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1.
OBJECTIVE: Both vascular endothelial growth factor (VEGF) and lysophosphatidic acid (LPA) are secreted by ovarian cancer cells and are known to promote cancer cell growth though the exact mechanism(s) are not completely understood. Since telomerase, a ribonucleprotein expressed in 95% of ovarian cancers, plays an important role in cellular immortalization, growth, and tumor progression, we examined whether telomerase is a molecular target of LPA and VEGF in ovarian cancer. METHODS: Telomerase-positive ovarian carcinoma cell lines PA-1, SW 626, and one telomerase-negative, non-tumorigenic SV40 large-T antigen-transfected human ovarian surface epithelial (IOSE) cell line, FHIOSE 118, derived from normal ovarian surface epithelium were cultured with and without VEGF and LPA for 4 h and 24 h, respectively. Telomerase PCR-ELISA, RT-PCR, VEGF ELISA and luciferase assays were performed to determine the effect of VEGF and LPA on telomerase activity in ovarian cancer cells. Western blot analyses were used to examine the signaling pathway involved in telomerase regulation by VEGF and LPA. RESULTS: We report that: (1) both VEGF and LPA upregulate telomerase activity; (2) LPA induction of telomerase activity is VEGF-dependent; (3) VEGF and LPA induction of telomerase activity is ERK 1/2-dependent; and (4) Sp1 binding sites within the proximal 976- to 378-bp regions of the hTERT promoter are essential for VEGF- and LPA-induced hTERT promoter activity. CONCLUSION: Consequently, these data show the novel finding that VEGF can regulate telomerase activity in non-endothelial cells and that telomerase appears to be a novel molecular target of LPA. 相似文献
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目的 探讨端粒酶在上皮性卵巢肿瘤发生发展中的作用,评价端粒酶作为卵巢癌诊断及预后指标的价值。方法 采用端粒酶PCR-ELISA法对25例卵巢上皮性肿瘤包括8例良性(5例浆液性、3例粘液性)、3例交界性(浆液性)和14例恶性(8例浆液性,4例粘液性,2例内膜样),6例正常卵巢表面上皮进行端粒酶活性定量检测。结果 2例良性、2例交界性和12例恶性卵巢上皮性肿瘤及1例正常上皮存在端粒酶活性,端粒酶活性的吸光度(A)平均值分别为0.080±0.070、0.408±0.208、1.659±0.930和0.086±0.060,统计学分析表明恶性卵巢肿瘤中端粒酶活性明显高于良性、交界性肿瘤和正常卵巢组织,端粒酶活性和卵巢上皮性肿瘤组织学类型、临床分期无关;而与肿瘤的分化程度呈负相关。结论 研究结果初步证明端粒酶活性增高在卵巢癌的无限增殖中是一重要环节,并提示端粒酶表达有可能成为卵巢癌早期诊断及判断预后的肿瘤标志物。端粒酶PCR-ELISA法具有定性又定量、特异性较高、敏感性强、简易快速、可避免同位素污染等优点。 相似文献
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Chen H Wang W Mo Y Ma Y Ouyang N Li R Mai M He Y Bodombossou-Djobo MM Yang D 《Journal of assisted reproduction and genetics》2011,28(9):797-807
Objective
To study the effect of telomerase activity (TA) in human luteinised granulosa cells (GCs) on the outcome of in vitro fertilisation treatment.Methods
Fifty-six women, aged 23 to 39 years, were enrolled and divided into four groups according to their levels of TA.Results
Seventeen cases in group A exhibited nondetectable TA, 16 cases in group B expressed low levels of TA (between 0.1 and 0.65 OD × mm), 14 cases in group C expressed moderate TA levels (between 0.66 and 1.00 OD × mm) and 9 cases in group D expressed high levels of TA (more than 1.00 OD × mm). The level of total serum testosterone (T) was significantly higher in groups C and D than in group A (1.43 ± 0.10 vs. 1.08 ± 0.11 nmol/L, P < 0.030 and 1.56 ± 0.08 vs. 1.08 ± 0.11 nmol/L, P < 0.005, respectively). The TA level was positively correlated with T (r = 0.291, P < 0.011). No obvious differences were observed in rates of fertilisation, cleavage, mature oocyte formation or good-quality embryos among the groups. The patients in group D exhibited the highest rates of embryo implantation and clinical pregnancy (with rates of 52.63% and 77.78%, respectively, compared with 18.92% and 29.41% in group A, 25.71% and 37.50% in group B and 48% and 50% in group C, with P < 0.018 and P = 0.112, respectively). The patients in group D also had a greater likelihood of becoming pregnant than those in group A (OR: 9.703, P < 0.023), group B (OR: 14.765, P < 0.009) or group C (OR: 5.560, P = 0.103).Conclusions
Luteinised GCs have a certain potential for proliferation and TA of luteinised GCs may predict the clinical outcomes of IVF treatment. Some unknown regulatory mechanisms between TA and T should be studied in further trials. 相似文献5.
