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Sample records for a2780 ovarian carcinoma

  1. Inhibition of A2780 Human Ovarian Carcinoma Cell Proliferation by a Rubus Component, Sanguiin H-6.

    PubMed

    Lee, Dahae; Ko, Hyeonseok; Kim, Young-Joo; Kim, Su-Nam; Choi, Kyung-Chul; Yamabe, Noriko; Kim, Ki Hyun; Kang, Ki Sung; Kim, Hyun Young; Shibamoto, Takayuki

    2016-02-03

    The effects of a red raspberry component, sanguiin H-6 (SH-6), on the induction of apoptosis and the related signaling pathways in A2780 human ovarian carcinoma cells were investigated. SH-6 caused an antiproliferative effect and a severe morphological change resembling that of apoptotic cell death but no effect on the cancer cell cycle arrest. In addition, SH-6 induced an early apoptotic effect and activation of caspases as well as the cleavage of PARP, which is a hallmark of apoptosis. The early apoptotic percentages of A2780 cells exposed to 20 and 40 μM SH-6 were 35.39 and 41.76, respectively. Also, SH-6 caused the activation of mitogen-activated protein kinases (MAPKs), especially p38, and the increase of truncated p15/BID. These results in the present study suggest that the apoptosis of A2780 human ovarian carcinoma cells by SH-6 is mediated by the MAPK p38 and a caspase-8-dependent BID cleavage pathway.

  2. Modulation of cisplatin sensitivity in human ovarian carcinoma A2780 and SKOV3 cell lines by sulforaphane.

    PubMed

    Hunakova, Luba; Gronesova, Paulina; Horvathova, Eva; Chalupa, Ivan; Cholujova, Dana; Duraj, Jozef; Sedlak, Jan

    2014-11-04

    Cisplatin resistance is one of the major obstacles in the treatment of ovarian cancer. In an effort to look for new possibilities of how to overcome this difficulty, we studied the mechanisms of the interactions between sulforaphane (SFN) and cisplatin (cisPt) in combined treatment of human ovarian carcinoma A2780 and SKOV3 cell lines. Synergy (A2780) and antagonism (SKOV3) found in MTT assay was confirmed by apoptosis. While SFN significantly potentiated cisPt-induced DNA damage in A2780 cells, it protected SKOV3 cells against cisPt-crosslinking. We revealed a less efficient Nrf-2 pathway inducibility by SFN in A2780 compared to SKOV3 cells, when activation of the Nrf-2 pathway incites its protectivity against cisPt. Thus, different activation of the Nrf-2 pathway may explain the dual effects of SFN.

  3. Cytotoxic Effects of Strawberry, Korean Raspberry, and Mulberry Extracts on Human Ovarian Cancer A2780 Cells

    PubMed Central

    Lee, Dahae; Kang, Ki Sung; Lee, Sanghyun; Cho, Eun Ju; Kim, Hyun Young

    2016-01-01

    Reactive oxygen species are tumorigenic by their ability to increase cell proliferation, survival, and cellular migration. The purpose of the present study was to compare the antioxidant activity and cytotoxic effects of 3 berry extracts (strawberry, Korean raspberry, and mulberry) in A2780 human ovarian carcinoma cells. Except for raspberry, the ethyl acetate or methylene chloride fractions of berries containing phenolic compounds exerted dose dependent free radical scavenging activities. In the raspberry fractions, the hexane fraction also exhibited potent antioxidant activity. The cytotoxic effects of berries extracts in A2780 human ovarian carcinoma cells were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Surprisingly, co-treatment with n-butanol (BuOH) fractions of berries showed stronger cytotoxic effects compared to the other fractions. These findings suggest that potent anticancer molecules are found in the BuOH fractions of berries that have stronger cytotoxic activity than antioxidants. PMID:28078263

  4. Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells

    SciTech Connect

    Barghout, Samir H.; Zepeda, Nubia; Xu, Zhihua; Steed, Helen; Lee, Cheng-Han; Fu, YangXin

    2015-12-04

    Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/β-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/β-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/β-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of β-catenin and higher β-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of β-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for β-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/β-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. - Highlights: • Wnt ligands and target genes are upregulated in cisplatin resistant A2780cp cells. • Negative regulators of Wnt signaling are down-regulated in A2780cp cells. • β-catenin transcriptional activity is higher in A2780cp cells compared to A2780s cells. • Inhibition of β-catenin activity increases carboplatin cytotoxicity in A2780cp cells.

  5. A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties.

    PubMed

    Han, Xiaofeng; DU, Fangfang; Jiang, Li; Zhu, Yifei; Chen, Zhen; Liu, Yanjun; Hong, Tingting; Wang, Teng; Mao, Yong; Wu, Xiaohong; Bruce, Iain C; Jin, Jian; Ma, Xin; Hua, Dong

    2013-11-01

    The use of chemotherapy to treat cancer is effective, but chemoresistance reduces this efficacy. Chemotherapy resistance involves several mechanisms, including the cancer stem cell (CSC) concept. The aim of the present study was to assess whether paclitaxel-resistant epithelial ovarian carcinoma is capable of generating cells with CSC-like properties. Using the paclitaxel-resistant A2780/PTX cell line, it was demonstrated that high aldehyde dehydrogenase 1 (ALDH1) activity identifies CSCs from diverse sources. Furthermore, the A2780/PTX cells had a strong ability to form colonies in soft agar assays. Notably, it was demonstrated that the inhibition of the PI3K signaling pathway abolished colony formation. These data suggest that there is a link between paclitaxel resistance and CSC enrichment. It is possible that therapeutic benefits, such as the restoration of chemosensitivity or the suppression of tumorigenicity, may be enabled by gaining further insights into the mechanisms underlying chemoresistance and the generation of CSCs.

  6. Lectin array and glycogene expression analyses of ovarian cancer cell line A2780 and its cisplatin-resistant derivate cell line A2780-cp.

    PubMed

    Zhao, Ran; Qin, Wenjun; Qin, Ruihuan; Han, Jing; Li, Can; Wang, Yisheng; Xu, Congjian

    2017-01-01

    Ovarian cancer is one of the most lethal gynecological malignancies, in which platinum resistance is a common cause of its relapse and death. Glycosylation has been reported to be involved in drug resistance, and glycomic analyses of ovarian cancer may improve our understanding of the mechanisms underlying cancer cell drug resistance and provide potential biomarkers and therapeutic targets. The serous ovarian cancer cell line A2780 and its platinum-resistant counterpart A2780-cp were used in this study. We performed a lectin array analysis to compare the glycosylation patterns of the two cell lines, a gene expression array was employed to probe the differences in glycogenes. Furthermore, the results were verified by lectin blots. A2780-cp cell exhibited stronger intensities of Lens culinaris (LCA) Canavalia ensiformis (ConA), and Lycopersicon esculentum (LEL) and weaker intensities of Sambucus nigra (SNA) lectins. The gene expression array analysis revealed increased expression of Fut8, B3gnt4, B3gnt5, B4galt2 and decreased expression of Fut1 and ST6GalNAc 6 expression were evident in the A2780-cp cells. The lectin blot confirmed the differences in LCA, ConA, SNA and LEL between the A2780 and A2780-cp cells. The combination of the lectin and gene expression analyses showed that the levels of core fucosylation and poly-LacNAc were increased in the A2780-cp cells and the levels of Fuc α1-2(gal β1-4) GlcNAc and α2-6-linked sialic structures were decreased in the A2780-cp cells. These glycans represent potential biomarkers and might be involved in the mechanism of drug resistance in ovarian cancer.

  7. Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells.

    PubMed

    Shin, Soon Young; Jung, Hyeryoung; Ahn, Seunghyun; Hwang, Doseok; Yoon, Hyuk; Hyun, Jiye; Yong, Yeonjoong; Cho, Hi Jae; Koh, Dongsoo; Lee, Young Han; Lim, Yoongho

    2014-03-15

    Ovarian carcinoma remains the most lethal among gynecological cancers. Chemoresistance is a clinical problem that severely limits treatment success. To identify potent anticancer agents against the cisplatin-resistant human ovarian cancer cell line A2780/Cis, 26 polyphenols bearing a cinnamaldehyde scaffold were synthesized. Structural differences in their inhibitory effect on clonogenicity of A2780/Cis cells were elucidated using comparative molecular field analysis and comparative molecular similarity indices analysis. Structural conditions required for increased inhibitory activity can be derived based on the analysis of their contour maps. The two most active compounds (16 and 19) were selected and further characterized their biological activities. We found that compounds 16 and 19 trigger cell cycle arrest at the G2/M phase and apoptotic cell death in cisplatin-resistant A2780/Cis human ovarian cancer cells. The molecular mechanism of compound 16 was elucidated using in vitro aurora A kinase assay, and the binding mode between the compound 16 and aurora A kinase was interpreted using in silico docking experiments. The findings obtained here may help us develop novel plant-derived polyphenols used for potent chemotherapeutic agents. In conclusion, compounds 16 and 19 could be used as promising lead compounds for the development of novel anticancer therapies in the treatment of cisplatin-resistant ovarian cancers.

  8. LC-MS Based Sphingolipidomic Study on A2780 Human Ovarian Cancer Cell Line and its Taxol-resistant Strain

    PubMed Central

    Huang, Hao; Tong, Tian-Tian; Yau, Lee-Fong; Chen, Cheng-Yu; Mi, Jia-Ning; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-01-01

    Drug resistance elicited by cancer cells continue to cause huge problems world-wide, for example, tens of thousands of patients are suffering from taxol-resistant human ovarian cancer. However, its biochemical mechanisms remain unclear. Sphingolipid metabolic dysregulation has been increasingly regarded as one of the drug-resistant mechanisms for various cancers, which in turn provides potential targets for overcoming the resistance. In the current study, a well-established LC-MS based sphingolipidomic approach was applied to investigate the sphingolipid metabolism of A2780 and taxol-resistant A2780 (A2780T) human ovarian cancer cell lines. 102 sphingolipids (SPLs) were identified based on accurate mass and characteristic fragment ions, among which 12 species have not been reported previously. 89 were further quantitatively analyzed by using multiple reaction monitoring technique. Multivariate analysis revealed that the levels of 52 sphingolipids significantly altered in A2780T cells comparing to those of A2780 cells. These alterations revealed an overall increase of sphingomyelin levels and significant decrease of ceramides, hexosylceramides and lactosylceramides, which concomitantly indicated a deviated SPL metabolism in A2780T. This is the most comprehensive sphingolipidomic analysis of A2780 and A2780T, which investigated significantly changed sphingolipid profile in taxol-resistant cancer cells. The aberrant sphingolipid metabolism in A2780T could be one of the mechanisms of taxol-resistance. PMID:27703266

  9. Extracellular matrix proteins expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line.

    PubMed

    Januchowski, Radosław; Zawierucha, Piotr; Ruciński, Marcin; Nowicki, Michał; Zabel, Maciej

    2014-01-01

    Ovarian cancer is the leading cause of death among gynaecological malignancies. Extracellular matrix (ECM) can affect drug resistance by preventing the penetration of the drug into cancer cells and increased resistance to apoptosis. This study demonstrates alterations in the expression levels of ECM components and related genes in cisplatin-, doxorubicin-, topotecan-, and paclitaxel-resistant variants of the A2780 ovarian cancer cell line. Affymetrix Gene Chip Human Genome Array Strips were used for hybridisations. The genes that had altered expression levels in drug-resistant sublines were selected and filtered by scatter plots. The genes that were up- or downregulated more than fivefold were selected and listed. Among the investigated genes, 28 genes were upregulated, 10 genes were downregulated, and two genes were down- or upregulated depending on the cell line. Between upregulated genes 12 were upregulated very significantly--over 20-fold. These genes included COL1A2, COL12A1, COL21A1, LOX, TGFBI, LAMB1, EFEMP1, GPC3, SDC2, MGP, MMP3, and TIMP3. Four genes were very significantly downregulated: COL11A1, LAMA2, GPC6, and LUM. The expression profiles of investigated genes provide a preliminary insight into the relationship between drug resistance and the expression of ECM components. Identifying correlations between investigated genes and drug resistance will require further analysis.

  10. Cisplatin induced apoptosis of ovarian cancer A2780s cells by activation of ERK/p53/PUMA signals.

    PubMed

    Song, Hao; Wei, Mei; Liu, Wenfen; Shen, Shulin; Li, Jiaqun; Wang, Liming

    2017-03-13

    Cisplatin (CDDP) is one of the most effective anticancer agents widely used in the treatment of solid tumors, including ovarian cancer. It is generally considered as a cytotoxic drug which kills cancer cells by causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, the underlying mechanisms leading to cell apoptosis remain obscure. In this study, the signaling pathways involved in CDDP -induced apoptosis were examined using CDDP-sensitive ovarian cancer A2780s cells. A2780s cells were treated with CDDP (1.5-3 μg/ml) for 6 h, 12 h and 24 h. Using siRNA targeting P53 and PUMA, and a selective MEK inhibitor, PD98059 to examine the relation between ERK1/2 activation, p53 and PUMA expression after exposure to CDDP, and the effect on CDDP-induced apoptosis. The results shown that treatment of A2780s cells with CDDP (3 μg/ml) for 6-24 h induced apoptosis, resulting in the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and accumulation of p53 and PUMA (p53 upregulated modulator of apoptosis) protein. Knockdown of P53 or PUMA by siRNA transfection blocked CDDP-induced apoptosis. Inhibition of ERK1/2 using PD98059, a selective MEK inhibitor, blocked the apoptotic cell death but prevented CDDP-induced accumulation of p53 and PUMA. Knockdown of P53 by siRNA transfection also blocked CDDP-induced accumulation of PUMA. We therefore concluded that CDDP activated ERK1/2 and induced-p53-dependent PUMA upregulation, resulting in triggering apoptosis in A2780s cells. Our study clearly demonstrates that the ERK1/2/p53/PUMA axis is related to CDDP-induced cell death in A2780s cells.

  11. The potassium ion channel opener NS1619 inhibits proliferation and induces apoptosis in A2780 ovarian cancer cells

    SciTech Connect

    Han Xiaobing; Xi Ling; Wang Hui; Huang Xiaoyuan; Ma Xiangyi; Han Zhiqiang; Wu Peng; Ma Xiaoli; Lu Yunping; Wang, Gang Zhou Jianfeng; Ma Ding

    2008-10-17

    Diverse types of voltage-gated potassium (K{sup +}) channels have been shown to be involved in regulation of cell proliferation. The maxi-conductance Ca{sup 2+}-activated K{sup +} channels (BK channels) may play an important role in the progression of human cancer. To explore the role of BK channels in regulation of apoptosis in human ovarian cancer cells, the effects of the specific BK channel activator NS1619 on induction of apoptosis in A2780 cells were observed. Following treatment with NS1619, cell proliferation was measured by MTT assay. Apoptosis of A2780 cells pretreated with NS1619 was detected by agarose gel electrophoresis of cellular DNA and flow cytometry. Our data demonstrate that NS1619 inhibits the proliferation of A2780 cells in a dosage and time dependent manner IC{sub 50} = 31.1 {mu}M, for 48 h pretreatment and induces apoptosis. Western blot analyses showed that the anti-proliferation effect of NS1619 was associated with increased expression of p53, p21, and Bax. These results indicate that BK channels play an important role in regulating proliferation of human ovarian cancer cells and may induce apoptosis through induction of p21{sup Cip1} expression in a p53-dependent manner.

  12. A Specific Mixture of Nutrients Suppresses Ovarian Cancer A-2780 Tumor Incidence, Growth, and Metastasis to Lungs

    PubMed Central

    Roomi, Mohd Waheed; Kalinovsky, Tatiana; Rath, Matthias; Niedzwiecki, Aleksandra

    2017-01-01

    Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. Despite advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a specific nutrient mixture (EPQ) containing ascorbic acid, lysine, proline, green tea extract, and quercetin on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were all inoculated intraperitoneally (IP) with 2 × 106 cells in 0.1 mL of phosphate buffered saline (PBS) and randomly divided into two groups. Upon injection, the Control group (n = 6) was fed a regular diet and the EPQ group (n = 6) a regular diet supplemented with 0.5% EPQ. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed, and processed for histology. Lungs were inspected for metastasis. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with EPQ in triplicate at concentrations between 0 and 1000 μg/mL. Cell proliferation was measured via MTT assay, MMP-9 secretion via gelatinase zymography, invasion through Matrigel and morphology via hematoxylin and eosin (H & E) staining. All Control mice developed large ovarian tumors, whereas 5 out of 6 mice in the EPQ group developed no tumors, and one, a small tumor. Control mice also showed lung metastasis in 6 out of 6 mice, while no lung metastasis was evident in EPQ mice. Zymography demonstrated only MMP-9 expression, which EPQ inhibited in a dose-dependent fashion, with virtual total block at 250 μg/mL concentration. EPQ significantly inhibited invasion through Matrigel with total block at 250 μg/mL concentration. MTT showed dose-dependent inhibition of cell proliferation

  13. A Specific Mixture of Nutrients Suppresses Ovarian Cancer A-2780 Tumor Incidence, Growth, and Metastasis to Lungs.

    PubMed

    Roomi, Mohd Waheed; Kalinovsky, Tatiana; Rath, Matthias; Niedzwiecki, Aleksandra

    2017-03-18

    Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. Despite advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a specific nutrient mixture (EPQ) containing ascorbic acid, lysine, proline, green tea extract, and quercetin on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were all inoculated intraperitoneally (IP) with 2 × 10⁶ cells in 0.1 mL of phosphate buffered saline (PBS) and randomly divided into two groups. Upon injection, the Control group (n = 6) was fed a regular diet and the EPQ group (n = 6) a regular diet supplemented with 0.5% EPQ. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed, and processed for histology. Lungs were inspected for metastasis. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with EPQ in triplicate at concentrations between 0 and 1000 μg/mL. Cell proliferation was measured via MTT assay, MMP-9 secretion via gelatinase zymography, invasion through Matrigel and morphology via hematoxylin and eosin (H & E) staining. All Control mice developed large ovarian tumors, whereas 5 out of 6 mice in the EPQ group developed no tumors, and one, a small tumor. Control mice also showed lung metastasis in 6 out of 6 mice, while no lung metastasis was evident in EPQ mice. Zymography demonstrated only MMP-9 expression, which EPQ inhibited in a dose-dependent fashion, with virtual total block at 250 μg/mL concentration. EPQ significantly inhibited invasion through Matrigel with total block at 250 μg/mL concentration. MTT showed dose-dependent inhibition of cell

  14. Comparative proteomic analysis of paclitaxel sensitive A2780 epithelial ovarian cancer cell line and its resistant counterpart A2780TC1 by 2D-DIGE: the role of ERp57.

    PubMed

    Cicchillitti, Lucia; Di Michele, Michela; Urbani, Andrea; Ferlini, Cristiano; Donat, Maria Benedetta; Scambia, Giovanni; Rotilio, Domenico

    2009-04-01

    Epithelial ovarian cancer is the leading cause of gynecological cancer mortality. Despite good response to surgery and initial chemotherapy, chemoresistance occurrence represents a major obstacle to a successful therapy. To better understand biological mechanisms at the basis of paclitaxel resistance, a comparative proteomic approach based on DIGE coupled with mass spectrometry (MALDI-TOF and LC-MS/MS) was applied to the human epithelial ovarian cancer cell lines A2780 and its paclitaxel resistant counterpart A2780TC1. Most of the differentially expressed proteins between the two cell lines belong to the class of stress response (29%), metabolism (21%), and cell cycle and apoptosis (17%). We focused on proteins which were most strongly modulated by paclitaxel resistance and in particular on the disulphide isomerase ERp57, which may represent a chemoresistance biomarker. ERp57 was found to interact with class III beta-tubulin (TUBB3), involved in paclitaxel resistance in ovarian and other cancers. Moreover, we demonstrated a novel localization of this protein in cytoskeleton and described that ERp57/TUBB3 interaction occurs also in the nuclear compartment and in association with a multimeric complex formed by nucleolin, nucleophosmin, hnRNPK, and mortalin. Our data suggest that ERp57 plays an important role in chemoresistance mechanisms in ovarian cancer by modulating the attachment of microtubules to chromosomes following paclitaxel treatment through its interaction with TUBB3.

  15. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    SciTech Connect

    Piotrowska, Hanna; Myszkowski, Krzysztof; Ziółkowska, Alicja; Kulcenty, Katarzyna; Wierzchowski, Marcin; Kaczmarek, Mariusz; Murias, Marek; Kwiatkowska-Borowczyk, Eliza; Jodynis-Liebert, Jadwiga

    2012-08-15

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC{sub 50} = 0.71 μM) and SKOV-3 (IC{sub 50} = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  16. Induction of drug resistance and protein kinase C genes in A2780 ovarian cancer cells after incubation with antineoplastic agents at sublethal concentrations.

    PubMed

    Brügger, Dorothee; Brischwein, Klaus; Liu, Chao; Bader, Peter; Niethammer, Dietrich; Gekeler, Volker; Beck, James F

    2002-01-01

    We examined the inducibility of drug resistance (MDR1, MRP1, LRP) and protein kinase C (PKC) isozyme (alpha, epsilon, eta, theta, tau, zeta) corresponding genes in A2780 ovarian cancer cells after a 24-hour treatment with adriamycin (ADR), camptothecin (CAM), etoposide (ETO) or vincristine (VCR). Sublethal concentrations of drugs were used to exclude short-term effects caused by selection. Cell cycle analysis was performed to identify possible correlation between resistance factors, PKC isozymes and proliferation. We found a mostly combined induction of MDR1, LRP, PKC tau and PKC zeta by CAM, ETO and VCR. PKC alpha, epsilon, eta and theta gene expression altered variably. Cell cycle analysis showed that A2780 cells responded with a marked G2/M arrest after a 24-hour treatment with CAM, ETO and VCR but an association between the induction of PKC isozymes corresponding genes and proliferation was not seen. Our analysis points to a possible link between atypical PKC tau/PKC zeta and MDR1/LRP in cytostatic stress response of cancer cells.

  17. Preclinical in vivo activity of a combination gemcitabine/liposomal doxorubicin against cisplatin-resistant human ovarian cancer (A2780/CDDP).

