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Patricia Shaw - One of the best experts on this subject based on the ideXlab platform.

  • molecular analysis of high grade serous ovarian carcinoma with and without associated serous tubal intra epithelial carcinoma
    Nature Communications, 2017
    Co-Authors: Patricia Shaw, Robert J Kurman, J A Ducie, Fanny Dao, Michael Considine, Narciso Olvera, Ie Ming Shih
    Abstract:

    Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the Fallopian Tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~ 50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. The RNA sequence and the miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal Fallopian Tube Epithelium than ovarian surface Epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal Fallopian Tube among all cases. High-grade serous carcinomas (HGSCs) are associated with precursor lesions (STICs) in the Fallopian Epithelium in only half of the cases. Here the authors report the molecular analysis of HGSCs with and without associated STICs and show similar profiles supporting a common origin for all HGSCs.

  • prolonged postovulatory proinflammatory signaling in the Fallopian Tube Epithelium may be mediated through a brca1 dab2 axis
    Clinical Cancer Research, 2012
    Co-Authors: Alicia A Tone, Patricia Shaw, Carl Virtanen, Theodore J Brown
    Abstract:

    Purpose: To assess inflammation-related gene expression in nonmalignant Fallopian Tube Epithelium (FTE) from BRCA1/2 mutation carriers and control patients obtained during the luteal and follicular phase, and to determine the impact of BRCA1 and disabled homolog 2 (DAB2) on NF-κB–mediated proinflammatory signaling. Experimental Design: A list of inflammation-related and NF-κB–responsive genes was compiled through gene set enrichment and PubMed database search, corresponding probes identified, and unpaired t tests conducted to identify differentially expressed genes in previously profiled FTE samples. ES2 and A549 cells were cotransfected with DAB2- or BRCA1-targeting siRNA and an NF-κB–responsive luciferase reporter, treated with TNF-α and luciferase activity determined. To determine whether DAB2 or BRCA1 alters mRNA expression of NF-κB target genes, cells were transfected with siRNA, treated with TNF-α, and harvested for total RNA extraction and quantitative real-time PCR. Results: A subset of BRCA1 -mutated luteal phase samples previously found to group with adnexal high–grade serous carcinomas (HGSCs) differentially expressed 124 inflammation–associated probesets relative to remaining FTE samples. These samples also differentially expressed 264 probes relative to other luteal phase samples exposed to the same postovulatory environment. Both BRCA1- and DAB2–targeting siRNA increased TNF-α-induced NF-κB activity and mRNA expression of NF-κB–dependent target gene SOD2 relative to nontargeting siRNA, suggesting that both proteins repress proinflammatory signaling. Conclusions: These data provide evidence of elevated proinflammatory signaling in a subset of BRCA1 -mutated luteal phase FTE, consistent with an altered response to ovulation-associated cytokines. Furthermore, both BRCA1 and DAB2 affect NF-κB activity, indicating a novel link between BRCA mutation status, ovulation, and predisposition to HGSC. Clin Cancer Res; 18(16); 4334–44. ©2012 AACR .

  • identification of abrogated pathways in Fallopian Tube Epithelium from brca1 mutation carriers
    The Journal of Pathology, 2011
    Co-Authors: Sophia George, Monika Sharma, James Greenaway, Anca Milea, Carl Virtanen, Victoria Clary, Sanjeev Shaw, Patricia Shaw
    Abstract:

    The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the Fallopian Tube Epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal Epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal Epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal Epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two-way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two-fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal Epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • abstract 2835 brca1 signature in high risk Fallopian Tube Epithelium
    Cancer Research, 2011
    Co-Authors: Sophia George, James Greenaway, Anca Milea, Carl Virtanen, Patricia Shaw
    Abstract:

    Background: High-grade serous ovarian cancer is rarely diagnosed at an early and potentially curable stage, effective early detection and preventative strategies are few. Recently the discovery of occult invasive and intraepithelial tubal carcinomas in BRCA1 mutation carriers, who are at high risk of serous cancer, undergoing prophylactic surgery has focused attention on the Fallopian Tube Epithelium as the cell of origin and has led to the reporting of putative serous cancer precursor lesions. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA 1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations are present in morphologically normal tubal Epithelium from BRCA1 heterozygotes, and that these changes may reflect the earliest alterations in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. To identify cancer predisposition candidate genes of high-risk Fallopian Tube Epithelium, we compared gene expression profiles of microdissected tubal Epithelium from BRCA1 mutation carriers, control women and patients with HGSC. Methodology: Snap-frozen tissues were selected from the UHN Biobank; control and BRCA cases controlled for age, ovarian cycle status at surgery, and hormone therapy. Cases included 12 BRCA1 mutation carriers and 12 control women, undergoing salpingo-oophorectomy for reasons other than adnexal malignancy or family history, 15 HGSC and 8 contralateral normal Tubes. Epithelium was microdissected in all cases using laser capture, RNA extracted and cDNA amplified. The gene expression profiles were generated using Affymetrix Human Genome U133 Plus 2.0 Array. Candidate genes were validated by qPCR and IHC on 2 Fallopian Tube TMAs. IHC was scored using Spectrum. Statistical analysis was performed using ANOVA (p Results: We focused the microarray analyses on identifying differential expression between BRCA1 heterozygotes and controls. Comparisons between FTE-nonBRCA and FTE-BRCA, resulted in 440 probe sets with more than 2-FC in gene expression. We selected 5 genes to validate by qPCR and IHC, based on gene ontology and known associations to cancer pathways. Conclusions: These results show that histological normal Fallopian Tube Epithelium from BRCA1 heterozygotes have altered gene expression and these differences are most pronounced in the post-ovulatory phase of the ovarian cycle in pre-menopausal women, suggesting that factors associated with the luteal phase are implicated in the increased risk of HGSC in BRCA1 mutation carriers. We also show that genes involved in inflammation pathways are up-regulated in mutation carriers and that these genetic signatures are maintained in HGSC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2011-2835

  • decreased progesterone receptor isoform expression in luteal phase Fallopian Tube Epithelium and high grade serous carcinoma
    Endocrine-related Cancer, 2011
    Co-Authors: Alicia A Tone, Patricia Shaw, Carl Virtanen, Theodore J Brown
    Abstract:

    We previously reported that BRCA1/2-mutated Fallopian Tube Epithelium (FTE) collected during the luteal phase exhibits gene expression profiles more closely resembling that of high-grade serous carcinoma (HGSC) specimens than FTE collected during the follicular phase or from control patients. Since the luteal phase is characterised by high levels of progesterone, we determined whether the expression of progesterone receptor (PR) and PR-responsive genes was altered in FTE obtained from BRCA mutation carriers during the luteal phase of the menstrual cycle. RT-qPCR confirmed a decreased expression of PR mRNA in FTE during the luteal phase relative to follicular phase, in both BRCA1/2 mutation carriers and control patients. Immunohistochemistry using isoform-specific antibodies confirmed a low level of both PR-A and PR-B in HGSC and a lower level of staining in FTE samples obtained during the luteal phase compared with the follicular phase. No significant difference in PR-A or PR-B staining was found based on patient BRCA mutation status. Analysis of our previously reported gene expression profiles based upon known PR-A- and PR-B-specific target genes did not partition samples by BRCA mutation status, indicating that overall FTE PR response is not altered in BRCA mutation carriers. HGSC samples grouped separately from other samples, consistent with the observed loss of PR expression. These findings indicate no overall difference in PR signalling in FTE as a function of BRCA mutation status. Thus, the molecular similarity of BRCA1/2-mutated luteal phase FTE and HGSC likely results from an altered response to luteal phase factors other than progesterone. Endocrine-Related Cancer (2011) 18 221‐234

Ronny Drapkin - One of the best experts on this subject based on the ideXlab platform.

