formation and development of endometriosis. Pigment epithelium derived factor (PEDF is a natural inhibitor of angiogenesis. We previously demonstrated a reduction of PEDF in the peritoneal fluid, serum and endometriotic lesions from women with endometriosis compared with women without endometriosis. Here, we aim to investigate the inhibitory effect of PEDF on human endometriotic cells in vivo and in vitro. We found that PEDF markedly inhibited the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro by up-regulating PEDF expression and down-regulating vascular endothelial growth factor (VEGF expression. Moreover, apoptotic index was significantly increased in endometriotic lesions in vivo and endometriotic stromal cells in vitro when treated with PEDF. In mice treated with PEDF, decreased microvessel density labeled by Von Willebrand factor but not by α-Smooth Muscle Actin was observed in endometriotic lesions. And it showed no increase in PEDF expression of the ovary and uterus tissues. These findings suggest that PEDF gene therapy may be a new treatment for endometriosis.

  4. Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro.

    Science.gov (United States)

    Sun, Yanmei; Che, Xuan; Zhu, Libo; Zhao, Mengdan; Fu, Guofang; Huang, Xiufeng; Xu, Hong; Hu, Fuqiang; Zhang, Xinmei

    2012-01-01

    Angiogenesis is a prerequisite for the formation and development of endometriosis. Pigment epithelium derived factor (PEDF) is a natural inhibitor of angiogenesis. We previously demonstrated a reduction of PEDF in the peritoneal fluid, serum and endometriotic lesions from women with endometriosis compared with women without endometriosis. Here, we aim to investigate the inhibitory effect of PEDF on human endometriotic cells in vivo and in vitro. We found that PEDF markedly inhibited the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro by up-regulating PEDF expression and down-regulating vascular endothelial growth factor (VEGF) expression. Moreover, apoptotic index was significantly increased in endometriotic lesions in vivo and endometriotic stromal cells in vitro when treated with PEDF. In mice treated with PEDF, decreased microvessel density labeled by Von Willebrand factor but not by α-Smooth Muscle Actin was observed in endometriotic lesions. And it showed no increase in PEDF expression of the ovary and uterus tissues. These findings suggest that PEDF gene therapy may be a new treatment for endometriosis.

  5. Organotypic in vitro models of human cutaneous squamous cell carcinoma

    NARCIS (Netherlands)

    Commandeur, Suzan

    2013-01-01

    Skin cancer is the most common type of cancer in fair-skinned populations. Cutaneous squamous cell carcinoma (SCC) comprises about 15% of all skin cancer diagnoses. Treatment associated with the high and rising prevalence of cutaneous SCC puts an increasingly high financial burden on society,

  6. Epac inhibits migration and proliferation of human prostate carcinoma cells

    NARCIS (Netherlands)

    Grandoch, M.; Rose, A.; ter Braak, M.; Jendrossek, V.; Ruebben, H.; Fischer, J. W.; Schmidt, M.; Weber, A. A.

    2009-01-01

    BACKGROUND: It was rec