    PubMed

    Gallo, D; Fruscella, E; Ferlini, C; Apollonio, P; Mancuso, S; Scambia, G

    2006-01-01

    Both gemcitabine and liposomal doxorubicin are antineoplastic drugs with clinical activity in platinum-refractory ovarian cancer. The purpose of this study was to evaluate the antitumor activity of a combination gemcitabine/liposomal doxorubicin administered to athymic mice bearing cisplatin-resistant human ovarian cancer (A2780/CDDP) xenografts. Emphasis was on the use of very low doses of each drug and of different dosing schedules. Data obtained showed that combined treatment with 80 mg/kg gemcitabine and 15 mg/kg liposomal doxorubicin produced a significant enhancement of antitumor activity compared with monotherapy at the same doses of these agents. Noteworthy is the fact that the majority of xenograft-bearing animals receiving the combination therapy demonstrated a complete tumor regression at the end of the study. A similar trend was observed when doses of both drugs were reduced to 20 mg/kg gemcitabine and to 6 mg/kg liposomal doxorubicin. Again, three out of ten mice receiving the combination were tumor free at the end of the study. No significant differences were observed in antitumor activity when comparing the simultaneous vs the consecutive dosing schedule. Remarkably, no additive toxicity was observed in any experimental trials. These data encourage clinical trials to prove the advantages of this combination treatment with respect to the single-agent chemotherapy in platinum-refractory ovarian cancer patients.

  18. Synthetic paclitaxel-octreotide conjugate reverses the resistance of paclitaxel in A2780/Taxol ovarian cancer cell line.

    PubMed

    Shen, Yang; Zhang, Xiao-Yu; Chen, Xi; Fan, Li-Li; Ren, Mu-Lan; Wu, Yong-Ping; Chanda, Kenneth; Jiang, Shi-Wen

    2017-01-01

    The high mortality of ovarian cancer is partly due to the frequent resistance of ovarian cancer to current chemotherapy agents such as paclitaxel and platinum. Somatostatin analogue (SSTA) has been shown to inhibit the proliferation of some tumors through binding to somatostatin receptor (SSTR) and activation of Ras-, Rapl- and B-Raf-dependent extracellular signal-regulated kinase 2 (Erk2). It was reported that paclitaxel-octreotide conjugate (POC) exhibited enhanced tumor growth inhibition with reduced toxicity. In the present study, we prepared the POC and investigated its effects and mechanism for the reversal of drug resistance in paclitaxel-resistant ovarian cancer cell line. We demonstrated that treatment with POC led to more cell apoptosis than either paclitaxel or octreotide (OCT) alone. Moreover, the expression of multidrug resistance 1 (MDR1) and vascular endothelial growth factor (VEGF) mRNA, and protein decreased in a dose-dependent manner while the expression of SSTR remained stable following treatment with POC. Although the exact action, in vivo effects and pharmacologic kinetics of POC remain to be investigated, we have demonstrated the feasibility for the synthesis of POC, and more significantly, provided a potential approach to overcome the resistance of ovarian cancer against taxol. The findings also shed some new light on the mechanisms underlying the development of resistance to taxol by ovarian cancer cells.

  19. Kudsuphilactone B, a nortriterpenoid isolated from Schisandra chinensis fruit, induces caspase-dependent apoptosis in human ovarian cancer A2780 cells.

    PubMed

    Jeong, Miran; Kim, Hye Mi; Kim, Hyun Ji; Choi, Jung-Hye; Jang, Dae Sik

    2017-04-01

    A phytochemical study on the fruits of Schisandra chinensis led to the isolation and characterization of nineteen compounds. The structures of the isolates were determined to be schizandrin, deoxyschizandrin, angeloylgomisin H, gomisin A, gomisin J, (-)-gomisin L1, (-)-gomisin L2, wuweizisu C, gomisin N, meso-dihydroguaiaretic acid, kadsuphilactone B, α-ylangenol, α-ylangenyl acetate, β-chamigrenal, β-chamigrenic acid, 4-hydroxybenzoic acid, protocatechuic acid, p-methylcarvacrol, and indole-3-acetic acid. Of these, some lignans and a nortriterpene showed cytotoxic activity in human ovarian and endometrial cancer cells. In particular, a nortriterpenoid kadsuphilactone B exhibited significant cytotoxic activity with IC50 values below 25 μM in both A2780 and Ishikawa cells. Kadsuphilactone B induced apoptotic cell death and stimulated the activation of caspase-3, -8, and -9 and the cleavages of poly (ADP-ribose) polymerase. Caspase inhibitors attenuated the pro-apoptotic activity of kudsuphilactone B. In addition, kadsuphilactone B altered the expression levels of B cell lymphoma 2 (Bcl-2) family proteins. Moreover, activation of MAPKs was modulated by kadsuphilactone B in a dose-dependent manner. Taken together, these results show that kadsuphilactone B induces caspase-dependent apoptosis in human cancer cells via the regulation of Bcl-2 family protein and MAPK signaling.

  20. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells

    PubMed Central

    Reza, Abu Musa Md Talimur; Choi, Yun-Jung; Yasuda, Hideyo; Kim, Jin-Hoi

    2016-01-01

    An enigmatic question exists concerning the pro- or anti-cancer status of mesenchymal stem cells (MSCs). Despite growing interest, this question remains unanswered, and the debate became intensified with new evidences backing each side. Here, we showed that human adipose MSC (hAMSC)-derived conditioned medium (CM) exhibited inhibitory effects on A2780 human ovarian cancer cells by blocking the cell cycle, and activating mitochondria-mediated apoptosis signalling. Explicitly, we demonstrated that exosomes, an important biological component of hAMSC-CM, could restrain proliferation, wound-repair and colony formation ability of A2780 and SKOV-3 cancer cells. Furthermore, hAMSC-CM-derived exosomes induced apoptosis signalling by upregulating different pro-apoptotic signalling molecules, such as BAX, CASP9, and CASP3, as well as downregulating the anti-apoptotic protein BCL2. More specifically, cancer cells exhibited reduced viability following fresh or protease-digested exosome treatment; however, treatment with RNase-digested exosomes could not inhibit the proliferation of cancer cells. Additionally, sequencing of exosomal RNAs revealed a rich population of microRNAs (miRNAs), which exhibit anti-cancer activities by targeting different molecules associated with cancer survival. Our findings indicated that exosomal miRNAs are important players involved in the inhibitory influence of hAMSC-CM towards ovarian cancer cells. Therefore, we believe that these comprehensive results will provide advances concerning ovarian cancer research and treatment. PMID:27929108

  1. Cellular Uptake, DNA Binding and Apoptosis Induction of Cytotoxic Trans-[PtCl2(N,N-dimethylamine)(Isopropylamine)] in A2780cisR Ovarian Tumor Cells

    PubMed Central

    Pérez, José M.; Montero, Eva I.; Quiroga, Adoración G.; Fuertes, Miguel A; Alonso, Carlos

    2001-01-01

    Trans-[PtCl2(N,N-dimethylamine)(isopropylamine)] is a novel trans-platinum compound that shows cytotoxic activity in several cisplatin resistant cell lines. The aim of this paper was to analyse, by means of molecular cell biology techniques and total reflection X-ray fluorescence (TXRF), the cytotoxic activity, the induction of apoptosis, the cellular uptake and the DNA binding of trans-[PtCl2(N,N-dimethylamine)(isopropylamine)] in the cisplatin resistant cell line A2780cisR. The results show that this drug is more cytotoxic and induces a higher amount of apoptotic cells than cisplatin in A2780cisR cells. However, the intracellular accumulation and extent of binding to DNA of trans-[PtCl2(N,N-dimethylamine)( isopropylamine)] is lower than that of cis-DDP. Moreover, trans-[PtCl2(N,N-dimethylamine)(isopropylaminae)] is partially inactivated by intracellular levels of glulathione. The result suggest that circumvention of ciplatin resistance by trans-[PtCl2(N,N-dimethylamine)(isopropylamine)] in A2780cisR cells might be related with the ability of this drug to induce apoptosis. PMID:18475973

  2. Targeting Ovarian Carcinoma Stem Cells

    DTIC Science & Technology

    2012-05-01

    expertise with expertise in gynecologic oncology /ovarian carcinoma and in animal models of cancer this proposal will: 1) Identify, isolate, and...more numerous differentiated progeny characterizing the malignancy . Although the clinical significance of these cancer stem cells (CSC) has been...the dramatic initial response rates in ovarian carcinoma represent therapeutic effectiveness against the differentiated cancer cells making up the

  3. Aflibercept in epithelial ovarian carcinoma

    PubMed Central

    Moroney, John W; Sood, Anil K; Coleman, Robert L

    2009-01-01

    Angiogenesis is a hallmark of malignant transformation. With improved understanding of angiogenic signaling in both the normal and malignant state, there have been a number of agents developed that target VEGF signaling. These targeted agents can affect downstream VEGF signal transduction via unique mechanisms at different cellular and extracellular locations. The aflibercept, or VEGF-Trap, molecule is the subject of this article. Its molecular structure, pharmacokinetic and pharmacodynamic profile, and preclinical and early clinical data in epithelial ovarian carcinoma is reviewed. For comparison, other anti-angiogenic agents that have been or are currently being studied in epithelial ovarian carcinoma are also summarized. Finally, the anticipated role of aflibercept in the treatment of epithelial ovarian carcinoma is also discussed. PMID:19519199

  4. Molecular Imaging of Ovarian Carcinoma Angiogenesis

    DTIC Science & Technology

    2009-03-01

    is found at a significantly higher rate in primary ovarian cancer than in ovarian tumors of low malignant potential, a fact which points to a role of...the correlation between αv-integrin expression and poor survival in ovarian carcinoma (11). Given that the initial critical step of ovarian cancer ...marker of poor prognosis in advanced-stage ovarian carcinoma . Clin Cancer Res. Dec 2001;7(12):4073-4079. 9. van der Flier A, Sonnenberg A. Function

  5. The anti-tumor effect of cross-reacting material 197, an inhibitor of heparin-binding EGF-like growth factor, in human resistant ovarian cancer

    SciTech Connect

    Tang, Xiao-han; Deng, Suo; Li, Meng; Lu, Mei-song

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer HB-EGF over-expression in A2780/Taxol, A2780/CDDP cells and the matched xenografts. Black-Right-Pointing-Pointer CRM197 induces enhanced apoptosis in A2780/Taxol and A2780/CDDP cells. Black-Right-Pointing-Pointer CRM197 arrests A2780/Taxol and A2780/CDDP cells at G0/G1 phase. Black-Right-Pointing-Pointer CRM197 suppressed the A2780/Taxol and A2780/CDDP growth of xenografts. -- Abstract: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. Cross-reacting material 197 (CRM197), a specific HB-EGF inhibitor, has been proven to represent possible chemotherapeutic agent for ovarian cancer. However, the effect of CRM197 on the resistant ovarian carcinoma cells has not been sufficiently elucidated. Here, we found that HB-EGF was over-expressed in a paclitaxel-resistant human ovarian carcinoma cell line (A2780/Taxol) and a cisplatin-resistant cell line (A2780/CDDP), as well as the xenograft mouse tissue samples with these cells. To investigate the possible significance of the HB-EGF over-expression in A2780/Taxol and A2780/CDDP cells, we inhibited HB-EGF expression by CRM197 to investigate the effect of CRM197 treatment on these cells. We observed that CRM197 significantly induced anti-proliferative activity in a dose-dependent manner with the cell-cycle arrest at the G0/G1 phase and enhanced apoptosis in A2780/Taxol and A2780/CDDP cells. The sensitive ovarian carcinoma parental cell line (A2780), A2780/Taxol and A2780/CDDP cells formed tumors in nude mice, and enhanced tumorigenicity was observed in drug-resistant tumors. Furthermore, we observed that CRM197 significantly suppressed the growth of drug-resistant ovarian cancer xenografts in vivo (p < 0.001). These results suggest that CRM197 as an HB-EGF-targeted agent has potent anti-tumor activity in paclitaxel- and cisplatin-resistant ovarian cancer which over-express HB-EGF.

  6. Encapsulation in PLGA-PEG enhances 9- nitro-camptothecin cytotoxicity to human ovarian carcinoma cell line through apoptosis pathway

    PubMed Central

    Ahmadi, F.; Derakhshandeh, K.; Jalalizadeh, A.; Mostafaie, A.; Hosseinzadeh, L.

    2015-01-01

    Ovarian cancer is the fifth leading cause of the cancer-related death among women. 9-nitrocamptothecin (9-NC) is a water-insoluble derivative of camptothecin used for the treatment of patients with advanced ovarian cancer. Previous studies showed that the encapsulation of 9-NC in poly (lactic-co-glycolic acid, PLGA) nanoparticles increased the cytotoxic effect of the drug on different cancer cell lines. In the present study, the cytotoxic effects of 9-NC, 9-NC-loaded PLGA and PLGA-polyethylene glycol (PLGA-PEG) nanoparticles with varying degree of PEG (5, 10, and 15%) were evaluated on human ovarian carcinoma cell line. Furthermore, the mode of cell death induced by 9-NC and the optimized 9-NC-loaded PLGA-PEG nanoparticles on A2780 cell line were investigated. 9-NC incorporating nanoparticles were prepared by nanopercipitation method and their physicochemical characteristics were evaluated using standard methods. The results showed that activation of caspase-3 and -9 significantly increased by free 9-NC and PLGA-PEG loaded nanoparticles in A2780 cells. In contrast to the free drug which increased the activation of caspase-8, 9-NC-loaded PLGA-PEG nanoparticles did not alter the activation of caspase-8. Collectively, it appears that apoptosis induced by 9-NC incorporated in PLGA-PEG 5% occurred through the activation of caspase-9 rather than activation of caspase-8 which is the mediator of extrinsic pathway. Moreover, our results confirmed that 9-NC in nanoparticles at the level of gene expression potentiated down-regulation of Bcl-2, up regulation of Bax, and Smac/DIABLO leading to a decrease in mitochondrial membrane potential. Taken together, our results showed that 9-NC incorporated in PLGA-PEG 5% nanoparticles is able to induce apoptosis in A2780 human ovarian carcinoma cells and has the potential for the treatment of ovarian carcinoma. PMID:26487893

  7. Gene Expression Patterns in Ovarian Carcinomas

    PubMed Central

    Schaner, Marci E.; Ross, Douglas T.; Ciaravino, Giuseppe; Sørlie, Therese; Troyanskaya, Olga; Diehn, Maximilian; Wang, Yan C.; Duran, George E.; Sikic, Thomas L.; Caldeira, Sandra; Skomedal, Hanne; Tu, I-Ping; Hernandez-Boussard, Tina; Johnson, Steven W.; O'Dwyer, Peter J.; Fero, Michael J.; Kristensen, Gunnar B.; Børresen-Dale, Anne-Lise; Hastie, Trevor; Tibshirani, Robert; van de Rijn, Matt; Teng, Nelson N.; Longacre, Teri A.; Botstein, David; Brown, Patrick O.; Sikic, Branimir I.

    2003-01-01

    We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers. PMID:12960427

  8. Versican regulates metastasis of epithelial ovarian carcinoma cells and spheroids

    PubMed Central

    2014-01-01

    Background Epithelial ovarian carcinoma is a deadly disease characterized by overt peritoneal metastasis. Individual cells and multicellular aggregates, or spheroids, seed these metastases, both commonly found in ascites. Mechanisms that foster spheroid attachment to the peritoneal tissues preceding formation of secondary lesions are largely unknown. Methods Cell culture models of SKOV-3, OVCAR3, OVCAR4, Caov-3, IGROV-1, and A2780 were used. In this report the role of versican was examined in adhesion of EOC spheroids and cells to peritoneal mesothelial cell monolayers in vitro as well as in formation of peritoneal tumors using an in vivo xenograft mouse model. Results The data demonstrate that versican is instrumental in facilitating cell and spheroid adhesion to the mesothelial cell monolayers, as its reduction with specific shRNAs led to decreased adhesion. Furthermore, spheroids with reduced expression of versican failed to disaggregate to complete monolayers when seeded atop monolayers of peritoneal mesothelial cells. Failure of spheroids lacking versican to disaggregate as efficiently as controls could be attributed to a reduced cell migration that was observed in the absence of versican expression. Importantly, both spheroids and cells with reduced expression of versican demonstrated significantly impaired ability to generate peritoneal tumors when injected intraperitoneally into athymic nude mice. Conclusions Taken together these data suggest that versican regulates the development of peritoneal metastasis originating from cells and spheroids. PMID:24999371

  9. Quercetin induces the apoptosis of human ovarian carcinoma cells by upregulating the expression of microRNA-145.

    PubMed

    Zhou, Junbo; Gong, Jian; Ding, Chun; Chen, Guiqin

    2015-08-01

    Ovarian cancer is one of the most malignant types of cancer of the female human reproductive track, posing a severe threat to the health of the female population. Numerous previous studies have demonstrated that microRNA (miR)-145 is downregulated in ovarian cancer, and that quercetin can inhibit the growth of cancer cells via regulating the expression of miRs. Therefore, the present study investigated the effect of quercetin on the expression of miR-145 in SKOV-3 and A2780 human ovarian cancer cell lines. The results revealed that the expression levels of cleaved caspase-3 in the SKOV-3 and A2780 cells were significantly increased following treatment to induce overexpression of miR-145 compared with treatment with quercetin alone (P<0.01). However, the expression of cleaved caspase-3 in the anti-miR-145 (miR-145 inhibitor) group of cells was markedly decreased compared with that in the miR-145 overexpression group (P<0.01). Taken together, the results suggested that treatment with quercetin induced the apoptosis of human ovarian carcinoma cells through activation of the extrinsic death receptor mediated and intrinsic mitochondrial apoptotic pathways.

  10. Denileukin Diftitox Used in Treating Patients With Advanced Refractory Ovarian Cancer, Primary Peritoneal Carcinoma, or Epithelial Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-05-02

    Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  11. An Immunohistochemical Algorithm for Ovarian Carcinoma Typing

    PubMed Central

    Rahimi, Kurosh; Rambau, Peter F.; Naugler, Christopher; Le Page, Cécile; Meunier, Liliane; de Ladurantaye, Manon; Lee, Sandra; Leung, Samuel; Goode, Ellen L.; Ramus, Susan J.; Carlson, Joseph W.; Li, Xiaodong; Ewanowich, Carol A.; Kelemen, Linda E.; Vanderhyden, Barbara; Provencher, Diane; Huntsman, David; Lee, Cheng-Han; Gilks, C. Blake; Mes Masson, Anne-Marie

    2016-01-01

    There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (χ2 Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials. PMID:26974996

  12. The effects of selenium on tumor growth in epithelial ovarian carcinoma.

    PubMed

    Park, Jin Sun; Ryu, Ji Yoon; Jeon, Hye-Kyung; Cho, Young Jae; Park, Young Ae; Choi, Jung-Joo; Lee, Jeong-Won; Kim, Byoung-Gie; Bae, Duk-Soo

    2012-07-01

    Epidemiological studies suggest that selenium protects against the development of several cancers. Selenium (sodium selenite) has been reported to interfere with cell growth and proliferation, and to induce cell death. In this study, we tested whether selenium could have growth-inhibiting effect in ovarian cancer cells and an orthotopic animal model. Cell growth in selenium-treated cells was determined in human ovarian cancer cells, A2780, HeyA8, and SKOV3ip1 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Animal experiment of selenium with paclitaxel was performed using SKOV3ip1 cells in nude mice to evaluate their inhibiting effect for tumor growth. In addition, another animal experiment of paclitaxel with or without selenium was performed to assess the effect of survival and food intake in mice. The in vitro growth of selenium-treated cells was significantly decreased dose-dependently in A2780, HeyA8, and SKOV3ip1 cells. Therapy experiment in mice was started 1 week after injection of the SKOV3ip1 cells. Treatment with selenium (1.5 mg/kg, 3 times/week) and paclitaxel injection showed no addictive effect of the inhibition of tumor growth. However, combination of selenium and paclitaxel showed the slightly increased food intake compared with paclitaxel alone. Although selenium has growth-inhibiting effect in ovarian carcinoma cells in vitro, there is no additive effect on tumor growth in mice treated with combination of paclitaxel and selenium. However, food intake is slightly higher in selenium-treated mice during chemotherapy.

  13. ELF5 in epithelial ovarian carcinoma tissues and biological behavior in ovarian carcinoma cells.

    PubMed

    Yan, Hongchao; Qiu, Linglin; Xie, Xiaolei; Yang, He; Liu, Yongli; Lin, Xiaoman; Huang, Hongxiang

    2017-03-01

    The expression of E74-like factor 5 (ELF5) in epithelial ovarian carcinoma tissues and its effects on biological behavior in ovarian carcinoma cells were assessed in search for a new approach for gene treatment of epithelial ovarian carcinoma. RT-PCR technology was applied to detect the expression of ELF5 mRNA in epithelial ovarian carcinoma (n=49), borderline ovarian epithelial tumor (n=19), benign ovarian epithelial tumor (n=31) and normal ovarian tissues (n=40). Then, we transfected recombinant plasmid pcDNA3.1‑ELF5+EGFP into human ovarian carcinoma SKOV3 cells (recombinant plasmid group) in vitro and screened out stably transfected cells to conduct multiplication culture. Western blot analysis was performed to detect the expression of ELF5 protein in the different groups. Flow cytometry was employed to detect cell apoptosis and cycles. ELF5 mRNA in epithelial ovarian carcinoma and borderline ovarian epithelial tumor tissues were significantly lower (P<0.05) than those in benign ovarian epithelial tumor and normal ovarian tissues. ELF5 protein expression in the cells of recombinant plasmid group was significantly higher compared with empty plasmid and blank control groups. The capacity of cell reproductive recombinant plasmid group at each time point decreased (P<0.05). Flow cytometry detection showed that 67.03% of cells in recombinant plasmid group was blocked in G0/G1 phase (P<0.05), compared with empty plasmid group (37.17%) and blank control group (38.24%). Apoptotic rate of recombinant plasmid group was significantly lower (31.4±1.9%; P<0.05), compared with that of empty plasmid group (9.1±2.2%) and blank control group (8.7±1.5%), and the differences were statistically significant. In conclusion, ELF5 interfered with cell cycle of human ovarian carcinoma SKOV3 cells and promoted apoptosis of human ovarian carcinoma SKOV3 cells inhibiting their growth and invasive capacity; and thus providing a new approach to gene treatment of ovarian carcinoma.