  • it s totally tubular riding the new wave of ovarian cancer research
    Cancer Research, 2016
    Co-Authors: Ruth Perets, Ronny Drapkin
    Abstract:

    Hereditary breast and ovarian cancer syndrome carries significant mortality for young women if effective preventive and screening measures are not taken. Preventive salpingo-oophorectomy is currently the only method known to reduce the risk of ovarian cancer-related death. Histopathological analyses of these surgical specimens indicate that a high proportion of ovarian cancers in women at high risk and in the general population arise from the Fallopian Tube. This paradigm shift concerning the cell of origin for the most common subtype of ovarian cancer, high-grade serous carcinoma, has sparked a major effort within the research community to develop new and robust model systems to study the Fallopian Tube Epithelium as the cell of origin of “ovarian” cancer. In this review, evidence supporting the Fallopian Tube as the origin of ovarian cancer is presented as are novel experimental model systems for studying the Fallopian Tube Epithelium in high-risk women as well as in the general population. This review also addresses the clinical implications of the newly proposed cell of origin, the clinical questions that arise, and novel strategies for ovarian cancer prevention. Cancer Res; 76(1); 10–17. ©2015 AACR .

  • co culture of human induced pluripotent stem cells ipscs with human Fallopian Tube Epithelium fte induces pax8 and ck7 expression initial steps in modeling Fallopian Tube Epithelium to study serous carcinogenesis
    Gynecologic Oncology, 2015
    Co-Authors: T J Vogel, Ronny Drapkin, Dhruv Sareen, Clive N Svendsen, E Suzuki, Xiaojiang Cui, Beth Y Karlan
    Abstract:

    strategies under investigation for several cancers. Although antigenic targets for the immune system exist in the form of tumor-associated antigens, no tumor-specific antigens have been identified for gynecologic cancers. Expression of cancer-testis (CT) antigens in ovarian cancer has been described. CT antigens are attractive targets for cancer immunotherapy due to their restricted expression in testis, germ cells, and tumors. The aim of our study was to evaluate the expression of a panel of 20 CT antigens in gynecologic tumor cell lines and to determine if antigen sharing occurs among different gynecologic cancers. Methods: RNA was isolated from 16 gynecologic cancer cell lines (9 epithelial ovarian cancer, 8 endometrial cancer, 1 cervical cancer, and 1 leiomyosarcoma cell line). Real-time polymerase chain reaction analysis was performed to determine the expression level of 20 CT antigens. Results: Expression of CT antigens was identified in gynecologic cancer cell lines. Among 20 evaluated antigens, 90% (18/20) expressed in ovarian and endometrial cancer cell lines, while only 30% (6/20) expressed in cervical cancer and leiomyosarcoma cell lines. The most frequently expressed CT antigens were SP-17 (93.8% of cell lines), MAGE-A4 (87.5%), OYTES (68.8%), BAGE (62.5%), CT-45 (62.5%), PIWIL2 (56.3%), and GAGE (56.3%). CT45, SP-17, and MAGE-A4 were expressed among all gynecologic cancers. We found that different gynecologic cancers shared the expression of CT antigens, with the mean number of antigens shared among cancer types ranging from 3 to 4.6 antigens. There was sharing of CT antigens between cell lines of the same tumor type and with cell lines of other gynecologic tumor types. Themeannumber of antigens shared amongendometrial cell lines (5.5) was higher than the one shared by the ovarian cancer cell lines (3.8) with their corresponding tumor type (P=0.0122). Conclusions: CT antigens are expressed in gynecologic cancers. No single antigen was universally expressed among all gynecologic cancer cell lines, although most expressed SP-17. Utilizing a multiepitope immunotherapy approach could provide a universal therapeutic option for gynecologic cancers.