黄素化颗粒细胞端粒酶的表达及与卵巢功能关系的初步研究 总被引:1,自引:0,他引:1
目的 了解端粒酶在人卵巢黄素化颗粒细胞的表达 ,及与卵巢生殖功能的关系。方法 收集 2 2例行体外受精 胚胎移植或卵胞浆单精子显微注射患者的卵巢黄素化颗粒细胞 ,采用原位杂交法及端粒末端重复序列扩增法 ,分别检测人端粒酶催化亚单位 (hTERT)mRNA及端粒酶活性。结果 黄素化颗粒细胞普遍表达hTERTmRNA ,但其表达强弱不一。 2 2份卵巢黄素化颗粒细胞标本中 ,16份 (73% )有端粒酶活性 ,与血清基础促卵泡激素水平呈负相关 (P <0 .0 1) ,且随年龄增长呈下降趋势。结论 端粒酶可能对维持卵巢功能起重要作用 ,卵巢功能下降可能与卵巢颗粒细胞端粒酶活性降低有关 相似文献
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The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells
Whitworth JM Londoño-Joshi AI Sellers JC Oliver PJ Muccio DD Atigadda VR Straughn JM Buchsbaum DJ 《Gynecologic oncology》2012,125(1):226-230
Objective
Retinoids are important modulators of cell growth, differentiation, and proliferation. 9cUAB30, 9cUAB124, and 9cUAB130 are three novel retinoid compounds that show cytotoxic effects in other malignancies. We evaluated these novel retinoids in combination with chemotherapy against ovarian cancer stem cells (CSCs) in vitro and in an ex vivo model.Methods
A2780 cells were plated in 96-well plates and treated with retinoid, carboplatin, or combination therapy. Cell viability was evaluated using ATPLite assay. The A2780 cell line was also analyzed for CSCs by evaluating ALDH activity using flow cytometry. A2780 cells treated ex vivo with retinoids and chemotherapy were injected into the flank of athymic nude mice in order to evaluate subsequent tumor initiating capacity.Results
A2780 cells were sensitive to treatment with retinoids and carboplatin. The best treatment resulted from the combination of retinoid 9cUAB130 and carboplatin. Untreated A2780 cells demonstrated ALDH activity in 3.3% of the cell population. Carboplatin treatment enriched ALDH activity to 27.3%, while 9cUAB130 ± carboplatin maintained the ALDH positive levels similar to untreated controls (2.3% and 6.7%, respectively). Similar results were found in tumorsphere-forming conditions. Flank injections of ex vivo treated A2780 cells resulted in 4/4 mice developing tumors at 40 days in the untreated group, while 0/4 tumors developed in the 9cUAB130 and carboplatin treated group.Conclusion
Combination treatment with carboplatin and retinoids reduced cell-viability, reduced CSC marker expression, and inhibited tumorigenicity, making it a more effective treatment when compared with carboplatin alone. 相似文献7.