  14. ELF5 in epithelial ovarian carcinoma tissues and biological behavior in ovarian carcinoma cells

    PubMed Central

    Yan, Hongchao; Qiu, Linglin; Xie, Xiaolei; Yang, He; Liu, Yongli; Lin, Xiaoman; Huang, Hongxiang

    2017-01-01

    The expression of E74-like factor 5 (ELF5) in epithelial ovarian carcinoma tissues and its effects on biological behavior in ovarian carcinoma cells were assessed in search for a new approach for gene treatment of epithelial ovarian carcinoma. RT-PCR technology was applied to detect the expression of ELF5 mRNA in epithelial ovarian carcinoma (n=49), borderline ovarian epithelial tumor (n=19), benign ovarian epithelial tumor (n=31) and normal ovarian tissues (n=40). Then, we transfected recombinant plasmid pcDNA3.1-ELF5+EGFP into human ovarian carcinoma SKOV3 cells (recombinant plasmid group) in vitro and screened out stably transfected cells to conduct multiplication culture. Western blot analysis was performed to detect the expression of ELF5 protein in the different groups. Flow cytometry was employed to detect cell apoptosis and cycles. ELF5 mRNA in epithelial ovarian carcinoma and borderline ovarian epithelial tumor tissues were significantly lower (P<0.05) than those in benign ovarian epithelial tumor and normal ovarian tissues. ELF5 protein expression in the cells of recombinant plasmid group was significantly higher compared with empty plasmid and blank control groups. The capacity of cell reproductive recombinant plasmid group at each time point decreased (P<0.05). Flow cytometry detection showed that 67.03% of cells in recombinant plasmid group was blocked in G0/G1 phase (P<0.05), compared with empty plasmid group (37.17%) and blank control group (38.24%). Apoptotic rate of recombinant plasmid group was significantly lower (31.4±1.9%; P<0.05), compared with that of empty plasmid group (9.1±2.2%) and blank control group (8.7±1.5%), and the differences were statistically significant. In conclusion, ELF5 interfered with cell cycle of human ovarian carcinoma SKOV3 cells and promoted apoptosis of human ovarian carcinoma SKOV3 cells inhibiting their growth and invasive capacity; and thus providing a new approach to gene treatment of ovarian carcinoma. PMID

  15. Intrauterine device found in an ovarian carcinoma.

    PubMed

    Koo, Hye Ryoung; Oh, Young Taik; Kim, Young Tae; Kim, Sang Wun; Kang, Jung-Ho; Kim, Ki Whang

    2008-01-01

    Displacement of an intrauterine device (IUD) through the perforation site is a rare but one of the major complications. Theoretically, an extrauterine IUD can be located anywhere in the abdominopelvic cavity. It may be asymptomatic or may cause serious complications, including infection, fistula, organ perforation, or bowel obstruction. However, there is no report of IUD located within an ovarian carcinoma to our knowledge, and our report is the first case of an IUD found in the center of an ovarian cancer.

  16. Inhibition of heat shock protein (Hsp) 90 potentiates the antiproliferative and pro-apoptotic effects of 2-(4'fluoro-phenylamino)-4H-1,3-thiazine[6,5-b]indole in A2780cis cells.

    PubMed

    Solárová, Zuzana; Kello, Martin; Varinská, Lenka; Budovská, Mariana; Solár, Peter

    2017-01-01

    Ovarian carcinoma is initially sensitive to platinum-based therapy, but become resistant over time. The study of cancer sensitizing substance is therefore the major challenge for a number of scientific groups. Our experiments were carried out on human ovarian adenocarcinoma A2780cis cells resistant to cisplatin and their response to 2-(4'fluoro-phenylamino)-4H-1,3-thiazine[6,5-b]indole (thiazine[6,5-b]indole) and/or heat shock protein (Hsp) 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using proliferation assay, cell cycle analysis and monitoring of apoptosis were examined. A2780cis cells revealed the same fold of resistance to Hsp90 inhibitor 17-DMAG as it is declared for cisplatin (18 times), but only 3.2 times for thiazine[6,5-b]indole. Our results showed that the combination of thiazine[6,5-b]indole and 17-DMAG significantly reduced proliferation of A2780cis cells and led to their accumulation in G2/M phase of the cell cycle. Moreover, both thiazine[6,5-b]indole as well as 17-DMAG increased the number of annexin V positive A2780cis cells in time dependent manner. Interestingly, thiazine[6,5-b]indole treatment significantly activated also caspase-3 compared to untreated or 17-DMAG-treated cells and reduced mitochondrial membrane potential (MMP) of A2780cis cells with more significant decline after combined treatment. In this regard, the incubation of A2780cis cells with thiazine[6,5-b]indole induced PARP protein cleavage as well as an increased level of Bad protein with more pronounced changes after combined treatment. Importantly, Hsp70 protein was not upregulated in A2780cis cells neither by individual treatment nor by mutual combination. Our results signify antiproliferative and pro-apoptotic effects of novel thiazine[6,5-b]indole potentiated by Hsp90 inhibitor 17-DMAG in ovarian adenocarcinoma cells resistant to cisplatin and therefore represents new strategy in cancer treatment.

  17. Pelvic irradiation for stage II ovarian carcinoma.

    PubMed

    Terada, K Y; Morley, G W; Roberts, J A

    1988-01-01

    Over a 20-year period, 34 patients with FIGO stage II ovarian carcinoma were treated with postoperative pelvic irradiation at the University of Michigan. Complications of radiation treatment were minimal. The overall actuarial disease-free 5-year survival was 53%. This was not significantly different for substages IIA, IIB, or IIC. Patients with well-differentiated tumors had a significantly better survival than patients with moderate or poorly differentiated tumors (P less than 0.05). The implications for managing stage II ovarian carcinoma are discussed.

  18. Bilateral ovarian carcinoma with bilateral uveal melanoma.

    PubMed Central

    Mullaney, J; Mooney, D; O'Connor, M; McDonald, G S

    1984-01-01

    A case of bilateral uveal melanoma in a 60-year-old woman in association with primary bilateral ovarian carcinoma is described. This is the first case in which ultrastructural studies have been performed on the ocular tumours. Seven previously described cases are summarised, and the extreme rarity of such reports would suggest that this may indeed be a new syndrome. Images PMID:6704361

  19. Transitional cell bladder carcinoma with presentation mimicking ovarian carcinoma.

    PubMed

    Erickson, D R; Dabbs, D J; Olt, G J

    1996-05-01

    In the case described here, the patient's initial presentation suggested ovarian carcinoma. She had recurrent ascites, a pelvic mass, elevated CA-125, and extensive peritoneal carcinomatosis with transitional cell histology. The presence of hematuria prompted a cystoscopy, which revealed the true site of origin to be the urinary bladder rather than ovaries. This presentation is extremely rare for bladder cancer. Since transitional cell tumors from the bladder have a much worse prognosis than those of ovarian origin, it is important to identify the primary site correctly. Therefore, cystoscopy is essential for patients with hematuria, and should be considered in cases of apparent primary peritoneal carcinoma with transitional cell histology.

  20. Ovarian carcinoma presenting as cutaneous nasal metastasis*

    PubMed Central

    António, Ana Marta; Alves, João Vitor; Goulão, João; Bártolo, Elvira

    2016-01-01

    Metastatic ovarian cancer uncommonly presents with skin metastasis. When present, skin metastases of ovarian cancer are usually localized in the vicinity of the primary tumor. We report a case of a 58-year-old woman with a rapid growing erythematous, well-defined nodule localized on the left nasal ala. A skin biopsy was performed and histopathological and immunohistochemical findings were compatible with a cutaneous metastasis of adenocarcinoma. A systematic investigation revealed a bilateral ovarian cystadenocarcinoma associated with visceral dissemination, likely associated with nose cutaneous metastasis. We report a very uncommon case because of the presentation of ovarian carcinoma as cutaneous metastasis. To our knowledge, this atypical localization on the nose has not been described yet in the literature. PMID:28300910

  1. [Expression and significance of heparin binding-epidermal growth factor-like growth factor in paclitaxel-resistant ovarian cancer].

    PubMed

    Tang, Xiaohan; Lu, Meisong; Li, Cuiping; Deng, Suo; Li, Meng

    2014-07-01

    To examine the expression of heparin binding-epidermal growth factor-like growth factor (HB- EGF) in paclitaxel- resistant ovarian cancer and elucidate the relationship between HB-EGF and the resistance of ovarian cancer to paclitaxel. The human ovarian carcinoma cell line A2780 and the paclitaxel- resistant human ovarian carcinoma cell line A2780/Taxol were cultured in vitro. Western blot was used to dectect the expression of HB-EGF protein in A2780 and A2780/Taxol groups. The A2780 cells were treated with cross- reacting material 197 (CRM197 and A2780 + CRM197 group) or dimethyl sulphoxide (DMSO; A2780 group), while the A2780/Taxol cells were treated with CRM197 (A2780/Taxol+CRM197 group) or DMSO (A2780/Taxol group). The effects of CRM197 on growth and proliferation was tested by methyl thiazolyl tetrazolium ( MTT) and the results were showed as absorbance (A). The effects of CRM197 on cell cycles was tested by flow cytometry, while the effects of CRM197 on apoptosis was examined by caspase- 3 activity assay and the results were showed as p- nitroaniline(pNa). In animal experiment, four groups of cells were inoculated to BALB/c nude mouse subcutaneously to observe tumor formation ability following CRM197 treatment. Immunohistochemistry was used to determine the expression of HB-EGF protein in A2780 and A2780/Taxol group. The expression level of HB-EGF protein in A2780/Taxol group (2.11 ± 0.41) was significantly higher than that of A2780 group (0.75 ± 0.20; P < 0.01). The inhibition effect of CRM197 on the cell growth of A2780+CRM197 and A2780/Taxol+CRM197 group was accompanied by the acceleration of CRM197 concentration(P < 0.01). When CRM197≥1 µg/ml, the inhibition effect of CRM197 on the cell growth of A2780/Taxol+CRM197 group was significantly higher than that in A2780/Taxol group(P < 0.05). In cell cycle experiment, CRM197 induced the cell-cycle arrest at the G0/G1 phase in A2780+CRM197 cells[(67 ± 4)%] compared with A2780 cells[(54 ± 6)%; P < 0

  2. Ovarian undifferentiated carcinoma with voluminous mesenteric presentation

    PubMed Central

    Salcedo-Hernández, Rosa Angélica; Lino-Silva, Leonardo Saúl; Cantú de León, David; Pérez-Montiel, María Delia; Luna-Ortiz, Kuauhyama

    2012-01-01

    INTRODUCTION About 5% of ovarian cancers are so poorly differentiated and difficult to classify that they are called undifferentiated carcinomas and usually have disseminated disease at presentation. Extra pelvic debulking it is difficult to complete. PRESENTATION OF CASE We report a case of a rare ovarian tumor presented as a large mesenteric tumor of 14 cm diameter in a 73 years old woman. DISCUSSION Undifferentiated carcinomas are usually large, solid with hemorrhage and necrosis, bilateral and most are difficult to classify histologically. Rarely are pure, generally identified through the extensive sampling of lesions, some other components of surface epithelial carcinoma and usually the predominant element is the latter. Cases with predominantly undifferentiated component are rare. CONCLUSION The treatment and diagnostic approach is the same as for other high-grade epithelial tumors of the ovary, but in this particular case the differential diagnosis and diagnostic approach is that of a mesenteric tumor. PMID:22922357

  3. Peripartum disseminated extrapulmonary tuberculosis simulating ovarian carcinoma.

    PubMed

    Sherer, David M; Osho, Joseph A; Zinn, Harry; Demetus, Spiro; Huang, Jennifer; Temkin, Sarah; Abulafia, Ovadia

    2005-10-01

    Disseminated extrapulmonary tuberculosis is an uncommon complication of pregnancy. We present a 26-year-old multiparous immigrant from Haiti who was admitted following an extramural preterm delivery. Marked ascites was confirmed by computerized tomography, which also revealed a thickened greater omentum. These findings were considered suggestive of advanced ovarian carcinoma, although extrapulmonary tuberculosis was also considered despite negative tuberculin skin test screening. Image-guided omental biopsy demonstrated caseating granulomas substantiating the diagnosis of abdominal tuberculosis, which was later confirmed by cultures. The patient responded well to antituberculosis medications. This case describes the unusual peripartum presentation of abdominal tuberculosis simulating advanced ovarian carcinoma, and demonstrates the importance of considering extrapulmonary tuberculosis when encountering ascites and omental thickening during pregnancy despite negative tuberculin skin test screening.

  4. In vitro activity of titanocenedichloride versus cisplatin in four ovarian carcinoma cell lines evaluated by a microtiter plate ATP bioluminescence assay.

    PubMed

    Kurbacher, C M; Bruckner, H W; Andreotti, P E; Kurbacher, J A; Sass, G; Krebs, D

    1995-10-01

    Titanocenedichloride (MKT 4) is a novel anticancer drug with a broad spectrum of activity in mammalian tumors. We investigated the anticancer efficacy of MKT 4 versus cisplatin and its chemomodulation by buthionine sulfoximine (BSO) in four different human ovarian carcinoma (OvCA) cell lines derived from both primary (A2780. OTN 14) and recurrent tumors (SKOV-3 and OV-MZ-1b) using an in vitro microplate ATP bioluminescence assay (ATP-TCA). Sensitivity against cisplatin was higher in A2780 and OTN 14 compared with MKT 4, whereas the opposite was found in SKOV-3 and OV-MZ-1b cells. In A2780, SKOV-3 and OV-MZ-1b, the cytotoxicity of both agents could be effectively improved by BSO with supraadditive effects observed for MKT 4 in all three cell lines. In OTN 14, however, BSO treatment failed to increase the cytotoxicity of both cisplatin and MKT 4. These results suggest antineoplastic activity of MKT 4 in cisplatin-sensitive and mainly in cisplatin-resistant OvCA cells which can be significantly modulated by BSO-mediated glutathione depletion. Since antineoplastic activity of both cisplatin and MKT-4 observed in OTN 14 could not be reversed by BSO, other mechanisms of drug resistance different from the glutathione redox cycle are likely to be important for both metal compounds.

  5. ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas

    PubMed Central

    Wiegand, Kimberly C.; Shah, Sohrab P.; Al-Agha, Osama M.; Zhao, Yongjun; Tse, Kane; Zeng, Thomas; Senz, Janine; McConechy, Melissa K.; Anglesio, Michael S.; Kalloger, Steve E.; Yang, Winnie; Heravi-Moussavi, Alireza; Giuliany, Ryan; Chow, Christine; Fee, John; Zayed, Abdalnasser; Prentice, Leah; Melnyk, Nataliya; Turashvili, Gulisa; Delaney, Allen D.; Madore, Jason; Yip, Stephen; McPherson, Andrew W.; Ha, Gavin; Bell, Lynda; Fereday, Sian; Tam, Angela; Galletta, Laura; Tonin, Patricia N.; Provencher, Diane; Miller, Dianne; Jones, Steven J.M.; Moore, Richard A.; Morin, Gregg B.; Oloumi, Arusha; Boyd, Niki; Aparicio, Samuel A.; Shih, Ie-Ming; Mes-Masson, Anne-Marie; Bowtell, David D.; Hirst, Martin; Gilks, Blake; Marra, Marco A.; Huntsman, David G.

    2010-01-01

    BACKGROUND Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. METHODS We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. RESULTS ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. CONCLUSIONS These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.) PMID:20942669

  6. ARID1A mutations in endometriosis-associated ovarian carcinomas.

    PubMed

    Wiegand, Kimberly C; Shah, Sohrab P; Al-Agha, Osama M; Zhao, Yongjun; Tse, Kane; Zeng, Thomas; Senz, Janine; McConechy, Melissa K; Anglesio, Michael S; Kalloger, Steve E; Yang, Winnie; Heravi-Moussavi, Alireza; Giuliany, Ryan; Chow, Christine; Fee, John; Zayed, Abdalnasser; Prentice, Leah; Melnyk, Nataliya; Turashvili, Gulisa; Delaney, Allen D; Madore, Jason; Yip, Stephen; McPherson, Andrew W; Ha, Gavin; Bell, Lynda; Fereday, Sian; Tam, Angela; Galletta, Laura; Tonin, Patricia N; Provencher, Diane; Miller, Dianne; Jones, Steven J M; Moore, Richard A; Morin, Gregg B; Oloumi, Arusha; Boyd, Niki; Aparicio, Samuel A; Shih, Ie-Ming; Mes-Masson, Anne-Marie; Bowtell, David D; Hirst, Martin; Gilks, Blake; Marra, Marco A; Huntsman, David G

    2010-10-14

    Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).

  7. Characteristic odour in the blood reveals ovarian carcinoma

    PubMed Central

    2010-01-01

    Background Ovarian carcinoma represents about 4% of all cancers diagnosed in women worldwide. Mortality rate is high, over 50%, mainly due to late diagnosis. Currently there are no acceptable screening techniques available, although ovarian cancer belongs to the group of malignancies for which mortality could be dramatically reduced by early diagnosis. In a recently published study, we clearly demonstrated that human ovarian carcinoma tissues can be characterized by a specific odour, detectable by a trained dog. Another recent study confirmed these results using an electronic nose. Methods In the present work, we examined whether the cancer-specific odour can also be found in the blood. Two specially trained dogs were used. Both ovarian cancer tissues and blood from patients with ovarian carcinoma were tested. Results The tissue tests showed sensitivity of 100% and specificity of 95%, while the blood tests showed sensitivity of 100% and specificity of 98%. Conclusions The present study strongly suggests that the characteristic odour emitted by ovarian cancer samples is also present in blood (plasma) taken from patients with the disease. This finding opens possibilities for future screening of healthy populations for early diagnosis of ovarian carcinoma. A future challenge is to develop a sensitive electronic nose for screening of ovarian carcinoma by testing the blood/plasma to detect the disease at a stage early enough for treatment to be effective. PMID:21106067

  8. Clinically-inspired automatic classification of ovarian carcinoma subtypes

    PubMed Central

    BenTaieb, Aïcha; Nosrati, Masoud S; Li-Chang, Hector; Huntsman, David; Hamarneh, Ghassan

    2016-01-01

    Context: It has been shown that ovarian carcinoma subtypes are distinct pathologic entities with differing prognostic and therapeutic implications. Histotyping by pathologists has good reproducibility, but occasional cases are challenging and require immunohistochemistry and subspecialty consultation. Motivated by the need for more accurate and reproducible diagnoses and to facilitate pathologists’ workflow, we propose an automatic framework for ovarian carcinoma classification. Materials and Methods: Our method is inspired by pathologists’ workflow. We analyse imaged tissues at two magnification levels and extract clinically-inspired color, texture, and segmentation-based shape descriptors using image-processing methods. We propose a carefully designed machine learning technique composed of four modules: A dissimilarity matrix, dimensionality reduction, feature selection and a support vector machine classifier to separate the five ovarian carcinoma subtypes using the extracted features. Results: This paper presents the details of our implementation and its validation on a clinically derived dataset of eighty high-resolution histopathology images. The proposed system achieved a multiclass classification accuracy of 95.0% when classifying unseen tissues. Assessment of the classifier's confusion (confusion matrix) between the five different ovarian carcinoma subtypes agrees with clinician's confusion and reflects the difficulty in diagnosing endometrioid and serous carcinomas. Conclusions: Our results from this first study highlight the difficulty of ovarian carcinoma diagnosis which originate from the intrinsic class-imbalance observed among subtypes and suggest that the automatic analysis of ovarian carcinoma subtypes could be valuable to clinician's diagnostic procedure by providing a second opinion. PMID:27563487

  9. Epidemiology in ovarian carcinoma: Lessons from autopsy.

    PubMed

    Güth, Uwe; Arndt, Volker; Stadlmann, Sylvia; Huang, Dorothy Jane; Singer, Gad

    2015-08-01

    We challenge epidemiologic knowledge regarding ovarian carcinoma (OC) by bridging the gap between clinical and autopsy data. Autopsy reports, histological slides and clinical files from 660 patients in whom OC was diagnosed from 1975-2005 were studied (autopsy cohort, n=233; Clinical Cancer Registry from the local gyneco-oncologic center, n=427). Out of the autopsy cohort, we identified four distinct subgroups of patients: 1) OC was diagnosed before autopsy, n=156 (67.0%). 2) OC was an incidental finding, n=16 (6.8%). 3) The ovarian tumors were not primary OC but rather metastases from other primary tumors; this revised diagnosis was first made by using current histopathological knowledge/techniques, n=24 (10.3%). 4) Death was directly due to OC in its final stage and OC was first diagnosed by autopsy, n=37 (15.9%); when these cases were added to the Clinical Cancer Registry to an adjusted OC incidence model, the autopsy cases comprised 8.8% of the adjusted cohort and almost doubled the percentage of oldest patients (≥80 years at diagnosis) from 4.9% to 9.3% (p=0.013). Epidemiological data from the 1970s-1990s may overestimate true incidence because up to 10% of carcinomas in the ovary were not properly classified. Patients who were first diagnosed with OC by autopsy comprise a distinct subgroup. These are patients who have not been seen by specialized oncologists and thus play no role in their perception of the disease. Nevertheless, these cases have impact on prevalence and incidence data of OC and in an era of reduced autopsy rates will probably be overlooked. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Single pre-treatment with hypericin, a St. John's wort secondary metabolite, attenuates cisplatin- and mitoxantrone-induced cell death in A2780, A2780cis and HL-60 cells.