  • the hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis
    Reproductive Biology and Endocrinology, 2014
    Co-Authors: Megan M Emori, Ronny Drapkin
    Abstract:

    Ovulation has long been associated with an increased risk in ovarian cancer, yet the underlying molecular mechanisms remain obscure. Two aspects of ovulation have been linked to ovarian cancer pathogenesis. The first is the impact of repetitive tissue injury and repair that occurs with each ovulatory event. The second is the release of follicular fluid that accompanies the follicular rupture and its effect on the ovarian and Fallopian Tube epithelial cells. Hormones are an important component of follicular fluid, which transiently bathes the ovarian surface and Fallopian Tube Epithelium during ovulation. Much work has been done exploring the role of hormones in fertility, but some, such as estrogen, have also been implicated in the pathogenesis of ovarian and other cancers. Understanding the role of hormones within follicular fluid, as well as how they are altered in disorders which increase ovarian cancer risk, will enhance our ability to assess risk and develop preventative strategies. This review provides an in depth discussion of the logistics of using and studying follicular fluid in ovarian cancer research, and discusses the fluctuations in follicular fluid hormone levels during normal physiological processes versus conditions that increase ovarian cancer risk.

  • stathmin 1 a marker of pi3k pathway activation and regulator of microtubule dynamics is expressed in early pelvic serous carcinomas
    Gynecologic Oncology, 2011
    Co-Authors: Alison M Karst, Ronny Drapkin, Keren Levanon, Sekhar Duraisamy, Michelle S Hirsch, Jonathan L Hecht
    Abstract:

    Background Most high-grade pelvic serous carcinomas (HGPSCs) arise from Fallopian Tube Epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma.

Joanna E Burdette - One of the best experts on this subject based on the ideXlab platform.

  • reply exposure of human Fallopian Tube Epithelium to elevated testosterone results in alteration of cilia gene expression and beating
    Human Reproduction, 2020
    Co-Authors: Tia Jacksonbey, Julie J Kim, Teresa K Woodruff, Joanna E Burdette, Jose A Colina, Brett C Isenberg, Jonathan R Coppeta, Margrit Urbanek, Angela Russo
    Abstract:

    Study question How does exposure to a testosterone rich environment affect the function and gene expression of human Fallopian Tube Epithelium (hFTE)? Summary answer Elevated testosterone level alters several gene transcripts that regulate cilia expression and negatively impacts the rate of cilia beating. What is known already The presence of estrogen in the follicular phase of the menstrual cycle increases the human Fallopian Tube ciliary beating frequency. The luteal phase, triggered by ovulation and increasing progesterone, is marked by a decrease in ciliary beating. Women with polycystic ovarian syndrome (PCOS) may have twice the serum level of testosterone than ovulatory women. To date, the effect of elevated androgens on the function of the human Fallopian Tube is not well-understood. We chose to examine the impact of elevated testosterone on hFTE. Study design, size, duration A prospective basic science study of human Fallopian Tube specimens from reproductive-aged women undergoing benign gynecologic surgery was performed. Fallopian Tube removal at a large US academic center was collected and provided to us to continue with Epithelium isolation and culturing. A total of 12 patients were analyzed in the study. Participants/materials, setting, methods Fallopian Tube Epithelium was isolated and exposed to two different conditions: normal with low testosterone concentration of 0.8 nM and PCOS-like, with high testosterone concentration of 2 nM. The study was conducted in both static and dynamic conditions in microfluidic devices for a total of 14 days, after which the tissue was collected for processing including RNA extraction, quantitative PCR and immunohistochemistry. After the first 7 days of each experiment, a sample of tissue from each condition was imaged to quantify cilia beating frequency. Main results and the role of chance hFTE exposed to the 2 nM testosterone displayed slower cilia beating, inhibited estrogen signaling and decreased expression of the ciliary marker FOXJ1 when compared to stimulation with 0.8 nM testosterone. Large scale data N/A. Limitations, reasons for caution The in vivo response to elevated testosterone may differ from in vitro studies. RNA amount was limited from tissue cultured in the microfluidic devices as compared to static culture. Wider implications of the findings Understanding elevated testosterone in tubal function may explain an additional contribution to subfertility in women with PCOS and other hyper-androgen disorders, aside from oligo-ovulation. Furthermore, this adds to the body of literature of Fallopian Tube function using a microfluidic device. Study funding/competing interest(s) NIH grants: UH3 ES029073 and R01 CA240301. There are no competing interests.