Alteration of telomerase activity in ovarian cancer after chemotherapy 总被引:11,自引:0,他引:11
Takahashi M Kigawa J Oishi T Itamochi H Shimada M Sato S Kamazawa S Akeshima R Terakawa N 《Gynecologic and obstetric investigation》2000,49(3):204-208
To elucidate the relationship between telomerase activity and chemosensitivity in epithelial ovarian cancer, telomerase activity and telomere length (TRF) were examined before and after chemotherapy. Of 21 patients, 9 patients responded to chemotherapy and 12 did not. The positivity of telomerase activity did not significantly differ between responders and nonresponders. There were no differences in the mean length and the distribution of TRF between the two groups. Those distributions became narrow after chemotherapy in both groups. Seven nonresponders (58.3%) exhibited an increase in telomerase activity after chemotherapy but none of the responders showed an increase in activity. Telomerase activity may relate to chemosensitivity in epithelial ovarian cancer. 相似文献
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Joyce F. Liu David Kindelberger Courtney Doyle Alarice Lowe William T. Barry Ursula A. Matulonis 《Gynecologic oncology》2013
Objective
To determine whether circulating tumor cells (CTCs), as detected and enumerated by the Veridex CellSearchTM system, could predict for clinical outcomes in women with newly diagnosed or recurrent epithelial ovarian cancer.Methods
Serial measurements of CTC s and paired serum CA125 were collected in a series of 78 women with newly diagnosed or recurrent ovarian cancer seen at our institution over a period of 15 months. Clinical data were abstracted from patient medical records. CTCs were detected and enumerated by the CellSearchTM protocol, and patients were divided into CTC negative (< 2 CTCs) or positive (≥ 2 CTCs) groups. CTC groups were correlated with clinical characteristics and outcomes. A longitudinal analysis of CTC change and CA125 trends was also performed.Results
At least one CTC was isolated from the peripheral blood of over 80% of the women participating in this study, with a range from 0 to 8. No correlations were observed between CTC numbers and clinical characteristics or outcomes. Although both serum CA125 and CTC number exhibited an overall significant decreasing trend over time, there was no correlation observed between change in CTCs and CA125.Conclusion
Using the FDA-approved CellSearchTM system, CTCs can be isolated from women with newly diagnosed or recurrent ovarian cancer. However, CTC numbers do not significantly correlate with clinical characteristics or patient outcomes. Future studies should focus on phenotypic characterization of CTCs and whether different isolation protocols yield a higher number of CTCs or add prognostic value. 相似文献9.
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Quality of life evaluations in patients with ovarian cancer during chemotherapy treatment 总被引:4,自引:0,他引:4
Le T Leis A Pahwa P Wright K Ali K Reeder B Hopkins L Fung MF 《Gynecologic oncology》2004,92(3):839-844
OBJECTIVES: To examine the impact of treatment- and disease-related factors on the quality of life of patients with ovarian cancers undergoing chemotherapy. PATIENTS AND METHODS: Over 18 months period, all patients with ovarian cancer receiving chemotherapy at the Saskatoon Cancer Center were recruited. The Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire was used to assess patients' quality of life before each chemotherapy cycle. Platinum-based chemotherapy was used initially or in patients with a platinum-free interval of more than 6 months in a recurrence setting. After progression on the platinum-based regimens, liposomal doxorubicin, topotecan, and cisplatinum/etoposide were used as salvage chemotherapy pending on drug availability and convenience of administration to patients. Regression analysis was used to identify significant disease and treatment-related factors that can significantly affect patients' quality of life measures. RESULTS: Seventy-two patients participated in the study providing 270 separate observations. The mean age was 57.81 years with a standard deviation of 13.40. The median duration of chemotherapy-free interval for patients with recurrent disease was 7 months. All patients had stage 3 or 4 disease. About half (52.2%) of the patients had optimal surgical resection with small (<1 cm) residual cancer masses before primary adjuvant chemotherapy. Seventy percent of the patients had either a first diagnosis or a first recurrence of cancer with the other 30% previously treated with two or more chemotherapy regimens. Sixty-two percent had an initial complete response to platinum-based chemotherapy. Multivariate regression analysis showed the use of topotecan or cisplatinum/etoposide, patients' poor responses to chemotherapy, experience with two or more previous line of chemotherapy treatment, and younger ages were significant predictors of poor quality of life during chemotherapy. CONCLUSION: There were significant differences in side effects of commonly used chemotherapy regimens on patients' quality of life. Quality of life assessments should be routinely incorporated in selecting specific chemotherapy to be used. Future research should be carried out to identify the best strategies to further integrate the results of quality of life assessments in cancer treatment protocols and to examine the long-term effects of cancer and its treatment on patients and their families. 相似文献