    PubMed

    Jendželovská, Zuzana; Jendželovský, Rastislav; Hiľovská, Lucia; Kovaľ, Ján; Mikeš, Jaromír; Fedoročko, Peter

    2014-10-01

    St. John's wort (SJW, Hypericum perforatum L.) is a commonly used natural antidepressant responsible for the altered toxicity of some anticancer agents. These interactions have been primarily attributed to the hyperforin-mediated induction of some pharmacokinetic mechanisms. However, as previously demonstrated by our group, hypericin induces the expression of two ABC transporters: multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). Because cisplatin (CDDP) and mitoxantrone (MTX) are potential substrates of ABC transporters, we investigated the effect of 24h hypericin pre-treatment on the cytotoxicity of CDDP and MTX in human cancer cell lines. CDDP-sensitive and -resistant ovarian adenocarcinoma cell lines A2780/A2780cis, together with HL-60 promyelocytic leukemia cells and ABCG2-over-expressing cBCRP subclone, were used in our experiments. We present CDDP cytotoxicity attenuated by hypericin pre-treatment in both A2780 and A2780cis cells and MTX cytotoxicity in HL-60 cells. In contrast, hypericin potentiated MTX-induced death in cBCRP cells. Interestingly, hypericin did not restore cell proliferation in rescued cells. Nevertheless, hypericin did increase the expression of MRP1 transporter in A2780 and A2780cis cells indicating the impact of hypericin on certain resistance mechanisms. Additionally, our results indicate that hypericin may be the potential substrate of BCRP transporter. In conclusion, for the first time, we report the ability of hypericin to affect the onset and/or progress of CDDP- and MTX-induced cell death, despite strong cell cycle arrest. Thus, hypericin represents another SJW metabolite that might be able to affect the effectiveness of anti-cancer drugs and that could interact with ABC transporters, particularly with BCRP. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy

    PubMed Central

    Sui, Hongying; Shi, Caixia; Yan, Zhipeng; Li, Hucheng

    2015-01-01

    Background Ovarian cancer is the leading cause of death in women with gynecological malignancy worldwide. Despite multiple new approaches to treatment, relapse remains almost inevitable in patients with advanced disease. The poor outcome of advanced ovarian cancer treated with conventional therapy stimulated the search for new strategies to improve therapeutic efficacy. Although epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) inhibitors have known activity in advanced ovarian cancer, the effect of combined therapy against EGFR and PARP in this population has not been reported. In the current study, we investigated the mechanisms of erlotinib used alone or in combination with olaparib (AZD2281), a potent inhibitor of PARP, in an EGFR-overexpressing ovarian tumor xenograft model. Methods A2780 (EGFR-overexpressing, BRCA1/2 wild-type) cells were subcutaneously injected into nude mice, which were then randomly assigned to treatment with vehicle, erlotinib, AZD2281, or erlotinib + AZD2281, for up to 3 weeks. All mice were then sacrificed and tumor tissues were subjected to Western blot analysis and monodansylcadervarine staining (for analysis of autophagy). Results Erlotinib could slightly inhibit growth of A2780 tumor xenografts, and AZD2281 alone had similar effects on tumor growth. However, the combination treatment had a markedly enhanced antitumor effect. Western blot analysis revealed that treatment with erlotinib could significantly reduce the phosphorylation level of ERK1/2 and AKT in A2780 tumor tissue. Of interest, monodansylcadervarine staining showed that the autophagic effects were substantially enhanced when the agents were combined, which may be due to downregulation of apoptosis. Conclusion These results suggest that combination of a selective EGFR inhibitor and a PARP inhibitor is effective in ovarian cancer A2780 xenografts, and depends on enhanced autophagy. PMID:26124641

  12. Telomerase Activity in Human Ovarian Carcinoma

    NASA Astrophysics Data System (ADS)

    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.

  13. Screening of the residual normal ovarian tissue adjacent to orthotopic epithelial ovarian carcinomas in nude mice.

    PubMed

    Zhu, G H; Wang, S T; Yao, M Z; Cai, J H; Chen, C Y; Yang, Z X; Hong, L; Yang, S Y

    2014-04-16

    The objective of this study was to explore the feasibility and methods of screening the residual normal ovarian tissue adjacent to orthotopic ovarian carcinomas in nude mice. Human epithelial ovarian cancer cells (OVCAR3) were subcutaneously implanted for a tumor source and ovarian orthotopic transplantation. The cancer tissue, proximal paraneoplastic tissue, middle paraneoplastic tissue, remote paraneoplastic tissue, and normal ovarian tissue were removed. CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was detected by reverse transcription polymerase chain reaction. We obtained 35 paraneoplastic residual ovarian tissues with normal biopsies from 40 cases of an orthotopic epithelial ovarian carcinoma model (87.5%). CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was lower in proximal paraneoplastic tissue than in cancer tissue (P < 0.05) and higher than in middle and remote paraneoplastic tissue (P < 0.01). There was no statistically significant difference between the expression of these genes in middle and proximal paraneoplastic tissue as well as among residual normal ovarian tissues with different severity (P > 0.05). In ovarian tissues of 20 normal nude mice, the expression of CK- 7, CA125, p53, survivin, MMP-2, and TIMP-2 was negative. Overall, the expression levels of CK-7, CA125, p53, survivin, MMP-2, TIMP-2, and other molecular markers showed a decreasing trend in the non-cancer tissue direction. The expression levels can be used as standards to screen residual normal ovarian tissue. We can obtain relatively safe normal ovarian tissues adjacent to epithelial ovarian cancer.

  14. Pure Primary Ovarian Squamous Cell Carcinoma Perforating the Rectum

    PubMed Central

    Okada, Aiko; Haraguchi, Naotsugu; Tomimatsu, Takuji; Kimura, Tadashi

    2017-01-01

    Rectal perforation is uncommon in ovarian cancer, even in advanced stages. Pure primary ovarian squamous cell carcinoma is a very rare subtype of ovarian cancer and has not been reported to cause rectal perforation. A 50-year-old woman presented with rectal bleeding. Rectosigmoidoscopy suggested perforation of a pelvic tumor into the rectum. Abdominopelvic magnetic resonance imaging revealed a 9 cm heterogeneous mass in the pouch of Douglas. We performed complete cytoreduction, including an en-bloc resection of the tumor and rectosigmoid colon. Histopathology showed squamous cell carcinoma of the left ovary penetrating the rectal wall. A common symptom of rectal bleeding was caused by a very rare entity of ovarian cancer penetrating the rectal wall, but thorough evaluation led to its accurate diagnosis and appropriate treatment. PMID:28316851

  15. Expression and Function of CD44 in Epithelial Ovarian Carcinoma

    PubMed Central

    Sacks, Joelle D.; Barbolina, Maria V.

    2015-01-01

    CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed. PMID:26569327

  16. Expression and Function of CD44 in Epithelial Ovarian Carcinoma.

    PubMed

    Sacks, Joelle D; Barbolina, Maria V

    2015-11-11

    CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed.

  17. BRCA1 mutations in primary breast and ovarian carcinomas

    SciTech Connect

    Futreal, P.A.; Cochran, C.; Bennett, L.M.; Haugen-Strano, A.; Terry, L.; Barrett, J.C.; Wiseman, R.; Liu, Q.; Shattuck-Eidens, D.; Harshman, K.

    1994-10-07

    Loss of heterozygosity data from familial tumors suggested that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.

  18. Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro

    SciTech Connect

    Xu, Yang; Pang, Xiaoyan; Dong, Mei; Wen, Fang Zhang, Yi

    2013-11-01

    Highlights: •Nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest. •Nesfatin-1 enhances HO-8910 cell apoptosis. •Nesfatin-1 inhibits HO-8910 cell proliferation via mTOR and RhoA/ROCK signaling pathway. •The first report of nesfatin-1-mediated proliferation in ovarian epithelial carcinoma. -- Abstract: Nesfatin-1, an 82-amino-acid peptide derived from a 396-amino-acid precursor protein nucleobindin 2 (NUCB2), was originally identified in hypothalamic nuclei involved in the regulation of food intake. It was recently reported that nesfatin-1 is a novel depot specific adipokine preferentially produced by subcutaneous tissue, with obesity- and food deprivation-regulated expression. Although a relation between ovarian cancer mortality and obesity has been previously established, a role of nesfatin-1 in ovarian epithelial carcinoma remains unknown. The aim of the present study is to examine the effect of nesfatin-1 on ovary carcinoma cells proliferation. We found that nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, this inhibition could be abolished by nesfatin-1 neutralizing antibody. Nesfatin-1 enhances HO-8910 cell apoptosis, activation of mammalian target of rapamycin (mTOR) and RhoA/ROCK signaling pathway block the effects of nesfatin-1-induced apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation by nesfatin-1. In conclusion, the present study demonstrated that nesfatin-1 can inhibit the proliferation in human ovarian epithelial carcinoma cell line HO-8910 cells through inducing apoptosis via mTOR and RhoA/ROCK signaling pathway. This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients.

  19. Tubal ligation and the risk of ovarian carcinoma.

    PubMed

    Cornelison, T L; Natarajan, N; Piver, M S; Mettlin, C J

    1997-01-01

    To assess the relationship of tubal ligation and risk of ovarian carcinoma, we conducted a case-control, retrospective analysis of 300 ovarian carcinoma cases and 606 nonmalignant disease controls, seen between 1982 and 1988 at Roswell Park Cancer Institute, Buffalo, New York. Women who had a tubal ligation had reduced risk for the development of ovarian cancer. This relative risk was 0.52, with a 95% confidence interval 0.31 to 0.85 (p = 0.0076). Controls were matched by age. Multivariate analysis adjusted for socioeconomic level, marital status, parity, age at first pregnancy, menarche age, menopause age, irregular menses, breast-feeding duration, body habitus, and oral contraceptive use. Suggested explanations for this observation are offered.

  20. Inherited Mutations in Women with Ovarian Carcinoma

    PubMed Central

    Norquist, Barbara M.; Harrell, Maria I.; Brady, Mark F.; Walsh, Tom; Lee, Ming K.; Gulsuner, Suleyman; Bernards, Sarah S.; Casadei, Silvia; Yi, Qian; Burger, Robert A.; Chan, John K.; Davidson, Susan A.; Mannel, Robert S.; DiSilvestro, Paul A.; Lankes, Heather A.; Ramirez, Nilsa C.; King, Mary Claire; Swisher, Elizabeth M.; Birrer, Michael J.

    2016-01-01

    Importance Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized. Objective To determine the frequency and importance of germline mutations in cancer-associated genes in OC. Design Subjects were ascertained from two phase III clinical trials in newly diagnosed advanced stage OC (GOG 218 and GOG 262), and a university-based gynecologic oncology tissue bank. Germline DNA was sequenced from women with OC using the targeted capture and multiplex sequencing assay BROCA. Setting Referral centers participating in NRG Oncology studies, and a University-based gynecologic oncology practice (UW). Participants The study population was 1915 women with OC with available germline DNA, unselected for age or family history, enrolled at the time of OC diagnosis (GOG 218, N=788; GOG 262, N=557; UW, N=570). Main Outcomes and Measures Mutation frequencies in OC were compared to the NHLBI GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status. Results Of 1915 subjects, 280 (15%) had mutations in BRCA1 (182), or BRCA2 (98) and 8 (0.4%) had mutations in DNA mismatch repair (MMR) genes. Mutations in BRIP1 (26), RAD51C (11), RAD51D (11), PALB2 (12) and BARD1 (4), were significantly more common in OC patients than in the ESP or ExAC, and in total were present in 3.3% of patients. Race, histologic subtype, and disease site were not predictive of mutation frequency. Mutation status affected survival, in particular for BRCA2 mutation carriers with HR 0.60 (95% CI 0.45 – 0.79, p<0.001) for progression-free survival, and HR 0.39 (95% CI 0.25 – 0.60, p<0.001) for overall survival in the GOG patients. Conclusions and Relevance In total, 347/1915 (18%) OC patients carried

  1. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

    PubMed Central

    Horiuchi, Akiko; Wang, Cuiju; Kikuchi, Norihiko; Osada, Ryosuke; Nikaido, Toshio; Konishi, Ikuo

    2006-01-01

    BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no significant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma. PMID:19690636

  2. Pegylated Liposomal Doxorubicin Hydrochloride, Carboplatin, Veliparib, and Bevacizumab in Treating Patients With Recurrent Ovarian Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-01-31

    Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  3. Genetic analysis of a morphologically heterogeneous ovarian endometrioid carcinoma.

    PubMed

    Geyer, Felipe C; Pareja, Fresia; Burke, Kathleen A; Schultheis, Anne M; Hussein, Yaser R; Ye, Jiqing; De Filippo, Maria R; Marchio, Caterina; Macedo, Gabriel S; Piscuoglio, Salvatore; Lim, Raymond S; Toy, Eugene; Murali, Rajmohan; Jungbluth, Achim A; Reis-Filho, Jorge S; Soslow, Robert A; Weigelt, Britta

    2017-09-01

    Low-grade ovarian endometrioid carcinomas may be associated with high-grade components. Whether the latter are clonally related to and originate from the low-grade endometrioid carcinoma remains unclear. The aim of this study was to use massively parallel sequencing to characterize the genomic landscape and clonal relatedness of an ovarian endometrioid carcinoma containing low-grade and high-grade components. DNA samples extracted from each tumour component (low-grade endometrioid, high-grade anaplastic and high-grade squamous) and matched normal tissue were subjected to targeted massively parallel sequencing with the 410-gene Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing assay. Somatic single nucleotide variants, small insertions and deletions, and copy number alterations were detected with state-of-the-art bioinformatics algorithms, and validated with orthogonal methods. The endometrioid carcinoma and the associated high-grade components shared copy number alterations and four clonal mutations, including SMARCA4 mutations, which resulted in loss of BRG1 protein expression. Subclonal mutations and mutations restricted to single components were also identified, such as distinct TP53 mutations restricted to each histological component. Histologically distinct components of ovarian endometrioid carcinomas may show intratumour genetic heterogeneity but be clonally related, harbouring a complex clonal composition. In the present case, SMARCA4 mutations were probably early events, whereas TP53 somatic mutations were acquired later in evolution. © 2017 John Wiley & Sons Ltd.

  4. MV-NIS Infected Mesenchymal Stem Cells in Treating Patients With Recurrent Ovarian Cancer

    ClinicalTrials.gov

    2017-03-14

    Malignant Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  5. Erlotinib Plus Carboplatin and Paclitaxel in Ovarian Carcinoma

    ClinicalTrials.gov

    2015-10-29

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  6. Converging Evidence for Efficacy from Parallel EphB4 Targeted Approaches in Ovarian Carcinoma

    PubMed Central

    Spannuth, Whitney A.; Mangala, Lingegowda S.; Stone, Rebecca L.; Carroll, Amy R.; Nishimura, Masato; Shahzad, Mian M.K.; Lee, Sun-Joo; Moreno-Smith, Myrthala; Nick, Alpa M.; Liu, Ren; Jennings, Nicholas B.; Lin, Yvonne G.; Merritt, William M.; Coleman, Robert L.; Vivas-Mejia, Pablo E.; Zhou, Yue; Krasnoperov, V.; Lopez-Berestein, Gabriel; Gill, Parkash S.; Sood, Anil K.

    2010-01-01

    EphB4 is a transmembrane receptor tyrosine kinase that plays an important role in neural plasticity and angiogenesis. EphB4 is overexpressed in ovarian cancer and is predictive of poor clinical outcome. However, the biological significance of EphB4 in ovarian cancer is not known and is the focus of the current study. Here, we examined the biological effects of two different methods of EphB4 targeting (a novel monoclonal antibody, EphB4-131 or siRNA) using several ovarian cancer models. EphB4 gene silencing significantly increased tumor cell apoptosis, and decreased migration (p<0.001) and invasion (p<0.001). Compared to controls, EphB4 siRNA-DOPC alone significantly reduced tumor growth in the A2780-cp20 (48%, p<0.05) and IGROV-af1 (61%, p<0.05) models. Combination therapy with EphB4 siRNA-DOPC and docetaxel resulted in the greatest reduction in tumor weight in both A2780-cp20 and IGROV-af1 models (89-95% reduction versus controls; p<0.05 for both groups). The EphB4-131 antibody, which reduced EphB4 protein level, decreased tumor growth by 80-83% (p<0.01 for both models) in the A2780-cp20 and IGROV-af1 models. Combination of EphB4-131 and docetaxel resulted in the greatest tumor reduction in both A2780-cp20 and IGROV-af1 models (94-98% reduction versus controls; p<0.05 for both groups). Compared to controls, EphB4 targeting resulted in reduced tumor angiogenesis (p<0.001), proliferation (p<0.001), and increased tumor cell apoptosis (p<0.001), which likely occurs through modulation of PI3K signaling. Collectively, these data identify EphB4 as a valuable therapeutic target in ovarian cancer and offer two new strategies for further development. PMID:20682653

  7. Overcoming Platinum Resistance in Ovarian Carcinoma

    PubMed Central

    Matsuo, Koji; Lin, Yvonne G.; Roman, Lynda D.; Sood, Anil K.

    2010-01-01

    Importance of the field Ovarian cancer remains a deadly malignancy because most patients develop recurrent disease that is resistant to chemotherapy, including platinum. Because response rates for current treatment regimens are relatively similar and unfortunately low, no standard chemotherapy for platinum-resistant ovarian cancer exists. Areas covered in this review A systematic literature review of clinical studies published between January 2005 and March 2010 was conducted using search engines, PubMed and MEDLINE with the entry keywords, ovarian cancer and platinum resistance. This search revealed 40 clinical trials (1793 patients). What the reader will gain Gemcitabine was the most common drug used in clinical trials reporting higher response rates, ≥+1 SD of overall response rate (5 out of 8). Gemcitabine-based combination therapy showed an average response rate of 27.2% (95%CI 22.4–32.0). Combination of gemcitabine and pegylated liposomal doxorubicin (PLD) was the most common regimen (n=3) and was associated with possible additive effects in platinum-resistant ovarian cancer patients: response rate, gemcitabine alone 6.1%, PLD alone 19.8%, and gemcitabine with PLD 28.7% (95%CI 20.4–37.0), respectively. Take home message Analysis of recent clinical trials showed that gemcitabine-based combination chemotherapy was associated with the highest anti-tumor effects in platinum-resistant ovarian cancer patients during the study period. PMID:20815774

  8. [Ovarian carcinoma antigen (CA 125) and ovarian cancer (clinical follow-up and prognostic studies)].

    PubMed

    Göcze, P; Vahrson, H

    1993-04-25

    Serum concentrations of ovarian carcinoma antigen (CA 125) were determined by Abbot CA 125-EIA Monoclonal kit from 66 patients with malignant ovarian tumor. The preoperative serum levels of CA 125 were elevated (> 35.0 IU/ml) in 93% (27/29). After the laparotomy and before the irradiation or chemotherapy in 36% (24/36) of patients had elevated levels. No significant correlation was seen between elevated levels and histology, tumor grade and clinical stage. However, the rate of positive cases were significantly higher in advanced stages than in the 1st stage (p < 0.05). No significant correlation was found between the preoperative levels of CA 125 and the clinical course. The postoperative elevated levels indicated bad prognosis. Good conformity was found between CA 125 levels and the therapy response. Serological follow up revealed a correlation with the clinical course of ovarian carcinoma in 84% (44/52). In patients with tumor progression the CA 125 levels increased before clinical signs of progression with median lead time of 97 days. The second look laparotomy proved, that residual tumor larger than 2 cm of diameter cause elevated levels. Smaller tumors remained marker negatives. CA 125 determination before operation, during and after therapy provide a useful tool in detecting progression and persistence of ovarian carcinoma.

  9. Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-01-31

    Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  10. Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

    PubMed Central

    Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

    2011-01-01

    Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

  11. Genome-wide significant risk associations for mucinous ovarian carcinoma

    PubMed Central

    Kelemen, Linda E.; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; M. Lee, Janet; Seo, Ji-Heui; Phelan, Catherine M.; Beesley, Jonathan; Chen, Xiaoqin; Spindler, Tassja J.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chen, Y. Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Engelholm, Svend Aage; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wlodzimierz, Sawicki; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Freedman, Matthew L.; Chenevix-Trench, Georgia; Pharoah, Paul D.; Gayther, Simon A.; Berchuck, Andrew

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  12. Integrated Genomic Analyses of Ovarian Carcinoma

    PubMed Central

    2011-01-01

    Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology. PMID:21720365

  13. Endonucleases induced TRAIL-insensitive apoptosis in ovarian carcinoma cells

    SciTech Connect

    Geel, Tessa M.; Meiss, Gregor; Gun, Bernardina T. van der; Kroesen, Bart Jan; Leij, Lou F. de; Zaremba, Mindaugas; Silanskas, Arunas; Kokkinidis, Michael; Ruiters, Marcel H.; McLaughlin, Pamela M.; Rots, Marianne G.

    2009-09-10

    TRAIL induced apoptosis of tumor cells is currently entering phase II clinical settings, despite the fact that not all tumor types are sensitive to TRAIL. TRAIL resistance in ovarian carcinomas can be caused by a blockade upstream of the caspase 3 signaling cascade. We explored the ability of restriction endonucleases to directly digest DNA in vivo, thereby circumventing the caspase cascade. For this purpose, we delivered enzymatically active endonucleases via the cationic amphiphilic lipid SAINT-18{sup Registered-Sign }:DOPE to both TRAIL-sensitive and insensitive ovarian carcinoma cells (OVCAR and SKOV-3, respectively). Functional nuclear localization after delivery of various endonucleases (BfiI, PvuII and NucA) was indicated by confocal microscopy and genomic cleavage analysis. For PvuII, analysis of mitochondrial damage demonstrated extensive apoptosis both in SKOV-3 and OVCAR. This study clearly demonstrates that cellular delivery of restriction endonucleases holds promise to serve as a novel therapeutic tool for the treatment of resistant ovarian carcinomas.

  14. The Clinical Relevance of Beta Blockers in Ovarian Carcinoma

    PubMed Central

    Hefner, J.; Csef, H.