  • loss of pten in Fallopian Tube Epithelium results in multicellular tumor spheroid formation and metastasis to the ovary
    Cancers, 2019
    Co-Authors: Angela Russo, Daniel D Lantvit, Matthew Dean, Vivian Jin, Tova M Bergsten, Julia R Austin, Joanna E Burdette
    Abstract:

    High-grade serous ovarian cancer (HGSOC) can originate in the Fallopian Tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8Cre/+ PTENflox/flox mice. MOE PTENshRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTENshRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the Fallopian Tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients.

  • activin a stimulates migration of the Fallopian Tube Epithelium an origin of high grade serous ovarian cancer through non canonical signaling
    Cancer Letters, 2017
    Co-Authors: Matthew Dean, David A Davis, Joanna E Burdette
    Abstract:

    Factors that stimulate the migration of Fallopian Tube epithelial (FTE)-derived high-grade serous ovarian cancer (HGSOC) to the ovary are poorly elucidated. This study characterized the effect of the ovarian hormone, activin A, on normal FTE and HGSOC. Activin A and TGFβ1 induced an epithelial-to-mesenchymal transition in murine oviductal epithelial (MOE) cells, but only activin A increased migration. The migratory effect of activin A was independent of Smad2/3 and required phospho-AKT, phospho-ERK, and Rac1. Exogenous activin A stimulated migration of the HGSOC cell line OVCAR3 through a similar mechanism. Activin A signaling inhibitors, SB431542 and follistatin, reduced migration in OVCAR4 cells, which expressed activin A subunits (encoded by INHBA). Murine superovulation increased phospho-Smad2/3 immunostaining in the FTE. In Oncomine, transcripts for the activin A receptors (ACVR1B and ACVR2A) were higher in serous tumors relative to the normal ovary, while inhibitors of activin A signaling (INHA and TGFB3) were lower. High expression of both INHBA and ACVR2A, but not TGFβ receptors or co-receptors, was associated with shorter disease-free survival in serous cancer patients. These results suggest activin A stimulates migration of FTE-derived tumors to the ovary.

  • human Fallopian Tube Epithelium co culture with murine ovarian follicles reveals crosstalk in the reproductive cycle
    Molecular Human Reproduction, 2016
    Co-Authors: Jie Zhu, Alexandra S Rashedi, Mary Ellen Pavone, Julie J Kim, Teresa K Woodruff, Joanna E Burdette
    Abstract:

    Study question Do interactions between human Fallopian Tube Epithelium and murine follicles occur during an artificial reproductive cycle in a co-culture system in vitro? Summary answer In a co-culture system, human Fallopian tissues responded to the menstrual cycle mimetic by changes in morphology and levels of secreted factors, and increasing murine corpus luteum progesterone secretion. What is known already The entire Fallopian Tube Epithelium, including ciliated and secretory cells, can be regulated in the reproductive cycle. Currently, there are no in vitro culture models that can monitor Fallopian tissues in real time in response to factors produced by the ovary. In addition, there are no reports on the impact of Fallopian tissue on ovarian function during the menstrual cycle. Study design, samples/materials, methods Human Fallopian tissue (n = 24) was obtained by routine hysterectomies from women (aged 26-50 years, mean age = 43.6) who had not undergone exogenous hormonal treatment for at least 3 months prior to surgery. CD1 female mice were used for ovarian follicle isolation. The human Fallopian Epithelium layers were either co-cultured with five murine multilayer secondary follicles (150-180 μm follicles, encapsulated in one alginate gel bead) for 15 days or received stepwise steroid hormone additions for 13 days. The Fallopian tissue morphology and cilia beating rate, as measured by an Andor Spinning Disk Confocal, were investigated. Oviduct-specific glycoprotein 1 (OVGP1), human insulin-like growth factor 1 (hIGF1), vascular endothelial growth factor A (VEGF-A) and interleukin 8 (IL8) as biological functional markers were measured either by ELISA or western blot to indicate dynamic changes in the Fallopian Epithelium during the reproductive cycle generated by mouse follicles or by stepwise steroid hormone induction. Three or four patients in each experiment were recruited for replicates. Data were presented as mean ± SD and further analyzed using one-way ANOVA followed by Tukey's multiple comparisons test. Main results and the role of chance The cultured Fallopian Tube Epithelium responded to exogenous steroid hormone stimulation, as demonstrated by enhanced cilia beating rate (~25% increase, P = 0.04) and an increase in OVGP1 secretion (P = 0.02) in response to 1 nM estradiol (E2) treatment when compared with 0.1 nM E2. Conversely, 10 nM progesterone plus 1 nM E2 suppressed cilia beating rate by ~30% (P = 0.008), while OVGP1 secretion was suppressed by 0.1 nM E2 plus 50 nM progesterone (P = 0.002 versus 1 nM E2 alone). Human Fallopian Tube Epithelium was co-cultured with murine secondary follicles to mimic the human menstrual cycle. OVGP1 and VEGF-A secretion from Fallopian tissue was similar with stepwise hormone treatment and when cultured with murine follicles. However, the secretion patterns of hIGF1 and IL8 differed in the luteal phase when comparing steroid treatment with follicle co-culture. In co-culture, hIGF1 secretion was suppressed in the luteal versus follicular phase (P = 0.005) but stepwise hormone treatment had no effect on hIGF1. In co-culture, IL8 secretion was also suppressed on luteal phase day 15 (P = 0.013) versus follicular phase day 7, but IL8 secretion increased continuously under high E2/progesterone treatment (P = 0.003 for D13 versus D3). In the co-culture system, the corpus luteum continuously produced progesterone in the presence of Fallopian Tube tissue until Day 18 while, without Fallopian tissue, progesterone started to drop from Day 13. Limitations, reasons for caution One limitation of this study is that murine follicles were used to mimic the human menstrual cycle. However, although secretion patterns of peptide hormones such as inhibins and activins differ in mice and humans, the co-culture system used here did reveal interactions between the tissues that govern reproductive function. Wider implications of the findings In vitro co-culture models of Fallopian reproductive tissues with ovarian follicles can provide an important tool for understanding fertility and for uncovering the mechanisms responsible for reduced fertility. In addition, the role of oviductal secretions and how they influence ovarian function, such as the production of progesterone during the menstrual cycle, can be uncovered using this model. Large-scale data None. Study funding and competing interests This work was funded by grants from the NIH (UH3TR001207), the American Cancer Society (RSG-12-230-01-TBG) and NIH (R01EB014806). The authors declare no competing financial interest.

  • mutant p53 expression in Fallopian Tube Epithelium drives cell migration
    International Journal of Cancer, 2015
    Co-Authors: Suzanne M Quartuccio, Sharon L Eddie, Eoghainin O Hainmhire, Daniel D Lantvit, Jianjun Wei, Subbulakshmi Karthikeyan, Dimple A Modi, Joanna E Burdette
    Abstract:

    Ovarian cancer is the fifth leading cause of cancer death among US women. Evidence supports the hypothesis that high-grade serous ovarian cancers (HGSC) may originate in the distal end of the Fallopian Tube. Although a heterogeneous disease, 96% of HGSC contain mutations in p53. In addition, the "p53 signature," or overexpression of p53 protein (usually associated with mutation), is a potential precursor lesion of Fallopian Tube derived HGSC suggesting an essential role for p53 mutation in early serous tumorigenesis. To further clarify p53-mutation dependent effects on cells, murine oviductal epithelial cells (MOE) were stably transfected with a construct encoding for the R273H DNA binding domain mutation in p53, the most common mutation in HGSC. Mutation in p53 was not sufficient to transform MOE cells but did significantly increase cell migration. A similar p53 mutation in murine ovarian surface Epithelium (MOSE), another potential progenitor cell for serous cancer, was not sufficient to transform the cells nor change migration suggesting tissue specific effects of p53 mutation. Microarray data confirmed expression changes of pro-migratory genes in p53(R273H) MOE compared to parental cells, which could be reversed by suppressing Slug expression. Combining p53(R273H) with KRAS(G12V) activation caused transformation of MOE into high-grade sarcomatoid carcinoma when xenografted into nude mice. Elucidating the specific role of p53(R273H) in the Fallopian Tube will improve understanding of changes at the earliest stage of transformation. This information can help develop chemopreventative strategies to prevent the accumulation of additional mutations and reverse progression of the "p53 signature" thereby, improving survival rates.