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芹菜素抑制人卵巢癌CAOV3细胞增殖的研究 总被引:8,自引:0,他引:8
目的探讨芹菜素对人卵巢癌CAOV3细胞增殖的抑制作用。方法2006年10月至12月在中国医科大学附属第一医院肿瘤研究所应用四甲基偶氮唑蓝(MTT)比色法检测芹菜素对CAOV3细胞增殖的抑制作用,流式细胞仪技术分析芹菜素对CAOV3细胞增殖周期的影响。结果20—160μmol/L芹菜素均能抑制CAOV3细胞的生长,且呈明显的时间、剂量依赖性关系。细胞周期分析显示芹菜素组G2/M期细胞比例明显增多,呈量效关系。结论芹菜素抑制CAOV3细胞增殖,可能通过使CAOV3细胞停滞在G2/M期而诱导其凋亡。 相似文献
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Nuria Romero-Laorden David Olmos Tanja Fehm Jesus Garcia-Donas Ivan Diaz-Padilla 《Gynecologic oncology》2014
Objectives
Detecting circulating tumor cells (CTCs) in the peripheral blood and disseminated tumor cells (DTCs) in the bone marrow of cancer patients has proven feasible and of prognostic value in different neoplasms. However, the clinical significance of CTCs and DTCs in ovarian cancer and its association with outcome remains unclear.Methods
A literature search in PubMed was performed from January 2000 to December 2013 for studies evaluating CTCs and/or DTCs and its association with clinicopathological characteristics and clinical outcome in ovarian cancer. The main outcome measures were progression-free survival (PFS) and overall survival (OS).Results
Fourteen studies met the inclusion criteria. Median study size was 84 patients (range 43–216). Median follow-up was 19 months (range 5–52). Most studies were small case series (n < 100; studies; 71%). The majority of studies used an immunophenotyping approach to identify CTCs and/or DTCs, but only 3 studies (21%) used the FDA-approved Cell Search method. Despite the differences in methodology among studies the presence of CTCs and DTCs tended to be associated with higher baseline CA-125 serum levels, higher odds of residual disease after surgery, and worse survival in ovarian cancer across studies. No consistent intra-patient correlation was observed between DTCs detected in the bone marrow and CTCs detected in the blood.Conclusions
The presence of CTCs and DTCs is associated with adverse clinicopathological characteristics and poor clinical outcomes in ovarian cancer patients. Its implementation as a valuable prognostic tool in the clinical setting requires uniform methodology and prospective validation. 相似文献13.
Emily Hinchcliff Alexander Melamed Amy Bregar Elisabeth Diver Joel Clemmer Marcela Del Carmen John O. Schorge J. Alejandro Rauh-Hain 《Gynecologic oncology》2018,148(1):168-173
Purpose
To identify clinical and non-clinical factors associated with utilization of primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT) in women with advanced stage epithelial ovarian cancer (EOC).Methods
Using the National Cancer Database, we identified women with stage IIIC and IV EOC diagnosed from 2012 to 2014. The primary outcome was receipt of NACT, defined in the primary analysis as utilization of chemotherapy as the first cancer-directed therapy, irrespective of whether interval surgery was performed. Univariable and multivariable associations between clinical and non-clinical factors and receipt of NACT were investigated using mixed-effect logistic regression models. A secondary analysis excluded women who received primary chemotherapy but did not receive interval cytoreductive surgery.Results
Among 17,302 eligible women, 10,948 (63.3%) underwent PCS and 6354 (36.7%) received NACT. Older age, stage IV disease, high-grade, and serous histology were associated with receipt of NACT in univariate (p < 0.001) and multivariable analyses (p < 0.001). Analysis of non-clinical factors revealed that residency in the Northeast region and receipt of treatment closer to home were associated with NACT in univariate (p < 0.05) but not multivariable analysis (p > 0.05). In multivariable analysis, African-American race/ethnicity (p = 0.04), low-income level (p = 0.02), treatment in high-volume centers (p < 0.01), and insurance by Medicare or other government insurance (p < 0.001) were associated with receipt of NACT. When women who received no surgery were excluded, all factors that were independent predictors of NACT in the main analysis remained significant, except for race/ethnicity.Conclusions
Non-clinical factors were associated with the use of NACT at a magnitude similar to that of clinically relevant factors. 相似文献14.