    2016-01-01

    The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma. There is a great need for new treatment strategies, and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response. This systematic review summarizes the current state of knowledge and research on the topic: A database analysis identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course. The 13 preclinical studies identified showed almost without exception both that catecholamines had detrimental effects on tumour progression, and that these effects could be influenced by pharmacological blockade. Overall the available evidence does not justify the use of beta blockers in clinical practice for ovarian carcinoma at the present time. This article also outlines details of research design required for further studies needed on the subject. Preclinical research findings are however very impressive: They not only form an important basis for the development of future clinical studies but also, through revealing new pathomechanisms, they already make an important contribution towards the development of new treatment strategies for ovarian carcinoma. PMID:27761025

  15. Ezrin Is Associated with Disease Progression in Ovarian Carcinoma

    PubMed Central

    Horwitz, Vered; Davidson, Ben; Stern, Dganit; Tropé, Claes G.; Tavor Re’em, Tali; Reich, Reuven

    2016-01-01

    Objective Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). Methods OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively. shRNA was used to reduce protein expression in the cells. The malignant potential was evaluated by chemo-invasion assay, branching capacity on Matrigel and rate of proliferation. Subsequently, clinical specimens of high-grade serous carcinoma effusions, ovarian tumors and solid metastases were analyzed for ezrin and p130Cas expression. Results Higher ezrin expression was found in cells composing the spheroids compared to their counterparts cultured on alginate scaffold and in clinical samples of malignant effusions compared to solid tumors. In addition, reduced Ezrin expression impaired the invasion ability and the branching capacity of OC cells to a greater extent than reduced p130Cas expression. However, ezrin and p130Cas expression in effusions was unrelated to clinical outcome. Conclusions The 3-dimensional cell cultures were found to mimic the different tumor sites and be applicable as a model. The in vitro results concur with the clinical specimen analysis, suggesting that in OC, the role of ezrin in disease progression is more pronounced than that of p130Cas. PMID:27622508

  16. TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88-positive human ovarian carcinoma in vitro

    PubMed Central

    WANG, AN-CONG; MA, YUE-BING; WU, FENG-XIA; MA, ZHI-FANG; LIU, NAI-FU; GAO, RONG; GAO, YONG-SHENG; SHENG, XIU-GUI

    2014-01-01

    In ovarian cancer patients, chemotherapy resistance is the principal factor restricting long-term treatment. Paclitaxel (Pac) has been previously reported to be a ligand to Toll-like receptor 4 (TLR4). It was determined that TLR4 signaling is divided into the following two pathways: Myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent. The present study investigated the effect of TLR4 ligation by Pac in MyD88-positive (MyD88+) and MyD88-negative (MyD88−) human ovarian cancer cell lines. An RNA interference expression vector was specifically constructed to target TLR4 mRNA, which was stably transfected into the human ovarian cancer cell lines (SKOV3, OVCAR3, A2780 and 3AO). Cytokines, including interleukin (IL)-6 and IL-8, were detected. Cell proliferation and apoptosis were assessed in the cells transfected with scramble control and TLR4 shRNA to explore the possible functions of TLR4 in ovarian cancer cell growth. It was found that lipopolysaccharide and Pac significantly increase the secretion of IL-6 and IL-8 in the SKOV3 cell line. Similarly, Pac resulted in a significant upregulation of IL-6 and IL-8 in OVCAR3 cells, but not in A2780 and 3AO cells. These results suggested that in MyD88+ ovarian cancer cell lines, TLR4 depletion shows increased sensitivity to Pac treatment in inhibiting cell proliferation compared with in cells without TLR4 knockdown. On the contrary, such changes were not found in MyD88− cells (A2780 and 3AO). TLR4 negatively regulates Pac chemotherapy, particularly in terms of cell proliferation, and TLR4 may be a novel treatment target in Pac-resistant ovarian cancer. PMID:24527095

  17. NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols.

    PubMed

    Bratasz, Anna; Selvendiran, Karuppaiyah; Wasowicz, Tomasz; Bobko, Andrey; Khramtsov, Valery V; Ignarro, Louis J; Kuppusamy, Periannan

    2008-02-26

    Ovarian carcinoma is the leading cause of mortality among gynecological cancers in the world. The high mortality rate is associated with lack of early diagnosis and development of drug resistance. The antitumor efficacy and mechanism of NCX-4040, a nitric oxide-releasing aspirin derivative, against ovarian cancer is studied. NCX-4040, alone or in combination with cisplatin (cis-diamminedichloroplatinum, cDDP), was studied in cisplatin-sensitive (A2780 WT) and cisplatin-resistant (A2780 cDDP) cell lines as well as xenograft tumors grown in nude mice. Electron paramagnetic resonance (EPR) was used for measurements of nitric oxide and redox state. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice was used for mechanistic studies. Cells treated with NCX-4040 (25 microM) showed a significant reduction of cell viability (A2780 WT, 34.9 +/- 8.7%; A2780 cDDP, 41.7 +/- 7.6%; p < 0.05). Further, NCX-4040 significantly enhanced the sensitivity of A2780 cDDP cells (cisplatin alone, 80.6 +/- 11.8% versus NCX-4040+cisplatin, 26.4 +/- 7.6%; p < 0.01) and xenograft tumors (cisplatin alone, 74.0 +/- 4.4% versus NCX-4040+cisplatin, 56.4 +/- 7.8%; p < 0.05), to cisplatin treatment. EPR imaging of tissue redox and thiol measurements showed a 5.5-fold reduction (p < 0.01) of glutathione in NCX-4040-treated A2780 cDDP tumors when compared to untreated controls. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice treated with NCX-4040 and cisplatin revealed significant downregulation of pEGFR (Tyr845 and Tyr992) and pSTAT3 (Tyr705 and Ser727) expression. The results suggested that NCX-4040 could resensitize drug-resistant ovarian cancer cells to cisplatin possibly by depletion of cellular thiols. Thus NCX-4040 appears to be a potential therapeutic agent for the treatment of human ovarian carcinoma and cisplatin-resistant malignancies.

  18. CT diagnosis of intrasplenic metastasis from ovarian carcinoma.

    PubMed

    Senturk, Senem; Karcaaltıncaba, Musturay; Akata, Deniz

    2012-06-01

    Intrasplenic metastases from ovarian carcinoma cannot be always demonstrated intraoperatively. CT is the most important imaging modality of choice for staging and follow-up ovarian cancer; in this study we searched CT appearances of intrasplenic metastases from ovarian carcinoma. We retrospectively reviewed imaging histories of the patients with ovarian cancer from the radiology information system, and found 12 patients with intrasplenic metastasis. All patients underwent abdominal CT with 16-MDCT. We searched number, density and maximum diameters of splenic metastasis. The growing rate of three lesions, which were followed up by CT, was calculated. Serum cancer antigen (CA) 125 levels were noted. We also evaluated clinical history and pathology reports of all patients. Splenic metastases, solitary or multiple, were detected most frequently during the follow-up (1-14 years after initial diagnosis) and most were associated with other sites of recurrence. The diameters of lesions ranged from 4 to 85mm. All lesions appeared hypodense except for one lesion with dense calcification. Densities of lesions ranged from 12 to 208 Hounsfield units (mean, 49±51HU). Most lesions appeared as solid well-defined nodules; however some lesions had lobulated and irregular contours with an infiltrative pattern. The growing rates of three lesions were 0.72mm/month, 1.75mm/month and 2.70mm/month. Eight patients had elevated serum CA 125 levels (40-1256U/mL). We concluded that CT can demonstrate intraparenchymal and infiltrative splenic metastasis in patients with ovarian cancer even in the absence of increased CA 125 levels. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Aberrant DNA Damage Response Pathways May Predict the Outcome of Platinum Chemotherapy in Ovarian Cancer

    PubMed Central

    Stefanou, Dimitra T.; Bamias, Aristotelis; Episkopou, Hara; Kyrtopoulos, Soterios A.; Likka, Maria; Kalampokas, Theodore; Photiou, Stylianos; Gavalas, Nikos; Sfikakis, Petros P.; Dimopoulos, Meletios A.; Souliotis, Vassilis L.

    2015-01-01

    Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that

  20. Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer.

    PubMed

    Stefanou, Dimitra T; Bamias, Aristotelis; Episkopou, Hara; Kyrtopoulos, Soterios A; Likka, Maria; Kalampokas, Theodore; Photiou, Stylianos; Gavalas, Nikos; Sfikakis, Petros P; Dimopoulos, Meletios A; Souliotis, Vassilis L

    2015-01-01

    Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that

  1. Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Stage III Ovarian Cancer

    ClinicalTrials.gov

    2016-03-17

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  2. The inherent cellular radiosensitivity of epithelial ovarian carcinoma

    SciTech Connect

    Rotmensch, J.; Schwartz, J.L.; Atcher, R.W.; Grdina, D.J.; Toohill, M.; Weichselbaum, R.W. )

    1989-12-01

    Ovarian carcinomas of similar histology have variable responses to radiation therapy. It has been suggested that inherent cellular resistance to radiation may in part underlie radiotherapy failure. To determine in vitro radiobiological parameters of papillary serous adenocarcinoma of the ovary, we investigated the cellular responses of 16 early-passage ovarian carcinoma cell lines to radiation. The radiosensitivity, as measured by D0, ranged from 1.05 to 2.40 Gy (mean 1.70 Gy), and, as measured by D, ranged from 1.65 to 3.54 Gy (mean 2.38 Gy). The extrapolation number -n ranged from 1.1 to 2.0 (mean 1.5). The cells had a 1.3- to 5.4-fold (mean 2.8) ability to recover from potential lethal damage (PLDR) 24 hr after irradiation and subculture from plateau-phase cultures. Their inherent radioresistance may be one factor in the failure of some ovarian cancers to be sterilized by radiation.

  3. Genome-wide significant risk associations for mucinous ovarian carcinoma.

    PubMed

    Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; Lee, Janet M; Seo, Ji-Heui; Phelan, Catherine M; Beesley, Jonathan; Chen, Xiaoqing; Spindler, Tassja J; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia

    2015-08-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

  4. Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma

    DTIC Science & Technology

    2013-07-01

    Precursor Lesions of Ovarian Serous Carcinoma PRINCIPAL INVESTIGATOR: Robert Kurman, M.D...5a. CONTRACT NUMBER Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma 5b. GRANT NUMBER W81XWH-09-1-0249...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS prevention, p53 mutations, high grade serous

  5. Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma

    DTIC Science & Technology

    2012-07-01

    was discussed. Dr. Soslow asked how to evaluate endometrial serous cancers if there is a lesion in the tubes and if peritoneal carcinoma was...received by all participants as well as from DoD OCRP staff. 15. SUBJECT TERMS prevention, p53 mutations, high grade serous ovarian cancer and STIC...ovarian cancer by characterizing the early lesions involved in the development of high-grade ovarian serous carcinoma, and 2) to provide biomarkers

  6. [Reverse of the resistance to paclitaxel of the heparin binding-epidermal growth factor-like growth factor inhibitor in ovarian cancer].

    PubMed

    Tang, X H; Lu, M S; Deng, S; Li, M

    2017-02-25

    Objective: To investigate the effect and mechanism of CRM197, the heparin binding-epidermal growth factor-like growth factor (HB-EGF) inhibitor, on the reverse of the resistance of ovarian cancer to paclitaxel. Methods: (1)The effect of CRM197 on the 50% inhibitory concentrations (IC(50)) of human ovarian carcinoma cell line A2780 and paclitaxel-resistant ovarian carcinoma cell line A2780/Taxol was tested by methyl thiazolyl tetrazolium (MTT) assay. Western blot was used to detect the effect of CRM197 on the expression of HB-EGF, epidermal growth factor receptor (EGFR) and plasma membrane glycoprotein (P-gp) protein in A2780 and A2780/Taxol cells. Real-time PCR was used to examine the MDR1 mRNA expression in these cells. (2) A2780/Taxol cells were divided into 4 groups, including the cells transfected with empty vector and saline treatment (empty vector group), MDR1 small interference RNA (siRNA) vector and saline treatment (MDR1 siRNA group), empty vector and CRM197 treatment (empty vector+CRM197 group) and MDR1 siRNA vector and CRM197 treatment (MDR1 siRNA+CRM197 group), respectively. Flow cytometry was used to detecte the effect of intracellular rhodomine 123 (Rh123) accumulation, and caspase-3 activity assay was used to test the effect of apoptosis in four groups of A2780/Taxol cells. (3) In experiments in vivo, A2780/Taxol cells were inoculated to nude mouse subcutaneously to determine the EGFR and P-gp protein expression following CRM197 treatment by immunohistochemistry. Results: (1) In vitro, MTT examination showed that the IC(50) of A2780/Taxol cells to paclitaxel in A2780/Taxol+CRM197 group [(6.4±0.3) μmol/L] was significantly lower than the IC(50) in A2780/Taxol group [ (34.1±0.5) μmol/L, P<0.01], and the reveral fold of CRM197 was 5.3. The expression level of HB-EGF protein in A2780/Taxol+CRM197 group (1.44±0.29) was significantly lower than HB-EGF protein in A2780/Taxol group (2.72±0.32), respectively (P<0.05). The expression level of EGFR

  7. Clinical and molecular comparison between borderline serous ovarian tumors and advanced serous papillary ovarian carcinomas.

    PubMed

    Halperin, R; Zehavi, S; Dar, P; Habler, L; Hadas, E; Bukovsky, I; Schneider, D

    2001-01-01

    The aim of this study was to characterize the clinical and molecular markers of borderline serous ovarian tumors (BSOT), and to study their expression in the progression from benign lesions to advanced serous papillary ovarian carcinomas (SPOC). The clinical records of 20 patients with BSOT and 22 patients with SPOC were reviewed. Specimens from all these cases and from six benign ovarian serous cystadenomas were evaluated for expression of estrogen receptors (ER), progesterone receptors (PR), p53. HER-2/neu and Ki-67 by immunohistochemical techniques. The mean patient age and the age at menarche differed significantly between the compared groups of BSOT and SPOC (p=0.0006 and p=0.0014, respectively). No difference was observed comparing the other clinical parameters. The immunohistochemical analysis demonstrated a significant increase in the expression of ER (100% vs 72.7%), and a significant decrease in the immunoreactivity for p53 (0% vs 45.4%) and Ki-67 (2% vs 26.8%) in cases of BSOT compared with those of SPOC (p=0.007, p=0.0003 and p=0.012, respectively). No significant difference was demonstrated comparing the expression of PR and HER-2/neu. The immunostaining of benign ovarian serous cystadenoma specimens did not differ significantly from immunoreactivity observed in cases of BSOT. According to immunohistochemical analysis, BSOT had much more in common with benign serous tumors than with SPOC. The main difference between BSOT and SPOC was regarding the overexpression of p53 and Ki-67.

  8. 3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells

    PubMed Central

    Wang, Yaomin; Compton, Casey; Rankin, Gary O.; Cutler, Stephen J.; Rojanasakul, Yon; Tu, Youying; Chen, Yi Charlie

    2017-01-01

    In the present study, we evaluated 3-Hydroxyter-phenyllin (3-HT) as a potential anticancer agent using the human ovarian cancer cells A2780/CP70 and OVCAR-3, and normal human epithelial ovarian cells IOSE-364 as an in vitro model. 3-HT suppressed proliferation and caused cytotoxicity against A2780/CP70 and OVCAR-3 cells, while it exhibited lower cytotoxicity in IOSE-364 cells. Subsequently, we found that 3-HT induced S phase arrest and apoptosis in a dose-independent manner. Further investigation revealed that S phase arrest was related with DNA damage which mediated the ATM/p53/Chk2 pathway. Downregulation of cyclin D1, cyclin A2, cyclin E1, CDK2, CDK4 and Cdc25C, and the upregulation of Cdc25A and cyclin B1 led to the accumulation of cells in S phase. The apoptotic effect was confirmed by Hoechst 33342 staining, depolarization of mitochondrial membrane potential and activation of cleaved caspase-3 and PARP1. Additional results revealed both intrinsic and extrinsic apoptotic pathways were involved. The intrinsic apoptotic pathway was activated through decreasing the protein levels of Bcl2, Bcl-xL and procaspase-9 and increasing the protein level of Puma. The induction of DR5 and DR4 indicated that the extrinsic apoptotic pathway was also activated. Induction of ROS and activation of ERK were observed in ovarian cancer cells. We therefore concluded that 3-HT possessed anti-proliferative effect on A2780/CP70 and OVCAR-3 cells, induced S phase arrest and caused apoptosis. Taken together, we propose that 3-HT shows promise as a therapeutic candidate for treating ovarian cancer. PMID:28259974

  9. 3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells.

    PubMed

    Wang, Yaomin; Compton, Casey; Rankin, Gary O; Cutler, Stephen J; Rojanasakul, Yon; Tu, Youying; Chen, Yi Charlie

    2017-03-02

    In the present study, we evaluated 3-Hydroxyter-phenyllin (3-HT) as a potential anticancer agent using the human ovarian cancer cells A2780/CP70 and OVCAR-3, and normal human epithelial ovarian cells IOSE-364 as an in vitro model. 3-HT suppressed proliferation and caused cytotoxicity against A2780/CP70 and OVCAR-3 cells, while it exhibited lower cytotoxicity in IOSE-364 cells. Subsequently, we found that 3-HT induced S phase arrest and apoptosis in a dose-independent manner. Further investigation revealed that S phase arrest was related with DNA damage which mediated the ATM/p53/Chk2 pathway. Downregulation of cyclin D1, cyclin A2, cyclin E1, CDK2, CDK4 and Cdc25C, and the upregulation of Cdc25A and cyclin B1 led to the accumulation of cells in S phase. The apoptotic effect was confirmed by Hoechst 33342 staining, depolarization of mitochondrial membrane potential and activation of cleaved caspase-3 and PARP1. Additional results revealed both intrinsic and extrinsic apoptotic pathways were involved. The intrinsic apoptotic pathway was activated through decreasing the protein levels of Bcl2, Bcl-xL and procaspase-9 and increasing the protein level of Puma. The induction of DR5 and DR4 indicated that the extrinsic apoptotic pathway was also activated. Induction of ROS and activation of ERK were observed in ovarian cancer cells. We therefore concluded that 3-HT possessed anti-proliferative effect on A2780/CP70 and OVCAR-3 cells, induced S phase arrest and caused apoptosis. Taken together, we propose that 3-HT shows promise as a therapeutic candidate for treating ovarian cancer.

  10. Carboplatin and Paclitaxel With or Without Bevacizumab Compared to Docetaxel, Carboplatin, and Paclitaxel in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Carcinoma (Cancer)

    ClinicalTrials.gov

    2013-03-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Carcinosarcoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Stage II Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  11. Clinical and Biological Significance of Tissue Transglutaminase in Ovarian Carcinoma

    PubMed Central

    Hwang, Jee Young; Mangala, Lingegowda S.; Fok, Jansina Y.; Lin, Yvonne G.; Merritt, William M.; Spannuth, Whitney A.; Nick, Alpa M.; Fiterman, Derek J.; Vivas-Mejia, Pablo E.; Deavers, Michael T.; Coleman, Robert L.; Lopez-Berestein, Gabriel; Mehta, Kapil; Sood, Anil K.

