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Gene expression analyses support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer.

ABSTRACT: Folate receptor alpha (FOLR1/FRA) is reported to be overexpressed in epithelial ovarian cancers (EOC), especially the serous histotype. Further, while dysregulation of the folate-dependent 1-carbon cycle has been implicated in tumorogenesis, little is known relative to the potential mechanism of action of FOLR1 expression in these processes. We therefore investigated the expression of FOLR1, other folate receptors, and genes within the 1-carbon cycle in samples of EOC, normal ovary and fallopian tube on a custom TaqMan Low Density Array. Also included on this array were known markers of EOC such as MSLN, MUC16 and HE4. While few differences were observed in the expression profiles of genes in the 1-carbon cycle, genes previously considered to be overexpressed in EOC (e.g., FOLR1, MSLN, MUC16 and HE4) showed significantly increased expression when comparing EOC to normal ovary. However, when the comparator was changed to normal fallopian tube, these differences were abolished, supporting the hypothesis that EOC derives from fallopian fimbriae and, further, that markers previously considered to be upregulated or overexpressed in EOC are most likely not of ovarian origin, but fallopian in derivation. Our findings therefore support the hypothesis that the cell of origin of EOC is tubal epithelium.

SUBMITTER: O'Shannessy DJ

PROVIDER: S-EPMC3742211 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Gene expression analyses support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer.

O'Shannessy Daniel J DJ Jackson Stephen M SM Twine Natalie C NC Hoffman Bryan E BE Dezso Zoltan Z Agoulnik Sergei I SI Somers Elizabeth B EB

International journal of molecular sciences 20130701 7

Folate receptor alpha (FOLR1/FRA) is reported to be overexpressed in epithelial ovarian cancers (EOC), especially the serous histotype. Further, while dysregulation of the folate-dependent 1-carbon cycle has been implicated in tumorogenesis, little is known relative to the potential mechanism of action of FOLR1 expression in these processes. We therefore investigated the expression of FOLR1, other folate receptors, and genes within the 1-carbon cycle in samples of EOC, normal ovary and fallopian ...[more]

PMID: 23880844

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Project description:Study questionHow does exposure to a testosterone rich environment affect the function and gene expression of human fallopian tube epithelium (hFTE)?Summary answerElevated testosterone level alters several gene transcripts that regulate cilia expression and negatively impacts the rate of cilia beating.What is known alreadyThe 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, durationA 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, methodsFallopian 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 chancehFTE 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 dataN/A.Limitations, reasons for cautionThe 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 findingsUnderstanding 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.

Dataset Information

Gene expression analyses support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer.

Publications

Gene expression analyses support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer.

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