Objective
The value of neoadjuvant chemotherapy (NAC) for the treatment of advanced ovarian cancer has yet to be determined. While NAC may facilitate and simplify complete cytoreduction and reduce the risk of surgery, the delay of surgery related to NAC needs to be balanced against any potential benefit.Methods
Surveillance, Epidemiology and End-Results (SEER) data linked to Medicare claims were used to identify 6844 women with treated stage III/IV epithelial ovarian cancer (1995-2005). Patients were classified by primary treatment (surgery (PDS) or chemotherapy), and the primary chemotherapy group was characterized as having NAC or palliative chemotherapy (PC) based on whether there was documentation that surgery was recommended. We compared surgical complications and survival between the groups.Results
4827 (71%) of women were treated with PDS, 958 received NAC (14%) and 1059 (15%) had PC. Only 577 (60%) of women with NAC underwent surgery and they had fewer ostomies (8.5% vs. 19.2%, p < 0.001) and fewer infections, gastrointestinal and pulmonary complications than PDS (all p < 0.01). Comparing NAC to PDS there was a 16% increase in the risk of death at 2 years (RR 1.16, 95%CI 1.01-1.34) for women with stage III disease and a 15% reduction in the risk for women with stage IV disease (RR 0.85, 95%CI 0.73-0.99).Conclusions
NAC followed by surgery was associated with fewer surgical complications than PDS. The direction and magnitude of the difference in survival between women receiving NAC and those receiving PDS differed according to the stage of disease and follow up time. 相似文献15.
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Jessica J. ShankKun Yang Jacob GhannamLourdes Cabrera Carolyn J. JohnstonR. Kevin Reynolds Ronald J. Buckanovich 《Gynecologic oncology》2012,127(2):390-397
Purpose
Studies in non-gynecologic tumors indicate that metformin inhibits growth of cancer stem cells (CSC). Diabetic patients with ovarian cancer who are taking metformin have better outcomes than those not taking metformin. The purpose of this study was to directly address the impact of metformin on ovarian CSC.Methods
The impact of metformin on ovarian cancer cell line growth and viability was assessed with trypan blue staining. Aldehyde dehydrogenase (ALDH) expressing CSC were quantified using FACS®. Tumor sphere assays were performed to determine the impact of metformin on cell line and primary human ovarian tumor CSC growth in vitro. In vivo therapeutic efficacy and the anti-CSC effects of metformin were confirmed using both tumor cell lines and ALDH(+) CSC tumor xenografts.Results
Metformin significantly restricted the growth of ovarian cancer cell lines in vitro. This effect was additive with cisplatin. FACS analysis confirmed that metformin reduced ALDH(+) ovarian CSC. Consistent with this, metformin also inhibited the formation of CSC tumor spheres from both cell lines and patient tumors. In vivo, metformin significantly increased the ability of cisplatin to restrict whole tumor cell line xenografts. In addition, metformin significantly restricted the growth of ALDH(+) CSC xenografts. This was associated with a decrease in ALDH(+) CSC, cellular proliferation, and angiogenesis.Conclusions
Metformin can restrict the growth and proliferation of ovarian cancer stem cells in vitro and in vivo. This was true in cell lines and in primary human CSC isolates. These results provide a rationale for using metformin to treat ovarian cancer patients. 相似文献17.