Clive N Svendsen - One of the best experts on this subject based on the ideXlab platform.

  • directed differentiation of human induced pluripotent stem cells into Fallopian Tube Epithelium
    Scientific Reports, 2017
    Co-Authors: Nur Yucer, Beth Y Karlan, M Holzapfel, T J Vogel, Lindsay Lenaeus, Loren Ornelas, Anna Laury, Dhruv Sareen, Robert Barrett, Clive N Svendsen
    Abstract:

    The Fallopian Tube Epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human Fallopian Tube as well as a luminal architecture that closely reflects the organization of Fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Mullerian cells and subsequent use of pro-Mullerian growth factors promoted FTE precursors. The expression and localization of Mullerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early Fallopian Tube epithelial cell transformation.

  • co culture of human induced pluripotent stem cells ipscs with human Fallopian Tube Epithelium fte induces pax8 and ck7 expression initial steps in modeling Fallopian Tube Epithelium to study serous carcinogenesis
    Gynecologic Oncology, 2015
    Co-Authors: T J Vogel, Ronny Drapkin, Dhruv Sareen, Clive N Svendsen, E Suzuki, Xiaojiang Cui, Beth Y Karlan
    Abstract:

    strategies under investigation for several cancers. Although antigenic targets for the immune system exist in the form of tumor-associated antigens, no tumor-specific antigens have been identified for gynecologic cancers. Expression of cancer-testis (CT) antigens in ovarian cancer has been described. CT antigens are attractive targets for cancer immunotherapy due to their restricted expression in testis, germ cells, and tumors. The aim of our study was to evaluate the expression of a panel of 20 CT antigens in gynecologic tumor cell lines and to determine if antigen sharing occurs among different gynecologic cancers. Methods: RNA was isolated from 16 gynecologic cancer cell lines (9 epithelial ovarian cancer, 8 endometrial cancer, 1 cervical cancer, and 1 leiomyosarcoma cell line). Real-time polymerase chain reaction analysis was performed to determine the expression level of 20 CT antigens. Results: Expression of CT antigens was identified in gynecologic cancer cell lines. Among 20 evaluated antigens, 90% (18/20) expressed in ovarian and endometrial cancer cell lines, while only 30% (6/20) expressed in cervical cancer and leiomyosarcoma cell lines. The most frequently expressed CT antigens were SP-17 (93.8% of cell lines), MAGE-A4 (87.5%), OYTES (68.8%), BAGE (62.5%), CT-45 (62.5%), PIWIL2 (56.3%), and GAGE (56.3%). CT45, SP-17, and MAGE-A4 were expressed among all gynecologic cancers. We found that different gynecologic cancers shared the expression of CT antigens, with the mean number of antigens shared among cancer types ranging from 3 to 4.6 antigens. There was sharing of CT antigens between cell lines of the same tumor type and with cell lines of other gynecologic tumor types. Themeannumber of antigens shared amongendometrial cell lines (5.5) was higher than the one shared by the ovarian cancer cell lines (3.8) with their corresponding tumor type (P=0.0122). Conclusions: CT antigens are expressed in gynecologic cancers. No single antigen was universally expressed among all gynecologic cancer cell lines, although most expressed SP-17. Utilizing a multiepitope immunotherapy approach could provide a universal therapeutic option for gynecologic cancers.

Beth Y Karlan - One of the best experts on this subject based on the ideXlab platform.

