The pattern of CD98 expression is different between uterine serous papillary carcinoma and endometrioid endometrial carcinoma.
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Carcinoma, Endometrioid↗
Biomedical subjects
Alistair R W Williams
Publications and source records attributed to Alistair R W Williams.
Gene expression profiling of mid to late secretory phase endometrial biopsies from women with menstrual complaint.
OBJECTIVE: The purpose of this study was to test whether a quantitative high-throughput molecular screen can be used to probe human endometrium and initiate the development of molecular diagnostic tools with potential for identification of therapeutic targets in women with menstrual complaints. STUDY DESIGN: Endometrium was collected from 10 patients with complaint of heavy bleeding, classified into mid or late secretory phase of the menstrual cycle by histologic dating and serum progesterone concentration. Total RNA was extracted and gene activity assessed using high-density oligonucleotide arrays. RESULTS: Statistical testing identified 83 'signature' genes whose expression levels differentiated the mid and late secretory phases of the menstrual cycle. CONCLUSION: The results show that the endometrium, a complex heterogeneous tissue, is amenable to high-throughput molecular analyses and this work provides further support for the future application of molecular profiling to clinical diagnosis.
Adult↗
Does liquid-based cytology really offer any advantage?
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Cytodiagnosis↗
A novel angiogenic role for prostaglandin F2alpha-FP receptor interaction in human endometrial adenocarcinomas.
Prostaglandins have been implicated in several neovascular diseases. In the present study, we found elevated FP receptor and vascular endothelial growth factor (VEGF) expression colocalized in glandular epithelial and vascular cells lining the blood vessels in endometrial adenocarcinomas. We investigated the signaling pathways activated by the FP receptor and their role in modulating VEGF expression in endometrial adenocarcinoma (Ishikawa) cells. Ishikawa cells were stably transfected with FP receptor cDNA in the sense or antisense orientations. Treatment of Ishikawa cells with prostaglandin F2alpha (PGF2alpha) rapidly induced transphosphorylation of the epidermal growth factor receptor (EGFR) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 via the FP receptor. Activation of EGFR-Ras-mitogen-activated protein kinase/ERK kinase (MEK) signaling via the FP receptor resulted in an increase in VEGF promoter activity, expression of VEGF mRNA, and secretion of VEGF protein. These effects of PGF2alpha on the FP receptor could be abolished by treatment of cells with a specific FP receptor antagonist, chemical inhibitors of c-Src, matrix metalloproteinase, and EGFR kinase or by inactivation of signaling with dominant-negative mutant isoforms of EGFR, Ras, or MEK or with small inhibitory RNA oligonucleotides targeted against the EGFR. Finally, we confirmed that PGF2alpha could potentiate angiogenesis in endometrial adenocarcinoma explants by transactivation of the EGFR and induction of VEGF mRNA expression.
Adenocarcinoma↗
A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F2alpha synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway.
Cyclooxygenase (COX) enzymes catalyze the biosynthesis of eicosanoids, including prostaglandin (PG) F2alpha. PGF2alpha exerts its autocrine/paracrine function by coupling to its G protein-coupled receptor [F-series-prostanoid (FP) receptor] to initiate cell signaling and target gene transcription. In the present study, we found elevated expression of COX-2 and FP receptor colocalized together within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF2alpha-FP receptor interaction in modulating COX-2 expression and PGF2alpha biosynthesis using an endometrial adenocarcinoma cell line stably transfected with the FP receptor cDNA (FPS cells). PGF2alpha-FP receptor activation rapidly induced COX-2 promoter, mRNA, and protein expression in FPS cells. These effects of PGF2alpha on the expression of COX-2 could be abolished by treatment of FPS cells with an FP receptor antagonist (AL8810) and chemical inhibitor of ERK1/2 kinase (PD98059), or by inactivation of ERK1/2 signaling with dominant-negative mutant isoforms of Ras or ERK1/2 kinase. We further confirmed that elevated COX-2 protein in FPS cells could biosynthesize PGF2alpha de novo to promote a positive feedback loop to facilitate endometrial tumorigenesis. Finally, we have shown that PGF2alpha could potentiate tumorigenesis in endometrial adenocarcinoma explants by inducing the expression of COX-2 mRNA.
Adenocarcinoma↗
Carcinosarcoma of the ovary: 19 years of prospective data from a single center.