    2008-01-01

    Tissue type transglutaminase (TG2) is a unique multifunctional protein that plays a role in many steps in the cancer metastatic cascade. Here, we examined the clinical (n = 93 epithelial ovarian cancers) and biological (in vitro adhesion, invasion, and survival and in vivo therapeutic targeting) significance of TG2 in ovarian cancer. The overexpression of TG2 was associated with significantly worse overall patient survival in both univariate and multivariate analyses. Transfection of TG2 into the SKOV3ip1 cells promoted attachment and spreading on fibronectin-coated surfaces and increased the in vitro invasive potential of these cells. Conversely, TG2 silencing with siRNA of HeyA8 cells significantly decreased the invasive potential of the cells, and also increased docetaxel-induced cell death. In vivo therapy experiments using chemotherapy-sensitive (HeyA8) and resistant (HeyA8-MDR, RMG2) models demonstrated significant anti-tumor activity both with TG2 siRNA-DOPC alone and in combination with docetaxel chemotherapy. This anti-tumor activity was related to decreased proliferation, angiogenesis and increased tumor cell apoptosis in vivo. Taken together, these findings indicate that TG2 overexpression is an adverse prognostic factor in ovarian carcinoma and TG2 targeting may be an attractive therapeutic approach. PMID:18632639

  12. Diagnosis of persistent ovarian carcinoma with three-step immunoscintigraphy

    PubMed Central

    Magnani, P; Fazio, F; Grana, C; Songini, C; Frigerio, L; Pecorelli, S; Mangili, G; Colombo, N; Mariani, C D A; Paganelli, G

    2000-01-01

    The diagnosis of recurrent ovarian carcinoma is usually determined at surgical re-exploration since the main non-invasive diagnostic tests have low accuracy. It would be desirable to have a high accuracy non-invasive diagnostic procedure. With this aim, we have assessed the utility of three-step immunoscintigraphy. Thirty patients were intravenously injected with biotinylated monoclonal antibodies MOv18 and B72.3, followed by avidin–streptavidin injection and finally by111In-biotin. Tumour recurrences were imaged 2 h post radioactivity injection. All patients underwent surgical re-exploration 3–4 days after immunoscintigraphy; the presence of tumour in the area of immunoscintigraphic uptake was evaluated in the biopsied material. Twenty-one patients studied were true-positive, five were true-negative, four were false-positive and none was false-negative. The diagnostic accuracy, positive predictive value and negative predictive value were 87%, 84% and 100% respectively. If these findings are confirmed in a larger number of patients, we expect immunoscintigraphy to be introduced as a cost-effective procedure in the follow-up of patients who have received surgery for ovarian carcinoma, since it promises to reliably identify patients who do not require surgical re-exploration, and guide biopsies when they are indicated. © 2000 Cancer Research Campaign PMID:10682674

  13. Polyglutamate Paclitaxel and Carboplatin in Treating Patients With Ovarian Epithelial, Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2015-05-07

    Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  14. Precursors of ovarian cancer in the fallopian tube: Serous tubal intraepithelial carcinoma – an update

    PubMed Central

    Zeppernick, Felix; Meinhold-Heerlein, Ivo; Shih, Ie-Ming

    2015-01-01

    Ovarian tumors comprise a wide variety of entities. The largest group, epithelial ovarian carcinoma, can be classified into two main groups, type I and type II tumors. Recent advances in the understanding of ovarian cancer development have resulted in the finding of ‘serous tubal intraepithelial carcinoma’, which is believed to represent the precursor lesion in high-grade serous ovarian carcinoma. In this review, lines of evidence for this are discussed and possible future implications for clinical and research settings are outlined. PMID:25330822

  15. Solitary Gastric Metastasis from a Stage IA Serous Ovarian Carcinoma: A Case Report with Literature Review

    PubMed Central

    Mizuguchi, Keishi; Minato, Hiroshi; Yoshida, Isao; Iwadare, Junpei; Kayahashi, Kayo; Mitani, Yuki; Watanabe, Kazuyoshi

    2017-01-01

    Gastric metastasis from ovarian cancer is exceptionally rare and generally occurs in advanced stages. A 71-year-old woman presented with a solitary gastric submucosal mass 8 years after the diagnosis of a stage IA ovarian serous adenocarcinoma. Endoscopy showed a tumor covered with normal gastric mucosa. Initially, a gastrointestinal stromal tumor was suspected, but biopsy revealed a histology of invasive micropapillary carcinoma, similar to the histological findings of the previously resected ovarian tumor. Clinicians should consider that in patients with a submucosal tumor and a history of ovarian cancer, gastric lesions may be secondary metastases from ovarian cancer. PMID:28420839

  16. Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma

    PubMed Central

    Li, Huiwen; Cui, Xuelian; Chen, Dingbao; Yang, Yang; Piao, Junjie; Lin, Zhenhua; Yan, Guanghai; Shen, Danhua

    2016-01-01

    T lymphoma invasion and metastasis 1 (Tiam1), a guanine nucleotide exchange factor, was originally identified as an invasion- and metastasis-inducing gene in T lymphoma cells. High expression levels of the human Tiam1 gene have been found in numerous human malignancies, suggesting a potential role as a modifier of tumor initiation and progression. However, little is known about the status of Tiam1 in ovarian carcinoma. The present study aimed to investigate the clinicopathological significance of high Tiam1 expression in serous ovarian carcinoma. Immunohistochemical staining for Tiam1 was performed in 182 patients with serous ovarian carcinoma, in 76 patients with ovarian borderline tumors and in 72 patients with benign ovarian tumors. Immunofluorescence staining was also performed to detect the subcellular localization of Tiam1 protein in SK-OV-3 ovarian carcinoma cells. The correlations between high Tiam1 expression and the clinicopathological features of the ovarian carcinomas were evaluated by the χ2 test and Fisher's exact test. The overall survival (OS) rates were calculated by the Kaplan-Meier method, and the association between prognostic factors and patient survival was analyzed by the Cox proportional hazard model. Tiam1 protein showed a cytoplasmic and nuclear staining pattern in ovarian carcinoma. Strongly-positive Tiam1 protein expression was observed in 59.3% (108/182) of ovarian carcinomas, which was significantly higher than in benign serous tumors (12.5%; 9/72). Moreover, the rate of strongly-positive Tiam1 expression in borderline serous tumors (31.6%; 24/76) was also significantly higher than that in benign serous tumors. High Tiam1 protein expression was closely associated with a high histological grade, metastasis, advanced clinical stage and lower OS rates in ovarian carcinoma. Multivariate analysis indicated that Tiam1 was an independent prognostic factor, along with metastasis and clinical stage, in patients with ovarian carcinoma. In

  17. Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma.

    PubMed

    Li, Huiwen; Cui, Xuelian; Chen, Dingbao; Yang, Yang; Piao, Junjie; Lin, Zhenhua; Yan, Guanghai; Shen, Danhua

    2016-11-01

    T lymphoma invasion and metastasis 1 (Tiam1), a guanine nucleotide exchange factor, was originally identified as an invasion- and metastasis-inducing gene in T lymphoma cells. High expression levels of the human Tiam1 gene have been found in numerous human malignancies, suggesting a potential role as a modifier of tumor initiation and progression. However, little is known about the status of Tiam1 in ovarian carcinoma. The present study aimed to investigate the clinicopathological significance of high Tiam1 expression in serous ovarian carcinoma. Immunohistochemical staining for Tiam1 was performed in 182 patients with serous ovarian carcinoma, in 76 patients with ovarian borderline tumors and in 72 patients with benign ovarian tumors. Immunofluorescence staining was also performed to detect the subcellular localization of Tiam1 protein in SK-OV-3 ovarian carcinoma cells. The correlations between high Tiam1 expression and the clinicopathological features of the ovarian carcinomas were evaluated by the χ(2) test and Fisher's exact test. The overall survival (OS) rates were calculated by the Kaplan-Meier method, and the association between prognostic factors and patient survival was analyzed by the Cox proportional hazard model. Tiam1 protein showed a cytoplasmic and nuclear staining pattern in ovarian carcinoma. Strongly-positive Tiam1 protein expression was observed in 59.3% (108/182) of ovarian carcinomas, which was significantly higher than in benign serous tumors (12.5%; 9/72). Moreover, the rate of strongly-positive Tiam1 expression in borderline serous tumors (31.6%; 24/76) was also significantly higher than that in benign serous tumors. High Tiam1 protein expression was closely associated with a high histological grade, metastasis, advanced clinical stage and lower OS rates in ovarian carcinoma. Multivariate analysis indicated that Tiam1 was an independent prognostic factor, along with metastasis and clinical stage, in patients with ovarian carcinoma. In

  18. A6 in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2015-02-27

    Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Recurrent Ovarian Carcinoma; Undifferentiated Ovarian Carcinoma

  19. Epigenetic determinants of ovarian clear cell carcinoma biology

    PubMed Central

    Yamaguchi, Ken; Huang, Zhiqing; Matsumura, Noriomi; Mandai, Masaki; Okamoto, Takako; Baba, Tsukasa; Konishi, Ikuo; Berchuck, Andrew; Murphy, Susan K.

    2015-01-01

    Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC, and 4 corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1 binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p<0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process. PMID:24382740

  20. Clonal chromosome abnormalities in 54 cases of ovarian carcinoma.

    PubMed

    Thompson, F H; Emerson, J; Alberts, D; Liu, Y; Guan, X Y; Burgess, A; Fox, S; Taetle, R; Weinstein, R; Makar, R

    1994-03-01

    As a prelude to assessing the relationship of chromosome alterations to clinical outcome in ovarian carcinoma, we report on the cytogenetic analysis on short-term cultures from 54 patients. All patients had histopathologically confirmed malignancy, with the majority of cases demonstrating serous ovarian adenocarcinomas. Structural alterations were evident in 52 cases, whereas numeric changes were identified in 13 cases. The most notable numeric abnormalities were loss of the X-chromosome (9/13 total cases) and +7 (3/9 diploid cases). Structural alterations most frequently involved chromosomes 1, 3, 6, 7, 11, and 12. Chromosomal breakpoints were shown to cluster in several chromosomal banding regions, including 1p36, 1p11-q21, 3p23-p10, 7p (especially 7p22), 11p, 11q, 12p13-q12, and 12q24. The frequency of structural alterations involving the following chromosome arms was found to be significantly increased: 1p (p < 0.01), 7p (p < 0.01), 11p (p < 0.01), 11q (p < 0.05), and 12p (p < 0.05). An analysis of the net gain or loss of chromosome segments was also performed, with the most consistent tendency observed being over-representation of 1q and chromosome 7, deletion of 1p, and loss of the X chromosome.

  1. Multimodality treatment of patients with advanced ovarian carcinoma

    SciTech Connect

    Torres, J.L.P.; Bross, D.S.; Hernandez, E.; Rosenshein, N.; Klein, J.L.; Ettinger, D.S.; Leichner, P.K.; Order, S.E.

    1982-10-01

    A multimodality treatment program has been applied to ovarian carcinoma at the Johns Hopkins Hospital since August 1975. Forty-nine patients were subdivided into 23 patients with maximally resected Stage III micrometastatic, and 26 patients with significant retained disease, 20 with Stage III macrometastatic and 6 with Stage IV. After initial pilot studies, those patients with minimally retained disease entered a randomized prospective study. Antiovarian antiserum was used in one arm of the study; in both study arms colloidal P-32, delayed split whole abdominal irradiation, and maintenance melphalan were used. For the 23 patients with micrometastatic disease the cumulative survival and survival without evidence of disease at four years is 78 and 34% respectively. Twenty-six patients with macrometastatic disease were treated with or without intraperitoneal antiserum and multiagent chemotherapy; their cumulative one year survival is 50%. The lack of significant toxicity of intraperitoneal antiovarian antiserum and the results of multimodality therapy indicate the feasibility of this therapeutic approach to further improve ovarian cancer therapy.

  2. Multimodality treatment of patients with advanced ovarian carcinoma

    SciTech Connect

    Pino y Torres, J.L.; Bross, D.S.; Hernandez, E.; Rosenshein, N.; Klein, J.L.; Ettinger, D.S.; Leichner, P.K.; Order, S.E.

    1982-10-01

    A multimodality treatment program has been applied to ovarian carcinoma at the Johns Hopkins Hospital since August 1975. Forty-nine patients were subdivided into 23 patients with maximally respected Stage III micrometastatic, and 26 patients with significant retained disease, 20 with Stage III macrometastic and 6 with STage IV. After initial pilot studies, those patients with minimally retained disease entered a randomized prospective study. Antiovarian antiserum was used in one arm of the study; in both study arms colloidal P-32, delayed split whole abdominal irradiation, and maintenance melphalan were used. For the 23 patients with micrometastiatic disease the cumulative survival and survival without evidence of disease at four years is 78 and 34% respectively. Twenty-six patients with macrometastatic disease were treated with or witout intraperitoneal antiserum and multiagent chemotherapy; their cummulative one year survival is 50%. The lack of significant toxicity of intraperitoneal antiovarian antiserum and the results of multimodality therapy indicate the feasibility of this therapeutic approach to further improve ovarian cancer therapy.

  3. Histone modifications silence the GATA transcription factor genes in ovarian cancer.

    PubMed

    Caslini, C; Capo-chichi, C D; Roland, I H; Nicolas, E; Yeung, A T; Xu, X-X

    2006-08-31

    Altered expression of GATA factors was found and proposed as the underlying mechanism for dedifferentiation in ovarian carcinogenesis. In particular, GATA6 is lost or excluded from the nucleus in 85% of ovarian tumors and GATA4 expression is absent in majority of ovarian cancer cell lines. Here, we evaluated their DNA and histone epigenetic modifications in five ovarian epithelial and carcinoma cell lines (human 'immortalized' ovarian surface epithelium (HIO)-117, HIO-114, A2780, SKOV3 and ES2). GATA4 and GATA6 gene silencing was found to correlate with hypoacetylation of histones H3 and H4 and loss of histone H3/lysine K4 tri-methylation at their promoters in all lines. Conversely, histone H3/lysine K9 di-methylation and HP1gamma association were not observed, excluding reorganization of GATA genes into heterochromatic structures. The histone deacetylase inhibitor trichostatin A, but not the DNA methylation inhibitor 5'-aza-2'-deoxycytidine, re-established the expression of GATA4 and/or GATA6 in A2780 and HIO-114 cells, correlating with increased histone H3 and H4 acetylation, histone H3 lysine K4 methylation and DNase I sensitivity at the promoters. Therefore, altered histone modification of the promoter loci is one mechanism responsible for the silencing of GATA transcription factors and the subsequent loss of a target gene, the tumor suppressor Disabled-2, in ovarian carcinogenesis.

  4. Genomic/Epigenomic Alterations in Ovarian Carcinoma: Translational Insight into Clinical Practice

    PubMed Central

    Dong, Anliang; Lu, Yan; Lu, Bingjian

    2016-01-01

    Ovarian carcinoma is the most lethal gynecological malignancy worldwide. Recent advance in genomic/epigenomic researches will impact on our prevention, detection and intervention on ovarian carcinoma. Detection of germline mutations in BRCA1/BRCA2, mismatch repair genes, and other genes in the homologous recombination/DNA repair pathway propelled the genetic surveillance of most hereditary ovarian carcinomas. Germline or somatic mutations in SMARCA4 in familial and sporadic small cell carcinoma of the ovary, hypercalcemia type, lead to our recognition on this rare aggressive tumor as a new entity of the atypical teratoma/rhaboid tumor family. Genome-wide association studies have identified many genetic variants that will contribute to the evaluation of ovarian carcinoma risk and prognostic prediction. Whole exome sequencing and whole genome sequencing discovered rare mutations in other drive mutations except p53, but demonstrated the presence of high genomic heterogeneity and adaptability in the genetic evolution of high grade ovarian serous carcinomas that occurs in cancer progression and chemotherapy. Gene mutations, copy number aberrations and DNA methylations provided promising biomarkers for the detection, diagnosis, prognosis, therapy response and targets of ovarian cancer. These findings underscore the necessity to translate these potential biomarkers into clinical practice. PMID:27471560

  5. Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics

    PubMed Central

    2013-01-01

    Background The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. Method The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. Results BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by >75% after infection with oncolytic viruses. Conclusions These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53

  6. B7-H4 expression in ovarian serous carcinoma: a study of 306 cases.

    PubMed

    Liang, Li; Jiang, Yi; Chen, Jun-Song; Niu, Na; Piao, Jin; Ning, Jing; Zu, Youli; Zhang, Jing; Liu, Jinsong

    2016-11-01

    The B7 family of immune costimulatory ligands is a group of cell surface proteins that bind to the surface receptors of lymphocytes to fine-tune immune responses. The aberrant expression of these proteins plays a key role in tumor immune evasion. Immunotherapy targeting certain B7 family members, including programmed death ligand 1, has proven quite effective in suppressing tumor growth. However, why such therapy works in only a subgroup of tumors is unclear. We hypothesized that other B7 family members, either alone or in concert with programmed death ligand 1, play a crucial role in tumor pathogenesis and progression. We therefore examined the expression of a newly discovered B7 family member, B7-H4, in 306 cases of ovarian serous carcinoma by immunohistochemistry. We found that 91% (267/293) of the high-grade ovarian serous carcinomas and 69% (9/13) of the low-grade ovarian serous carcinomas expressed B7-H4. The difference between B7-H4 expression in high-grade and low-grade ovarian serous carcinoma was statistically significant (P=.002). Moreover, B7-H4 protein expression in high-grade serous carcinoma was associated with tumor stage (P<.01) but not overall survival or disease-free survival. In conclusion, B7-H4 is frequently expressed in ovarian serous carcinomas, especially high-grade serous carcinomas, and may represent a novel immunotherapeutic target in this cancer.

  7. Metastatic ovarian carcinoma to the brain: an approach to identification and classification for neuropathologists.

    PubMed

    Nafisi, Houman; Cesari, Matthew; Karamchandani, Jason; Balasubramaniam, Gayathiri; Keith, Julia Lee

    2015-04-01

    Brain metastasis is an uncommon but increasing manifestation of ovarian epithelial carcinoma and neuropathologists' collective experience with these tumors is limited. We present clinicopathological characteristics of 13 cases of brain metastases from ovarian epithelial carcinoma diagnosed at two academic institutions. The mean ages at diagnosis of the ovarian carcinoma and their subsequent brain metastases were 58.7 and 62.8 years, respectively. At the time of initial diagnosis of ovarian carcinoma the majority of patients had an advanced stage and none had brain metastases as their first manifestation of malignancy. Brain metastases tended to be multiple with ring-enhancing features on neuroimaging. Primary tumors and their brain metastases were all high-grade histologically and the histologic subtypes were: nine high-grade serous carcinoma (HGSC) cases, two clear cell carcinoma (CCC) cases and a single case each of carcinosarcoma and high-grade adenocarcinoma. A recommended histo- and immunopathological approach to these tumours are provided to aid neuropathologists in the recognition and classification of metastatic ovarian carcinoma to the brain.

  8. PET Imaging of Ovarian Carcinoma With 18F-FSPG

    ClinicalTrials.gov

    2016-08-16

    Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  9. ERBB4 Expression in Ovarian Serous Carcinoma Resistant to Platinum-Based Therapy.

    PubMed

    Saglam, Ozlen; Xiong, Yin; Marchion, Douglas C; Strosberg, Carolina; Wenham, Robert M; Johnson, Joseph J; Saeed-Vafa, Daryoush; Cubitt, Christopher; Hakam, Ardeshir; Magliocco, Anthony M

    2017-01-01

    Few data exist on the prognostic and predictive impact of erb-b2 receptor tyrosine kinase 4 (ERBB4) in ovarian cancer. Thus, we evaluated ERBB4 expression by immunohistochemistry in a tumor microarray consisting of 100 ovarian serous carcinoma specimens (50 complete responses [CRs] and 50 incomplete responses [IRs] to platinum-based therapy), 51 normal tissue controls, and 16 ovarian cancer cell lines. H scores were used to evaluate expression and were semiquantitatively classified into low, intermediate, and high categories. Category frequencies were compared between tumor specimens vs controls using an unpaired t test. Among tumors, category frequencies were compared between CR and IR to chemotherapy. Overall survival (OS) was stratified by category. In total, 74 ovarian serous carcinoma samples (32 CRs and 42 IRs), 28 normal controls, and 16 ovarian cancer cell lines were evaluable. High-level ERBB4 expression was observed at a significantly higher frequency in ovarian serous carcinoma compared with normal control tissue. Among tumor specimens, ERBB4 expression was significantly higher for those with an IR to chemotherapy compared with CR (P = .033). OS was inversely correlated with ERBB4 expression levels. Median rates of OS were 18, 22, and 58 months among high-, intermediate-, and low-expression tumors, respectively. Our results indicate that ERBB4 expression by immunohistochemistry may correlate with chemotherapy-resistant ovarian serous carcinoma and shortened OS.

  10. Oophorectomy versus radiation ablation of ovarian function in patients with metastatic carcinoma of the breast

    SciTech Connect

    Lees, A.W.; Giuffre, C.; Burns, P.E.; Hurlburt, M.E.; Jenkins, H.J.

    1980-12-01

    A retrospective study of two methods of ovarian ablation as primary therapy for metastatic carcinoma of the breast was carried out using records from this cancer institute. Sixty-one radiation and 97 surgical ovarian ablations, performed from 1972 to 1977, were assessed. Over-all response was similar for the surgical and irradiation groups. Survival from the time of ovarian ablation was greater in both groups in those who responded positively than in those who did not. Factors other than estrogen receptor status can determine the response of patients with metastatic carcinoma of the breast to ovarian ablation. The results indicate that clinical determinates and not the efficiency of one method over the other should be the main criteria for choosing between ovarian ablation by irradiation or by oophorectomy.

  11. Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

    PubMed Central

    2010-01-01

    Background Ovarian cancer is the most common cause of cancer related death from gynecologic tumors in the United States. The insidious nature of the disease precludes early diagnosis, therefore surgical debulking and chemotherapy are considered as standard treatment modalities for advanced stages. We investigated the effect of the LXR agonist, T0901317, on ovarian cancer cell proliferation and apoptosis as a potential therapeutic agent. Results T0901317 treatment resulted in a significant (P <0.001) inhibition of cell proliferation in a time- and dose-dependent manner in CaOV3, SKOV3 and A2780 cells. Western blot analysis demonstrated an induction of p21 and p27 with a concominant reduction in phospho-RB protein levels. Cell cycle analysis demonstrated a significant (P <0.001) arrest in the G1 cell cycle phase. Significant induction of Caspase-3 and BAX gene expression occurred with treatment. Induction of apoptosis was confirmed by significant (P < 0.001) elevation of caspase activity on FACS analysis, caspase-glo assay, BAX protein induction and decreased caspase 3 precursor protein expression on Western blot analysis. LXR α/β knockdown experiments did not reverse the anti-proliferative and cytotoxic effects of T0901317. Conclusions The LXR agonist, T0901317, significantly suppresses cell proliferation and induces programmed cell death in a dose- and time-dependent manner. Our results indicate that T0901317 induces its anti-proliferative and cytotoxic effects via an LXR-independent mechanism. PMID:20504359

  12. Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells.

    PubMed

    Rough, James J; Monroy, M Alexandra; Yerrum, Smitha; Daly, John M

    2010-05-26

    Ovarian cancer is the most common cause of cancer related death from gynecologic tumors in the United States. The insidious nature of the disease precludes early diagnosis, therefore surgical debulking and chemotherapy are considered as standard treatment modalities for advanced stages. We investigated the effect of the LXR agonist, T0901317, on ovarian cancer cell proliferation and apoptosis as a potential therapeutic agent. T0901317 treatment resulted in a significant (P <0.001) inhibition of cell proliferation in a time- and dose-dependent manner in CaOV3, SKOV3 and A2780 cells. Western blot analysis demonstrated an induction of p21 and p27 with a concominant reduction in phospho-RB protein levels. Cell cycle analysis demonstrated a significant (P <0.001) arrest in the G1 cell cycle phase. Significant induction of Caspase-3 and BAX gene expression occurred with treatment. Induction of apoptosis was confirmed by significant (P < 0.001) elevation of caspase activity on FACS analysis, caspase-glo assay, BAX protein induction and decreased caspase 3 precursor protein expression on Western blot analysis. LXR alpha/beta knockdown experiments did not reverse the anti-proliferative and cytotoxic effects of T0901317. The LXR agonist, T0901317, significantly suppresses cell proliferation and induces programmed cell death in a dose- and time-dependent manner. Our results indicate that T0901317 induces its anti-proliferative and cytotoxic effects via an LXR-independent mechanism.

  13. Elesclomol Sodium and Paclitaxel in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2014-12-23

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  14. TLR8 Agonist VTX-2337 and Pegylated Liposomal Doxorubicin Hydrochloride or Paclitaxel in Treating Patients With Recurrent or Persistent Ovarian Epithelial, Fallopian Tube, or Peritoneal Cavity Cancer

    ClinicalTrials.gov

    2014-12-23

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  15. Influence of reducing agents on the cytotoxic activity of platinum(IV) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines.