  • directed differentiation of human induced pluripotent stem cells into Fallopian Tube Epithelium
    Scientific Reports, 2017
    Co-Authors: Nur Yucer, Beth Y Karlan, M Holzapfel, T J Vogel, Lindsay Lenaeus, Loren Ornelas, Anna Laury, Dhruv Sareen, Robert Barrett, Clive N Svendsen
    Abstract:

    The Fallopian Tube Epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human Fallopian Tube as well as a luminal architecture that closely reflects the organization of Fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Mullerian cells and subsequent use of pro-Mullerian growth factors promoted FTE precursors. The expression and localization of Mullerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early Fallopian Tube epithelial cell transformation.

  • salpingectomy as a means to reduce ovarian cancer risk
    Cancer Prevention Research, 2015
    Co-Authors: Mary B Daly, Charles W Dresher, Melinda S Yates, Joanne M Jeter, Beth Y Karlan, David S Alberts
    Abstract:

    Bilateral salpingo-oophorectomy (BSO) has become the standard-of-care for risk reduction in women at hereditary risk of ovarian cancer. Although this procedure significantly decreases both the incidence of and mortality from ovarian cancer, it affects quality of life, and the premature cessation of ovarian function may have long-term health hazards. Recent advances in our understanding of the molecular pathways of ovarian cancer point to the Fallopian Tube Epithelium as the origin of most high-grade serous cancers (HGSC). This evolving appreciation of the role of the Fallopian Tube in HGSC has led to the consideration of salpingectomy alone as an option for risk management, especially in premenopausal women. In addition, it is postulated that bilateral salpingectomy with ovarian retention (BSOR), may have a public health benefit for women undergoing benign gynecologic surgery. In this review, we provide the rationale for salpingectomy as an ovarian cancer risk reduction strategy.

  • co culture of human induced pluripotent stem cells ipscs with human Fallopian Tube Epithelium fte induces pax8 and ck7 expression initial steps in modeling Fallopian Tube Epithelium to study serous carcinogenesis
    Gynecologic Oncology, 2015
    Co-Authors: T J Vogel, Ronny Drapkin, Dhruv Sareen, Clive N Svendsen, E Suzuki, Xiaojiang Cui, Beth Y Karlan
    Abstract:

    strategies under investigation for several cancers. Although antigenic targets for the immune system exist in the form of tumor-associated antigens, no tumor-specific antigens have been identified for gynecologic cancers. Expression of cancer-testis (CT) antigens in ovarian cancer has been described. CT antigens are attractive targets for cancer immunotherapy due to their restricted expression in testis, germ cells, and tumors. The aim of our study was to evaluate the expression of a panel of 20 CT antigens in gynecologic tumor cell lines and to determine if antigen sharing occurs among different gynecologic cancers. Methods: RNA was isolated from 16 gynecologic cancer cell lines (9 epithelial ovarian cancer, 8 endometrial cancer, 1 cervical cancer, and 1 leiomyosarcoma cell line). Real-time polymerase chain reaction analysis was performed to determine the expression level of 20 CT antigens. Results: Expression of CT antigens was identified in gynecologic cancer cell lines. Among 20 evaluated antigens, 90% (18/20) expressed in ovarian and endometrial cancer cell lines, while only 30% (6/20) expressed in cervical cancer and leiomyosarcoma cell lines. The most frequently expressed CT antigens were SP-17 (93.8% of cell lines), MAGE-A4 (87.5%), OYTES (68.8%), BAGE (62.5%), CT-45 (62.5%), PIWIL2 (56.3%), and GAGE (56.3%). CT45, SP-17, and MAGE-A4 were expressed among all gynecologic cancers. We found that different gynecologic cancers shared the expression of CT antigens, with the mean number of antigens shared among cancer types ranging from 3 to 4.6 antigens. There was sharing of CT antigens between cell lines of the same tumor type and with cell lines of other gynecologic tumor types. Themeannumber of antigens shared amongendometrial cell lines (5.5) was higher than the one shared by the ovarian cancer cell lines (3.8) with their corresponding tumor type (P=0.0122). Conclusions: CT antigens are expressed in gynecologic cancers. No single antigen was universally expressed among all gynecologic cancer cell lines, although most expressed SP-17. Utilizing a multiepitope immunotherapy approach could provide a universal therapeutic option for gynecologic cancers.