BACKGROUND: A review of clinicopathologic features and outcome in women with carcinosarcoma of the ovary (also known as malignant mixed mesodermal tumor [MMMT]) compared with a group of women with serous adenocarcinoma (SAC) of the ovary was conducted. METHODS: Between 1984 and 2002, 1568 patients with epithelial ovarian carcinoma and 70 patients with ovarian carcinosarcoma underwent treatment at the Edinburgh Cancer Centre. Analysis was performed on 65 patients with MMMT, and 746 patients with SAC were selected as a group for comparison. Baseline variables were recorded prospectively and response to chemotherapy and progression-free and cause-specific survival between the groups were compared. RESULTS: Patients with carcinosarcoma had a mean age of 66.6 years, which is significantly older than those with SAC (62.0 years) (P < 0.001). The objective response rate to platinum-based chemotherapy was found to be significantly lower in patients with carcinosarcoma (25% vs. 60%; P = 0.02). Cause-specific survival in the carcinosarcoma group was poor and significantly shorter than that observed in the SAC group (median survival of 8.2 months vs. 20.7 months; P < 0.0001). Progression-free survival in patients with carcinosarcoma also was found to be significantly shorter compared with patients with SAC (median progression-free survival of 6.4 months vs. 12.1 months; P < 0.001). Achieving optimal debulking at the time of initial surgery was found to be a highly significant factor in patients with carcinosarcoma with regard to determining outcome (median survival of 14.8 months for patients with optimally debulked International Federation of Gynecology and Obstetrics Stage III disease vs. 3.1 months for patients with suboptimally/nondebulked Stage III disease; P < 0.001). CONCLUSIONS: Ovarian carcinosarcoma is a distinct entity with a poor prognosis. Patients with carcinosarcoma differ from those with SAC with regard to having an older mean age of onset, an inferior response to platinum-based chemotherapy, and worse progression-free and cause-specific survival. The extent of benefit from chemotherapy is unclear.
Aged↗
Expression, localization, and signaling of prostaglandin F2 alpha receptor in human endometrial adenocarcinoma: regulation of proliferation by activation of the epidermal growth factor receptor and mitogen-activated protein kinase signaling pathways.
Prostaglandin F(2 alpha)(PGF(2 alpha)) is a bioactive lipid biosynthesized by cyclooxygenase (COX) enzymes and mediates its biological activity via the heptahelical G(q)-coupled PGF(2 alpha)receptor (FP receptor). This study investigated the expression and molecular signaling of the FP receptor in human endometrial adenocarcinomas. Real-time RT-PCR and Western blot analysis confirmed FP receptor expression in endometrial adenocarcinoma of all grades and differentiation. The expression of FP receptor was up-regulated in all endometrial adenocarcinomas compared with normal endometrium. The site of FP receptor expression was localized by in situ hybridization and immunohistochemistry to the neoplastic epithelial cells in all adenocarcinomas. Treatment of endometrial adenocarcinoma explants with PGF(2 alpha) resulted in mobilization of inositol phosphate signaling, indicating functional FP receptor expression. We investigated whether PGF(2 alpha) could trans-activate the epidermal growth factor receptor (EGFR) and trigger the MAPK signaling pathway. Treatment of adenocarcinoma explants and endometrial adenocarcinoma cells (Ishikawa) with PGF(2 alpha)-phosphorylated EGFR, triggered MAPK signaling and enhanced the proliferation of Ishikawa cells. Inactivation of phospholipase C, EGFR kinase, and MAPK kinase with specific inhibitors abolished PGF(2 alpha)-induced trans-activation of EGFR, MAPK signaling, and Ishikawa cell proliferation. These data suggest that PGF(2 alpha)-FP receptor promote endometrial tumorigenesis via a phospholipase C-mediated phosphorylation of the EGFR and MAPK signaling pathways.
Adenocarcinoma↗
Prostaglandin E2 mediates phosphorylation and down-regulation of the tuberous sclerosis-2 tumor suppressor (tuberin) in human endometrial adenocarcinoma cells via the Akt signaling pathway.