    PubMed

    Pichler, Verena; Göschl, Simone; Schreiber-Brynzak, Ekaterina; Jakupec, Michael A; Galanski, Markus; Keppler, Bernhard K

    2015-07-01

    The concept of Pt(IV) prodrug design is one advanced strategy to increase the selectivity for cancer cells and to reduce systemic toxicity in comparison to established platinum-based chemotherapy. Pt(IV) complexes are thought to be activated by reduction via physiological reductants, such as ascorbic acid or glutathione. Nevertheless, only few investigations on the link between the reduction rate, which is influenced by the reductant, and the ligand sphere of the Pt(IV) metal centre have been performed so far. Herein, we investigated a set of Pt(IV) compounds with varying rates of reduction with respect to their cytotoxicity and drug accumulation in A2780 and A2780cis ovarian cancer cell lines, their influence on the cell cycle, efficiency of triggering apoptosis, and ability to interfere with plasmid DNA (pUC19). The effects caused by Pt(IV) compounds were compared without or with extracellularly added ascorbic acid and glutathione (or its precursor N-acetylcysteine) to gain understanding of the impact of increased levels of the reductant on the activity of such complexes. Our results demonstrate that reduction is required prior to plasmid interaction. Furthermore, the rate of reduction is crucial for the efficiency of this set of Pt(IV) compounds. The substances that are reduced least likely showed similar performances, whereas the fastest reducing substance was negatively affected by an increased extracellular level of reducing agents, with reduced cytotoxicity and lower efficiency in inducing apoptosis and G2/M arrest. These results confirm the connection between reduction and activity, and prove the strong impact of the reduction site on the activity of Pt(IV) complexes.

  16. PPP2R1A mutation is a rare event in ovarian carcinoma across histological subtypes.

    PubMed

    Rahman, Munmun; Nakayama, Kentaro; Rahman, Mohammed Tanjimur; Nakayama, Naomi; Katagiri, Hiroshi; Katagiri, Atsuko; Ishibashi, Tomoka; Ishikawa, Masako; Iida, Kouji; Otsuki, Yoshiro; Nakayama, Satoru; Miyazaki, Kohji

    2013-01-01

    Somatic mutations in PPP2R1A, which encodes a scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have recently been described in different types of gynecological neoplasias. To extend this observation, we examined the frequency of PPP2R1A mutation in some major histological subtypes of type I and type II ovarian carcinoma. Mutational analysis of PPP2R1A (exons 5 and 6) was performed on 88 primary ovarian carcinomas, including mucinous, clear cell, high-grade serous, and high-grade endometrioid ovarian carcinoma. In addition, exons 9 and 20 of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and exon 15 of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) were sequenced and compared across the different histological subtypes. Finally, survival analysis was performed to determine any prognostic significance of these mutations. Mutations in PPP2R1A were rare: detected in 4.5% (1/22) of clear cell, 4.5% (1/22) of high-grade serous, and 6.7% (1/15) of high-grade endometrioid ovarian carcinoma. Interestingly, no PPP2R1A mutations were observed in mucinous ovarian carcinoma. A higher frequency of PIK3CA mutations (50%, 11/22) was found in clear cell carcinoma and a higher frequency of KRAS mutations (24.1%, 7/29) was observed in mucinous carcinoma. In addition, high-grade endometrioid ovarian carcinoma exhibited KRAS and PIK3CA mutations in 26.7% (4/15) and 20% (3/15) of cases, respectively. Survival analysis showed no significant association between mutational status and overall survival of patients. This study indicates that the PPP2R1A mutation occurs at a lower frequency compared to other gynecological malignancies, irrespective of the histological subtype.

  17. RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer.

    PubMed

    Zou, Yang; Wang, Feng; Liu, Fa-Ying; Huang, Mei-Zhen; Li, Wei; Yuan, Xiao-Qun; Huang, Ou-Ping; He, Ming

    2013-11-15

    Ring finger protein 43 (RNF43) is an E3 ubiquitin-protein ligase that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme and directly transfers the ubiquitin to targeted substrate proteins. Recently, large-scale sequencing efforts have identified prevalent RNF43 mutations in pancreatic and ovarian mucinous carcinomas. In the present study, we sequenced the entire coding sequences of RNF43 in 251 Chinese patients with distinct subtypes of ovarian cancers for the presence of RNF43 mutations. A total of 2 novel heterozygous nonsynonymous RNF43 mutations were identified in 2 out of 15 (13.3%) patients with mucinous ovarian carcinoma, these mutations were evolutionarily highly conserved; while no mutation was detected in other samples. In addition, none of the RNF43-mutated samples harbored DICER1 (dicer 1, ribonuclease type III), PPP2R1A (protein phosphatase 2, regulatory subunit A, alpha), TRRAP (transformation/transcription domain-associated protein) and DNMT3A (DNA (cytosine-5-)-methyltransferase 3 alpha) hot-spot mutations. Recurrent RNF43 mutations existed in mucinous ovarian carcinomas implicated that these mutations might play crucial roles in the tumorigenesis of these patients, while the absence of DICER1, PPP2R1A, TRRAP and DNMT3A hot-spot mutations suggested that these genetic alterations might not play synergistic roles with RNF43 mutations in these individuals. Additionally, the absence of RNF43 mutations in other subtypes of ovarian carcinoma implicated that RNF43 mutations might not be actively involved in the pathogenesis of these disorders. © 2013 Elsevier B.V. All rights reserved.

  18. Low Grade Serous Ovarian Carcinoma: from the molecular characterization to the best therapeutic strategy.

    PubMed

    Della Pepa, Chiara; Tonini, Giuseppe; Santini, Daniele; Losito, Simona; Pisano, Carmela; Di Napoli, Marilena; Cecere, Sabrina Chiara; Gargiulo, Piera; Pignata, Sandro

    2015-02-01

    Low Grade Serous Ovarian Carcinoma, LGSOC, is certainly a rare disease, accounting for only a small proportion of all ovarian carcinomas, nevertheless in the last decade we have acquired many data about its molecular and clinical features and it has been largely accepted that it has distinct pathogenesis, genetic aberrations and clinical behavior compared to High Grade Serous Ovarian Carcinoma, HGSOC, which is the most common ovarian cancer histotype. A large number of series pointed out the high rate of KRAS and BRAF mutations in LGSOCs and Serous Borderline Tumors, SBLTs, in contrast with their rarity in HGSOC. Such finding, together with the recurrent observation of focus of LGSOC associated with areas of SBLT in the same lesion, led to abandon the traditional histology classification, defining three types of serous carcinomas, in favor of a new dualistic grading system which recognizes only LG and HG carcinomas corresponding to distinct tumorigenesis pathways, the former based on KRAS/BRAF mutations and alteration of the MAP/ERK signaling, the latter characterized by early genetic instability and wild type status of KRAS and BRAF. LGSOC shows favorable overall survival, compared to general ovarian cancer population, but worrying resistance to conventional treatments. MEK inhibitors are emerging as active agents and may well represent an effective therapeutic strategy in the near future.

  19. Expression of CD44v6 and Its Association with Prognosis in Epithelial Ovarian Carcinomas.

    PubMed

    Zhou, Dang-Xia; Liu, Yun-Xia; Xue, Ya-Hong

    2012-01-01

    The aim of this study was to evaluate CD44v6 protein expression and its prognostic value of CD44v6 in ovarian carcinoma. The expression of CD44v6 was analyzed in 62 patients with ovarian carcinoma by immunohistochemical method. The data obtained were analyzed by univariate and multivariate analyses. The present study clearly demonstrates that tumor tissues from 41 (66.1%) patients showed positive expression with CD44v6. The expression of CD44v6 was significantly correlated with histological type, FIGO stage and histological grade of ovarian carcinomas. Concerning the prognosis, the survival period of patients with CD44v6 positive was shorter than that of patients with CD44v6 negative (36.6% versus 66.7%, 5-year survival, P < 0.05). Univariate analysis showed that CD44v6 expression, histological type, FIGO stage and histological grade were associated with 5-year survival, and CD44v6 expression was associated with histological type, FIGO stage and histological grade and 5-year survival. In multivariate analysis, using the COX-regression model, CD44v6 expression was important prognostic factor. In conclusion, these results suggest that CD44v6 may be related to histological type, FIGO stage and histological grade of ovarian carcinomas, and CD44v6 may be an important molecular marker for poor prognosis in ovarian carcinomas.

  20. Cross-reacting material 197 reverses the resistance to paclitaxel in paclitaxel-resistant human ovarian cancer.

    PubMed

    Tang, Xiao-Han; Deng, Suo; Li, Meng; Lu, Mei-Song

    2016-04-01

    Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been proven to be a promising chemotherapeutic target for ovarian cancer. Our previous studies have demonstrated that inhibition of HB-EGF by the special inhibitor, cross-reacting material 197 (CRM197), potently inhibits the anti-tumor activity in paclitaxel-resistant ovarian cancer. Here, we found that inhibition of HB-EGF by CRM197 significantly reverses the resistance to paclitaxel in paclitaxel-resistant ovarian carcinoma cell line (A2780/Taxol). A2780/Taxol cells over-expressed HB-EGF and epidermal growth factor receptor (EGFR) and CRM197 notably suppressed the expression of HB-EGF and EGFR. Experiments performed in vitro and in vivo further suggested that CRM197 markedly down-regulated the ATP-binding cassette sub-family B member 1 (ABCB1/MDR1) messenger RNA (mRNA) expression (P = 0.01), plasma membrane glycoprotein (P-gp) protein (P = 0.009), and P-gp-mediated efflux (P = 0.007) through inhibition of nuclear factor-κB (NF-κB) expression, which were classical chemoresistance-related targets with respect to paclitaxel therapy. Meanwhile, inhibition of HB-EGF enhanced caspase-3 activity to induce apoptosis via MDR1 inhibition in A2780/Taxol cells (P = 0.038). Collectively, HB-EGF is a molecular target for the resistance of ovarian cancer to paclitaxel and CRM197 as a HB-EGF-targeted agent might be a chemosensitizing agent for paclitaxel-resistant ovarian carcinoma. Our findings provide novel possible mechanisms for HB-EGF to be a target to restore the chemosensitivity to paclitaxel.

  1. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy.

    PubMed

    Pastorek, Michal; Simko, Veronika; Takacova, Martina; Barathova, Monika; Bartosova, Maria; Hunakova, Luba; Sedlakova, Olga; Hudecova, Sona; Krizanova, Olga; Dequiedt, Franck; Pastorekova, Silvia; Sedlak, Jan

    2015-07-01

    One of the recently emerging anticancer strategies is the use of natural dietary compounds, such as sulforaphane, a cancer-chemopreventive isothiocyanate found in broccoli. Based on the growing evidence, sulforaphane acts through molecular mechanisms that interfere with multiple oncogenic pathways in diverse tumor cell types. Herein, we investigated the anticancer effects of bioavailable concentrations of sulforaphane in ovarian carcinoma cell line A2780 and its two derivatives, adriamycin-resistant A2780/ADR and cisplatin-resistant A2780/CP cell lines. Since tumor microenvironment is characterized by reduced oxygenation that induces aggressive tumor phenotype (such as increased invasiveness and resistance to chemotherapy), we evaluated the effects of sulforaphane in ovarian cancer cells exposed to hypoxia (2% O2). Using the cell-based reporter assay, we identified several oncogenic pathways modulated by sulforaphane in hypoxia by activating anticancer responses (p53, ARE, IRF-1, Pax-6 and XRE) and suppressing responses supporting tumor progression (AP-1 and HIF-1). We further showed that sulforaphane decreases the level of HIF-1α protein without affecting its transcription and stability. It can also diminish transcription and protein level of the HIF-1 target, CA IX, which protects tumor cells from hypoxia-induced pH imbalance and facilitates their migration/invasion. Accordingly, sulforaphane treatment leads to diminished pH regulation and reduced migration of ovarian carcinoma cells. These effects occur in all three ovarian cell lines suggesting that sulforaphane can overcome the chemoresistance of cancer cells. This offers a path potentially exploitable in sensitizing resistant cancer cells to therapy, and opens a window for the combined treatments of sulforaphane either with conventional chemotherapy, natural compounds, or with other small molecules.

  2. Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium.

    PubMed

    Lurie, Galina; Wilkens, Lynne R; Thompson, Pamela J; Shvetsov, Yurii B; Matsuno, Rayna K; Carney, Michael E; Palmieri, Rachel T; Wu, Anna H; Pike, Malcolm C; Pearce, Celeste L; Menon, Usha; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Pharoah, Paul D P; Song, Honglin; Gronwald, Jacek; Jakubowska, Anna; Cybulski, Cezary; Lubinski, Jan; Schildkraut, Joellen M; Berchuck, Andrew; Krüger Kjær, Susanne; Høgdall, Estrid; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Hein, Alexander; Chenevix-Trench, Georgia; Webb, Penelope M; Beesley, Jonathan; Goodman, Marc T

    2011-01-01

    The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.

  3. Estrogen Receptor Beta rs1271572 Polymorphism and Invasive Ovarian Carcinoma Risk: Pooled Analysis within the Ovarian Cancer Association Consortium

    PubMed Central

    Lurie, Galina; Wilkens, Lynne R.; Thompson, Pamela J.; Shvetsov, Yurii B.; Matsuno, Rayna K.; Carney, Michael E.; Palmieri, Rachel T.; Wu, Anna H.; Pike, Malcolm C.; Pearce, Celeste L.; Menon, Usha; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Ramus, Susan J.; Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva; Pharoah, Paul D. P.; Song, Honglin; Gronwald, Jacek; Jakubowska, Anna; Cybulski, Cezary; Lubinski, Jan; Schildkraut, Joellen M.; Berchuck, Andrew; Krüger Kjær, Susanne; Høgdall, Estrid; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Chenevix-Trench, Georgia; Webb, Penelope M.; Beesley, Jonathan; Goodman, Marc T.

    2011-01-01

    The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01–1.21; p = 0.04); the OR was 1.09 (CI: 0.99–1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12–1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11–1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women. PMID:21673961

  4. Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma

    PubMed Central

    Redondo, Andrés; Mariño-Enríquez, Adrián; Madero, Rosario; Espinosa, Enrique; Vara, Juan Ángel Fresno; Sánchez-Navarro, Iker; Hernández-Cortes, Ginés; Zamora, Pilar; Pérez-Fernández, Elia; Miguel-Martín, María; Suárez, Asunción; Palacios, José; González-Barón, Manuel; Hardisson, David

    2008-01-01

    Background Ovarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies. Despite the improved median overall survival in patients receiving chemotherapy regimens such as paclitaxel and carboplatin combination, relapse still occurs in most advanced diseased patients. Increased angiogenesis is associated with rapid recurrence and decreased survival in ovarian cancer. This study was planned to identify an angiogenesis-related gene expression profile with prognostic value in advanced ovarian carcinoma patients. Methodology/Principal Findings RNAs were collected from formalin-fixed paraffin-embedded samples of 61 patients with III/IV FIGO stage ovarian cancer who underwent surgical cytoreduction and received a carboplatin plus paclitaxel regimen. Expression levels of 82 angiogenesis related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays. A 34-gene-profile which was able to predict the overall survival of ovarian carcinoma patients was identified. After a leave-one-out cross validation, the profile distinguished two groups of patients with different outcomes. Median overall survival and progression-free survival for the high risk group was 28.3 and 15.0 months, respectively, and was not reached by patients in the low risk group at the end of follow-up. Moreover, the profile maintained an independent prognostic value in the multivariate analysis. The hazard ratio for death was 2.3 (95% CI, 1.5 to 3.2; p<0.001). Conclusions/Significance It is possible to generate a prognostic model for advanced ovarian carcinoma based on angiogenesis-related genes using formalin-fixed paraffin-embedded samples. The present results are consistent with the increasing weight of angiogenesis genes in the prognosis of ovarian carcinoma. PMID:19112514

  5. Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation

    PubMed Central

    Sørensen, Belinda Halling; Nielsen, Dorthe; Thorsteinsdottir, Unnur Arna; Hoffmann, Else Kay

    2016-01-01

    The leucine-rich repeat containing 8A (LRRC8A) protein is an essential component of the volume-sensitive organic anion channel (VSOAC), and using pharmacological anion channel inhibitors (NS3728, DIDS) and LRRC8A siRNA we have investigated its role in development of Cisplatin resistance in human ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21Waf1/Cip1, Bax, Noxa, MDM2, and activation of Caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter apoptosis, i.e., their p53 and downstream signaling are reduced and caspase activity unaltered following Cisplatin exposure. Reduced LRRC8A expression and VSOAC activity are previously shown to correlate with Cisplatin resistance, and here we demonstrate that pharmacological inhibition and transient knockdown of LRRC8A reduce the protein level of p53, MDM2, and p21Waf1/Cip1 as well as Caspase-9/-3 activation in Cisplatin-sensitive cells. Cisplatin resistance is accompanied by reduction in total LRRC8A expression (A2780) or LRRC8A expression in the plasma membrane (A549). Activation of Caspase-3 dependent apoptosis by TNFα-exposure or hyperosmotic cell shrinkage is almost unaffected by pharmacological anion channel inhibition. Our data indicate 1) that expression/activity of LRRC8A is essential for Cisplatin-induced increase in p53 protein level and its downstream signaling, i.e., Caspase-9/-3 activation, expression of p21Waf1/Cip1 and MDM2; and 2) that downregulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A-containing channels is upstream to apoptotic volume decrease as hypertonic cell shrinkage induces apoptosis independent of the presence of LRRC8A. PMID:26984736

  6. Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

    PubMed Central

    Soriano, Amata Amy; Monticelli, Antonella; Affinito, Ornella; Cocozza, Sergio; Zannini, Mariastella

    2016-01-01

    Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma. PMID:27259239

  7. Mucin-1 and its relation to grade, stage and survival in ovarian carcinoma patients

    PubMed Central

    2012-01-01

    Background Mucin-1 is known to be over-expressed by various human carcinomas and is shed into the circulation where it can be detected in patient’s serum by specific anti-Mucin-1 antibodies, such as the tumour marker assays CA 15–3 and CA 27.29. The prognostic value of Mucin-1 expression in ovarian carcinoma remains uncertain. One aim of this study was to compare the concentrations of Mucin-1 in a cohort of patients with either benign or malignant ovarian tumours detected by CA 15–3 and CA 27.29. Another aim of this study was to evaluate Mucin-1 expression by immunohistochemistry in a different cohort of ovarian carcinoma patients with respect to grade, stage and survival. Methods Patients diagnosed with and treated for ovarian tumours were included in the study. Patient characteristics, histology including histological subtype, tumour stage, grading and follow-up data were available from patient records. Serum Mucin-1 concentrations were measured with ELISA technology detecting CA 15–3 and CA 27.29, Mucin-1 tissue expression was determined by immunohistochemistry using the VU4H5 and VU3C6 anti-Mucin-1 antibodies. Statistical analysis was performed by using SPSS 18.0. Results Serum samples of 118 patients with ovarian tumours were obtained to determine levels of Mucin-1. Median CA 15–3 and CA 27.29 concentrations were significantly higher in patients with malignant disease (p< 0.001) than in patients with benign disease. Paraffin-embedded tissue of 154 patients with ovarian carcinoma was available to determine Mucin-1 expression. The majority of patients presented with advanced stage disease at primary diagnosis. Median follow-up time was 11.39 years. Immunohistochemistry results for VU4H5 showed significant differences with respect to tumour grade, FIGO stage and overall survival. Patients with negative expression had a mean overall survival of 9.33 years compared to 6.27 years for patients with positive Mucin-1 expression. Conclusions This study found

  8. PARP Inhibitors for Recurrent Ovarian Carcinoma: Current Treatment Options and Future Perspectives

    PubMed Central

    Sehouli, J.; Braicu, E. I.; Chekerov, R.

    2016-01-01

    More than simply a promising management option, PARP inhibitors can be regarded as a milestone in the development of personalised treatment of recurrent ovarian carcinoma. Their mechanism of action, known as “synthetic lethality”, is dependent on functional differences of the DNA repair mechanisms of healthy cells and tumour cells; cells that repair DNA damage less efficiently are particularly sensitive to PARP inhibitors. Olaparib, licensed for use this year, is the best-studied PARP inhibitor used for treatment of high-grade serous ovarian carcinoma (HGSC). The efficacy of PARP inhibitors appears to be increased when used in combination with other treatments. PMID:26941449

  9. Magnetic Resonance Imaging Characteristics of Ovarian Clear Cell Carcinoma

    PubMed Central

    Wang, Wei; Ding, Jianhui; Zhu, Xiaoli; Li, Yuan; Gu, Yajia; Peng, Weijun

    2015-01-01

    Purpose To probe the magnetic resonance imaging (MRI) features of ovarian clear cell carcinoma (OCCC). Methods This study retrospectively collected MRI data for 21 pathology-confirmed OCCCs from 19 female patients. The MRI findings were analyzed to determine the tumor size, shape/edge, shape and number of protrusions within the cyst, cystic or necrotic components, signal intensity (SI) and enhancement features. Results The age of the 19 patients ranged from 28 to 63 years (mean age: 53 years). Unilateral tumors were found in 17 patients (17/19, 89%); the average size of all tumors was 10.8 cm. The tumors on MRI were classified into two categories: (a) “cystic adnexal mass with solid protrusions” in 12 (57%) and (b) “solid adnexal mass with cystic areas or necrosis” in 9 (43%). For group a, high to very high SI was observed for most tumors (10/12, 83%) on T1-weighted images (T1WIs), and very high SI was observed on T2-weighted images (T2WIs) for all 12 tumors. Most solid protrusions were irregular and few in number and exhibited heterogeneous intermediate SI on T1WIs and T2WIs and prolonged enhanced SI in the contrast study. All 9 OCCCs in group b were predominantly solid masses with unequally sized necrotic or cystic areas in which some cysts were located at the periphery of the tumor (4/9, 44%). The solid components in all 9 tumors showed iso- or slightly high SI on T1WIs, heterogeneous iso-high SI on T2WIs and heterogeneous prolonged enhancement. According to FIGO classification, 14 tumors (14/19, 74%) were stages I-II, and 5 (5/19, 26%) were stages III-IV. Conclusions On MRI, OCCCs present as large unilateral multilocular or unilocular cystic masses with irregular intermediate SI solid protrusions or predominantly solid masses with cysts or necrosis at an early FIGO stage. PMID:26161555

  10. Low-Stage High-Grade Serous Ovarian Carcinomas: Support for an Extraovarian Origin.

    PubMed

    Morency, Elizabeth; Leitao, Mario M; Soslow, Robert A

    2016-05-01

    Many adnexal high-grade serous carcinomas (HGSCs) may derive from microscopic precursors in the fallopian tube. By studying a series of low-stage ovarian carcinomas, we anticipated that HGSCs would be distributed in a pattern suggesting secondary involvement, helping to indirectly validate the fallopian tube origin theory, and that most ovarian carcinomas other than serous carcinomas would demonstrate features consistent with derivation from precursors located in or transplanted to the ovary. Seventy-six patients with low-stage (FIGO I/II) sporadic ovarian carcinoma who underwent primary surgical management at Memorial Sloan Kettering Cancer Center from 1980 to 2000 were included in the study. Histologic type was assigned using Gilks' criteria. Similar to the approach taken when distinguishing primary and metastatic mucinous or endometrioid carcinoma involving ovary, cases interpreted as showing a "primary" pattern of ovarian involvement had ≥3 of the following features: unilateral tumor, size >12 cm, no surface involvement, no multinodularity, and no destructive stromal invasion. All other cases were considered to show a "metastatic" pattern of ovarian involvement. Cases were evaluated for p53 and WT-1 expression, using standard techniques on a tissue microarray. TP53 gene sequencing was also performed. Cases comprised HGSC (n=22), endometrioid carcinoma (n=30), clear cell carcinoma (n=13), and mucinous carcinoma (n=11). HGSCs displayed substantially more "metastatic features" than the non-HGSC group and a mean overall size that was smaller (8.85 vs. 14.1 cm). Statistically significant differences were found for bilaterality (63% vs. 7.3%), P=0.0001; multinodularity (55% vs. 7.3%), P=0.0001; tumor size, P=0.003; and surface involvement (50% vs. 13%), P=0.002. Five of 22 (23%) of HGSCs showed a "primary pattern" of ovarian involvement. There were no significant differences between these cases and "metastatic pattern" HGSCs when comparing morphology

  11. Mammary serine protease inhibitor and CD138 immunohistochemical expression in ovarian serous and clear cell carcinomas.