Boris J. Winterhoff Makayla Maile Amit Kumar Mitra Attila Sebe Martina Bazzaro Melissa A. Geller Juan E. Abrahante Molly Klein Raffaele Hellweg Sally A. Mullany Kenneth Beckman Jerry Daniel Timothy K. Starr 《Gynecologic oncology》2017,144(3):598-606
Objectives
The purpose of this study was to determine the level of heterogeneity in high grade serous ovarian cancer (HGSOC) by analyzing RNA expression in single epithelial and cancer associated stromal cells. In addition, we explored the possibility of identifying subgroups based on pathway activation and pre-defined signatures from cancer stem cells and chemo-resistant cells.Methods
A fresh, HGSOC tumor specimen derived from ovary was enzymatically digested and depleted of immune infiltrating cells. RNA sequencing was performed on 92 single cells and 66 of these single cell datasets passed quality control checks. Sequences were analyzed using multiple bioinformatics tools, including clustering, principle components analysis, and geneset enrichment analysis to identify subgroups and activated pathways. Immunohistochemistry for ovarian cancer, stem cell and stromal markers was performed on adjacent tumor sections.Results
Analysis of the gene expression patterns identified two major subsets of cells characterized by epithelial and stromal gene expression patterns. The epithelial group was characterized by proliferative genes including genes associated with oxidative phosphorylation and MYC activity, while the stromal group was characterized by increased expression of extracellular matrix (ECM) genes and genes associated with epithelial-to-mesenchymal transition (EMT). Neither group expressed a signature correlating with published chemo-resistant gene signatures, but many cells, predominantly in the stromal subgroup, expressed markers associated with cancer stem cells.Conclusions
Single cell sequencing provides a means of identifying subpopulations of cancer cells within a single patient. Single cell sequence analysis may prove to be critical for understanding the etiology, progression and drug resistance in ovarian cancer. 相似文献18.
Sun PM Wei LH Luo MY Liu G Wang JL Mustea A Könsgen D Lichtenegger W Sehouli J 《European journal of obstetrics, gynecology, and reproductive biology》2007,130(2):249-257
OBJECTIVE: The aim of this study was to evaluate the clinicopathological significance of telomerase activity and expression of hTERT gene in human ovarian cancer. The potential value of them as indicators for chemotherapy in ovarian cancer cells was also studied. MATERIALS AND METHODS: A total of 73 samples and ovarian cancer cell lines HO-8910 and COC1 were studied. Telomerase activity was detected by PCR-TRAP-ELISA assay and the expression of the hTERT mRNA was analyzed by semi-quantitative RT-PCR. Alteration of the telomerase activity and hTERT mRNA were also analyzed in the ovarian cancer cells treated with different concentration and different time of cisplatin. Cytogenetic analysis was performed to compare the telomere status in the OH-8910 cells pre- and post-cisplatin treatment. The associations between these two markers and cisplatin induced-apoptosis were respectively analyzed in COC1 cells by the flow cytometry. RESULTS: Telomerase activity are highly increased in malignancy (0.795+/-0.168(A450-655 nm)) than borderline (0.389+/-0.174(A450-655 nm)), benign tumors (0.236+/-0.102(A450-655 nm)) and normal ovary (0.213+/-0.070(A450-655 nm)) (p < 0.05). Twenty samples showed detectable levels of hTERT. The hTERT gene positive lesion showed significantly higher telomerase activity than negative (p = 0.004). There is a significant correlation between the telomerase activity and expression of hTERT (r = 0.921). Both telomerase activity and expression of hTERT can reflect the chemotherapeutic effect of cisplatin in a time-dependent and dose-dependent manner. Treatment with 10 microM cisplatin, the hTERT mRNA decreased after 12h and completely disappeared after 48 h, whereas the telomerase activity did not decrease until 24h. Results from cytogenetic analysis and flow cytometry assay confirmed that the alterations of these two markers are associated with the anti-cancer treatment of cisplatin. CONCLUSION: Expression of hTERT gene is rate-limiting with the activation of telomerase. Both of they may be useful in the predicting of chemotherapeutic effect in ovarian cancer. 相似文献
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Janelle M. Fauci Francesco Sabbatino YangYang Wang Angelina I. Londoño-Joshi J. Michael Straughn Jr. Charles N. Landen Soldano Ferrone Donald J. Buchsbaum 《Gynecologic oncology》2014