Prostaglandin (PG) E2 promotes tumor growth via interaction with its G protein-coupled receptors and activation of intracellular signaling. Tuberous sclerosis 2 (tuberin) is a tumor suppressor, which negatively regulates cell growth. Its phosphorylation results in its inactivation and targeted down- regulation, thus lifting the growth inhibition effects. This study investigated the expression and localization of tuberin in neoplastic and normal endometrium and the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Quantitative RT-PCR and Western blot analysis demonstrated reduced expression of tuberin in neoplastic tissue, compared with normal endometrial tissue. Tuberin expression was localized by immunohistochemistry to the glandular epithelial compartment in neoplastic and normal endometrium. We investigated the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Treatment of neoplastic and normal endometrium with 100 nm PGE2 enhanced phosphorylated tuberin immunoreactivity in the glandular epithelium. PGE2 also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells, leading to a reduction in expression of total tuberin protein. Cotreatment of cells with wortmannin or LY294002 inhibited the PGE2-induced phosphorylation of Akt and tuberin. These data suggest that PGE2 signaling may promote endometrial tumorigenesis by inactivation of tuberin after its phosphorylation via the Akt signaling pathway.
Adenocarcinoma↗
Mifepristone: a novel estrogen-free daily contraceptive pill.
When the first synthetic progesterone antagonist (mifepristone) was synthesized over 20 years ago, it was clear that it had a potential as an antifertility agent. Research into the use of antiprogestogens for contraception have concentrated on three general approaches: (1) inhibition of ovulation, (2) inhibition of implantation and (3) disruption of implantation or "menstrual induction". The effect of mifepristone on the ovarian and endometrial cycle depends on dose, timing and frequency of administration. Doses of 10 mg per day or more suppress follicular development and estradiol levels. Ovulatory cycles are maintained in the dose of less than 2 mg although there is increased variability in cycle length. The endometrium shows some minor asynchronous changes, although these are not sufficient to prevent pregnancy. We have chosen to investigate daily doses between 2 and 5 mg which inhibit ovulation and menstruation in over 90% of cycles while still maintaining follicular development and levels of estradiol within the range found during the follicular phase. The endometrium shows proliferative or cystic changes lined by a layer of inactive glandular epithelium set in densely packed stroma. There is, however, an absence of proliferative activity as reflected by a reduced mitotic index and Ki67 staining. These unusual histological appearances are associated with downregulation of PR but a massive upregulation of AR in particularly glandular epithelium. The antiproliferative effect of mifepristone is reassuring suggesting that the risk of atypical hyperplasia due to the effect of prolonged exposure to estrogen unopposed by progesterone is low. In a pilot study, there were no pregnancies in 200 months of exposure in 50 women who used this method as their sole method of contraception. Daily mifepristone could provide a novel contraceptive method which should be devoid of the risks associated with estrogen containing combined oral contraceptive (COC), e.g. venous thromboembolism. The health benefits of avoiding the morbidity associated with menstruation are considerable. Recent surveys suggest that amenorrhoea would be popular with many women.
Cell Division↗
Hormonal contraception can suppress natural antimicrobial gene transcription in human endometrium.
OBJECTIVE: To determine the effect of hormonal contraception with a combined oral contraceptive pill and levonorgestrel intrauterine system on the expression of the natural antimicrobials secretory leukocyte protease inhibitor, beta-defensins 1 and 2, and granulysin in human endometrium. DESIGN: Observational study. SETTING: Day case ward in a department of obstetrics and gynecology. PATIENT(S): Fifty seven women undergoing gynecologic procedures for benign conditions; 24 received no contraception for more than 3 months, 20 received a combined oral contraceptive for more than 3 months, and 13 wore a levonorgestrel intrauterine system for more than 3 months. MAIN OUTCOME MEASURE(S): Endometrial samples were collected from all women. Messenger RNA was extracted and quantitative polymerase chain reaction was used to investigate expression of secretory leukocyte protease inhibitor, beta-defensin 1, beta-defensin 2, and granulysin. Immunohistochemistry for secretory leukocyte protease inhibitor was performed. RESULT(S): All antimicrobials varied cyclically. The level of secretory leukocyte protease inhibitor was maximal in the late secretory and menstrual phase, beta-defensin 1 in the mid secretory phase, granulysin in the late secretory phase, and beta-defensin 2 in the menstrual phase. Use of a combined oral contraceptive or levonorgestrel intrauterine system use decreased messenger RNA expression of beta-defensin 1 and 2 and granulysin but not secretory leukocyte protease inhibitor. CONCLUSION(S): Endogenous and exogenous sex-steroid hormones, in the form of a combined oral contraceptive or levonorgestrel intrauterine system, influence gene transcription of secretory leukocyte protease inhibitor, beta-defensin 1, beta-defensin 2, and granulysin in the endometrium.
Antigens, Differentiation, T-Lymphocyte↗