    PubMed

    Hasby, Eiman Adel

    2016-04-01

    This study aims to investigate the immunohistochemical expression of mammary serine protease inhibitor (maspin) and CD138 in primary ovarian high-grade serous carcinomas (HGSC) as compared to low-grade serous carcinomas (LGSC) and clear cell carcinomas and investigate if the studied markers have a correlation to International Federation of Gynaecology and Obstetrics (FIGO) stage, Ki67 proliferation index, and to each other. Maspin cellular location varied significantly between studied groups with only nuclear expression seen in 46.7 % of LGSC group, mixed nuclear and cytoplasmic in 13.3, 28.6, and 20 % of LGSC, HGSC, and clear cell carcinoma, respectively, and was only cytoplasmic in 26.7, 71.4, and 80 % of LGSC, HGSC, and clear cell carcinoma, respectively. Mean maspin and CD138 counts were significantly higher in HGSC and clear cell carcinoma compared to LGSC. Both maspin and CD138 scores varied significantly between studied groups and were positively correlated with adverse prognostic factors in studied carcinomas including FIGO stage and Ki67 proliferation index. Besides, both maspin and CD138 had significant correlation to each other. These findings suggest that epithelial cytoplasmic expression of maspin and CD138 may have a significant role in tumorigenesis in ovarian high-grade serous carcinomas and clear cell carcinomas; these markers may regulate tumor cell proliferation, and their significant correlation to each other may suggest that CD138 probably induces maspin expression to protect tumor growth factors from being lysed by proteolytic enzymes.

  12. High grade serous ovarian carcinoma with serous tubal intraepithelial carcinoma in a case presented with atypical glandular cell favor neoplasm cervical cytology and dermatomyositis.

    PubMed

    Hong, Mun-Kun; Lee, Ming-Hsun; Ding, Dah-Ching; Chu, Sung-Chao; Chu, Tang-Yuan

    2015-04-01

    This report describes a case of serous ovarian carcinoma with occult serous tubal intraepithelial carcinoma (STIC), which presented as atypical glandular cells favor neoplasia (AGC-FN) with Pap cytology and dermatomyositis. A 48-year-old woman presented with symptoms of dermatomyositis. An AGC-FN result from a Pap smear, with an absence of a cervical or endometrial lesion was noted. After cancer surveillance, ovarian high grade serous carcinoma associated with serous tubal intraepithelial carcinoma was diagnosed. Two weeks following surgical excision of the carcinoma, dramatic remission of the dermatomyositis symptoms was evident. The patient had serous carcinoma of the ovary with tubal STIC, which presented as dermatomyositis. The AGC-FN identified from a Pap smear hinted at a diagnosis of ovarian carcinoma. These presentations point to an occult malignancy in the genital tract and demand careful diagnostic workup. Copyright © 2015. Published by Elsevier B.V.

  13. Identification of novel candidate plasma metabolite biomarkers for distinguishing serous ovarian carcinoma and benign serous ovarian tumors

    PubMed Central

    Buas, Matthew F.; Gu, Haiwei; Djukovic, Danijel; Zhu, Jiangjiang; Drescher, Charles W.; Urban, Nicole; Raftery, Daniel; Li, Christopher I.

    2017-01-01

    OBJECTIVE Serous ovarian carcinoma (OC) represents a leading cause of cancer-related death among U.S. women. Non-invasive tools have recently emerged for discriminating benign from malignant ovarian masses, but evaluation remains ongoing, without widespread implementation. In the last decade, metabolomics has matured into a new avenue for cancer biomarker development. Here, we sought to identify novel plasma metabolite biomarkers to distinguish serous ovarian carcinoma and benign ovarian tumor. METHODS Using liquid chromatography-mass spectrometry, we conducted global and targeted metabolite profiling of plasma isolated at the time of surgery from 50 serous OC cases and 50 serous benign controls. RESULTS Global lipidomics analysis identified 34 metabolites (of 372 assessed) differing significantly (P<0.05) between cases and controls in both training and testing sets, with 17 candidates satisfying FDR q<0.05, and two reaching Bonferroni significance. Targeted profiling of ~150 aqueous metabolites identified a single amino acid, alanine, as differentially abundant (P<0.05). A multivariate classification model built using the top four lipid metabolites achieved an estimated AUC of 0.85 (SD=0.07) based on Monte Carlo cross validation. Evaluation of a hybrid model incorporating both CA125 and lipid metabolites was suggestive of increased classification accuracy (AUC=0.91, SD=0.05) relative to CA125 alone (AUC=0.87, SD=0.07), particularly at high fixed levels of sensitivity, without reaching significance. CONCLUSIONS Our results provide insight into metabolic changes potentially correlated with the presence of serous OC versus benign ovarian tumor and suggest that plasma metabolites may help differentiate these two conditions. PMID:26521694

  14. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    SciTech Connect

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  15. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    SciTech Connect

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  16. [Expression Level of Membrane-associated Proteins Numb in Epithelial Ovarian Carcinoma and Its Relationship with Ovarian Cancer Stem Cell Markers CD117, CD133, ALDH1.

    PubMed

    Jing, Hong; Liu, Xiao-Yu; Chen, Ya-Li; Bai, Li-Ping; Zheng, Ai

    2016-11-01

    To explore the expression level of membrane-associated protein Numb in epithelial ovarian carcinoma and its relationship with ovarian cancer stem cell markers CD117,CD133,acetaldehyde dehydrogenase 1(ALDH1). A total of 136 patients who had ovarian tumors and 22 patients who had not ovarian tumors in Department of Gynaecology and Obstetrics,West China Second University Hospital,Sichuan University were chosen as the study subjects.According to the histopathologic examination results,they were divided into epithelial ovarian carcinoma group (n=92),ovarian borderline tumor group (n=23),ovarian benign tumor group (n=21) and normal ovary group (n=22).Expression levels of Numb protein,CD117,CD133 and ALDH1 in ovarian tissue were detected by immunohistochemical SP method and these several kinds of protein expression differences and correlation statistical analysis were performend. 1 The positive expression rate of Numb protein in epithelial ovarian carcinoma group was higher than that in benign tumor or normal ovary group,also Numb protein positive expression rate in ovarian borderline tumor group was higher than that in normal ovary group,and the differences were statistically significant (P<0.05).2 Numb protein positive expression rate in ovarian tissue in patients with epithelial ovarian carcinoma FIGO stage1-2 was lower than that in stage 3-4,also the same in no lymph nodes metastasis compared with lymph nodes invasion,and the differences of positive expression rate were statistically significant (P<0.05).While there were no significant differences among different age,histopathological types,pathological grades and residual tumor size (P>0.05).3 There was no correlation between Numb protein and CD117 and CD133 positive expression rate in epithelial ovarian carcinoma tissue [correlation coefficient (r)=0.116,P=0.261; r=0.083,P=0.425].However,the positive expression rate of Numb protein and ALDH1 was positively correlated (r=0.296,P=0.261). The expression of Numb protein

  17. Ovarian macrocysts and gonadotrope-ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease.

    PubMed

    Salenave, Sylvie; Bernard, Valérie; Do Cao, Christine; Guignat, Laurence; Bachelot, Anne; Leboulleux, Sophie; Droumaguet, Céline; Bry-Gauillard, Hélène; Pierre, Peggy; Crinière, Lise; Santulli, Pietro; Touraine, Philippe; Chanson, Philippe; Schlumberger, Martin; Maiter, Dominique; Baudin, Eric; Young, Jacques

    2015-02-01

    Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown. To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women. We studied 21 premenopausal women (ACC: n=13; CD: n=8; median age 33 years, range 18-45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5-6 g/day). Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E2), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy. In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3-36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1-4) and the median diameter of the largest cysts was 50 mm (range: 26-90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E2 levels were also increased, and SHBG levels rose markedly. Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed. © 2015 European Society of Endocrinology.

  18. Epithelial ovarian carcinoma diagnosis by desorption electrospray ionization mass spectrometry imaging

    PubMed Central

    Dória, Maria Luisa; McKenzie, James S.; Mroz, Anna; Phelps, David L.; Speller, Abigail; Rosini, Francesca; Strittmatter, Nicole; Golf, Ottmar; Veselkov, Kirill; Brown, Robert; Ghaem-Maghami, Sadaf; Takats, Zoltan

    2016-01-01

    Ovarian cancer is highly prevalent among European women, and is the leading cause of gynaecological cancer death. Current histopathological diagnoses of tumour severity are based on interpretation of, for example, immunohistochemical staining. Desorption electrospray mass spectrometry imaging (DESI-MSI) generates spatially resolved metabolic profiles of tissues and supports an objective investigation of tumour biology. In this study, various ovarian tissue types were analysed by DESI-MSI and co-registered with their corresponding haematoxylin and eosin (H&E) stained images. The mass spectral data reveal tissue type-dependent lipid profiles which are consistent across the n = 110 samples (n = 107 patients) used in this study. Multivariate statistical methods were used to classify samples and identify molecular features discriminating between tissue types. Three main groups of samples (epithelial ovarian carcinoma, borderline ovarian tumours, normal ovarian stroma) were compared as were the carcinoma histotypes (serous, endometrioid, clear cell). Classification rates >84% were achieved for all analyses, and variables differing statistically between groups were determined and putatively identified. The changes noted in various lipid types help to provide a context in terms of tumour biochemistry. The classification of unseen samples demonstrates the capability of DESI-MSI to characterise ovarian samples and to overcome existing limitations in classical histopathology. PMID:27976698

  19. Identification and Characterization of Ovarian Carcinoma Peptide Epitopes Recognized by Cytotoxic T Lymphocytes

    DTIC Science & Technology

    2007-11-01

    β1 and 2 in ovarian carcinoma. Clin. Cancer Res. 5:2498-2505. 23. Toutirais, O., P. Chartier , D. Dubois, F. Bouet, J. Leveque, V. Catros-Quemener...immune surveillance. Cancer Cell 8:369–380 62. Toutirais O, Chartier P, Dubois D, Bouet F, Leveque J, Catros- Quemener V, Genetet N (2003) Constitutive

  20. Identification and Characterization of Ovarian Carcinoma Peptide Epitopes Recognized by Cylotoxic T Lymphocytes

    DTIC Science & Technology

    2008-11-01

    transforming growth factor β1 and 2 in ovarian carcinoma. Clin. Cancer Res. 5:2498-2505. 23. Toutirais, O., P. Chartier , D. Dubois, F. Bouet, J... Chartier P, Dubois D, Bouet F, Leveque J, Catros- Quemener V, Genetet N (2003) Constitutive expression of TGF- beta1, interleukin-6 and interleukin-8 by

  1. High dose intensity combination chemotherapy for advanced epithelial ovarian carcinoma: results of a pilot study.

    PubMed Central

    Sweetenham, J. W.; McKendrick, J. J.; Jones, D. H.; Whitehouse, J. M.; Williams, C. J.

    1990-01-01

    Retrospective studies have recently demonstrated a significant correlation between dose intensity of chemotherapy and response rates and survival in various diseases including epithelial ovarian carcinoma. As part of a proposed randomised trial to assess the effect of dose intensity on outcome in ovarian carcinoma, a pilot study has been undertaken to determine the toxicity and efficacy of the high intensity therapy. Nineteen patients with advanced ovarian carcinoma received initial treatment with cisplatin 120 mg m-2 i.v. day 1, and cyclophosphamide 1,000 mg-2 i.v. day 1, given at 21-day intervals for six cycles. The average relative dose intensity of this therapy is 1.14 when compared with the CHAP regimen. Severe toxicity was experienced by most patients. The median received average relative dose intensity was 0.90, with only one patient receiving treatment to the proposed intensity. Randomised studies of the effect of dose intensity in ovarian carcinoma are essential, but an initial step must be to assess whether the proposed high dose treatment can be delivered. PMID:2155645

  2. Erlotinib in Treating Patients With Advanced Non-Small Cell Lung Cancer, Ovarian Cancer, or Squamous Cell Carcinoma of the Head and Neck

    ClinicalTrials.gov

    2013-01-08

    Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx

  3. The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis.

    PubMed

    Hofmann, Nicole A; Yang, Jiang; Trauger, Sunia A; Nakayama, Hironao; Huang, Lan; Strunk, Dirk; Moses, Marsha A; Klagsbrun, Michael; Bischoff, Joyce; Graier, Wolfgang F

    2015-08-01

    Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and GPR55 agonist, L-α-lysophosphatidylinositol (LPI), into the circulation. We aimed to assess the involvement of this agonist and its receptor in ovarian cancer angiogenesis. Secretion of LPI by three ovarian cancer cell lines (OVCAR-3, OVCAR-5 and COV-362) was tested by mass spectrometry. Involvement of cancer cell-derived LPI on angiogenesis was tested in the in vivo chicken chorioallantoic membrane (CAM) assay along with the assessment of the effect of LPI on proliferation, network formation, and migration of neonatal and adult human endothelial colony-forming cells (ECFCs). Engagement of GPR55 was verified by using its pharmacological inhibitor CID16020046 and diminution of GPR55 expression by four different target-specific siRNAs. To study underlying signal transduction, Western blot analysis was performed. Ovarian carcinoma cell-derived LPI stimulated angiogenesis in the CAM assay. Applied LPI stimulated proliferation, network formation, and migration of neonatal ECFCs in vitro and angiogenesis in the in vivo CAM. The pharmacological GPR55 inhibitor CID16020046 inhibited LPI-stimulated ECFC proliferation, network formation and migration in vitro as well as ovarian carcinoma cell- and LPI-induced angiogenesis in vivo. Four target-specific siRNAs against GPR55 prevented these effects of LPI on angiogenesis. These pro-angiogenic effects of LPI were transduced by GPR55-dependent phosphorylation of ERK1/2 and p38 kinase. We conclude that inhibiting the pro-angiogenic LPI/GPR55 pathway appears a promising target against angiogenesis in ovarian carcinoma. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  4. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts.

    PubMed

    Valoti, G; Nicoletti, M I; Pellegrino, A; Jimeno, J; Hendriks, H; D'Incalci, M; Faircloth, G; Giavazzi, R

    1998-08-01

    The antitumor activity of ecteinascidin (ET)-743, a novel marine natural product, was evaluated against a panel of human ovarian carcinoma xenografts characterized by different malignant behaviors and drug responsiveness in nude mice. These tumor models included three xenografts transplanted s.c. (HOC18, HOC22-S, and MNB-PTX-1) into nude mice, representing different levels of sensitivity to cisplatinum (DDP), which was used as reference drug for ovarian carcinoma, and two other xenografts (HOC22 and HOC8), which are highly malignant in the peritoneal cavity of nude mice, representing the growth pattern of this neoplasm. At the maximum tolerated dose of 0.2 mg/kg using an intermittent schedule of one i.v. injection every 4 days, ET-743 was highly active against HOC22-S (sensitive to DDP), inducing long-lasting, complete regressions, and against HOC18 (marginally sensitive to DDP), inducing partial tumor regressions. Moreover, significant growth delay was observed in mice bearing late-stage HOC18 tumor (400-mg tumor weight; nonresponsive to DDP). ET-743, however, was not active against MNB-PTX-1, a tumor that is highly resistant to chemotherapy, including DDP. In the i.p. ovarian carcinoma xenograft model, ET-743 at the maximum tolerated dose induced complete tumor remissions in all mice bearing HOC22 tumor, with 25% histopathologically confirmed cures, and produced marginal tumor growth delay against HOC8. These results indicate that ET-743 is a potent drug against ovarian carcinoma xenografts, being equally as active or more efficacious than DDP in the same tumor line. Our findings with human ovarian carcinoma xenografts justify clinical assessment of this drug with this tumor target.

  5. MV-NIS or Investigator's Choice Chemotherapy in Treating Patients With Ovarian, Fallopian, or Peritoneal Cancer

    ClinicalTrials.gov

    2017-04-19

    Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Clear Cell Tumor; Malignant Ovarian Endometrioid Tumor; Malignant Ovarian Serous Tumor; Ovarian Seromucinous Carcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  6. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas

    PubMed Central

    Zang, Xingxing; Sullivan, Peggy S; Soslow, Robert A; Waitz, Rebecca; Reuter, Victor E; Wilton, Andrew; Thaler, Howard T; Arul, Manonmani; Slovin, Susan F; Wei, Joyce; Spriggs, David R; Dupont, Jakob; Allison, James P

    2010-01-01

    B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and

  7. Ovarian carcinoma apparently confined to the ovaries--the accuracy of surgical staging in Israel.

    PubMed

    Menczer, J; Chetrit, A; Sadetzki, S

    2009-01-01

    In order to allot an ovarian malignancy to FIGO Stage I, in addition to abdominal exploration and the basic operation, it is also necessary to do peritoneal washings for cytological examination, random peritoneal biopsies (including diaphragmatic assessment) and omental and retroperitoneal lymph node assessment. The aim of the study was to assess the accuracy of surgical staging of ovarian carcinoma classified as Stage I in Israel. Included were all patients with histologically confirmed epithelial ovarian carcinoma (EOC) classified as Stage I in a data base of a nationwide incidence case control epidemiological study of ovarian carcinoma conducted in Israeli Jewish women during the period 1994-1999. Surgical staging data of these patients were retrieved from pathological reports, and from clinical records when available. A total of 182 EOC patients were classified as Stage I. About 86% of the patients underwent hysterectomy and bilateral salpingo-oophorectomy. The most commonly performed staging procedure was omental assessment (85.2%) while peritoneal biopsy was the least common one (34.1%). In 17 (9.3%) of the patients none of the staging procedures were done and only 34 (18.7%) had optimal staging. Although the data are from a decade ago, they seem to indicate the need for an increased awareness of the necessity for accurate surgical staging of tumors apparently confined to the ovaries since it can identify a group of patients who require surgical therapy alone and who can be spared the complications, inconvenience and cost of adjuvant chemotherapy.

  8. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma.

    PubMed

    Zhang, G Y; Ahmed, N; Riley, C; Oliva, K; Barker, G; Quinn, M A; Rice, G E

    2005-01-17

    The peroxisome proliferator-activated receptors (PPARs) belong to a subclass of nuclear hormone receptor that executes important cellular transcriptional functions. Previous studies have demonstrated the expression of PPARgamma in several tumours including colon, breast, bladder, prostate, lung and stomach. This study demonstrates the relative expression of PPARgamma in normal ovaries and different pathological grades of ovarian tumours of serous, mucinous, endometrioid, clear cell and mixed subtypes. A total of 56 ovarian specimens including 10 normal, eight benign, 10 borderline, seven grade 1, nine grade 2 and 12 grade 3 were analysed using immunohistochemistry. Immunoreactive PPARgamma was not expressed in normal ovaries. Out of eight benign and 10 borderline tumours, only one tumour in each group showed weak cytoplasmic PPARgamma expression. In contrast, 26 out of 28 carcinomas studied were positive for PPARgamma expression with staining confined to cytoplasmic and nuclear regions. An altered staining pattern of PPARgamma was observed in high-grade ovarian tumours with PPARgamma being mostly localized in the nuclei with little cytoplasmic immunoreactivity. On the other hand, predominant cytoplasmic staining was observed in lower-grade tumours. Significantly increased PPARgamma immunoreactivity was observed in malignant ovarian tumours (grade 1, 2 and 3) compared to benign and borderline tumours (chi2 = 48.80, P < 0.001). Western blot analyses showed significant elevation in the expression of immunoreactive PPARgamma in grade 3 ovarian tumours compared with that of normal ovaries and benign ovarian tumours (P < 0.01). These findings suggest an involvement of PPARgamma in the onset and development of ovarian carcinoma and provide an insight into the regulation of this molecule in the progression of the disease.

  9. Minimal-change disease as a paraneoplastic syndrome in a patient with ovarian carcinoma.

    PubMed

    González-Fontal, Guido R; Restrepo, Juan G; Henao-Martínez, Andrés F

    2011-12-01

    Minimal-change disease (MCD) is an exceptional paraneoplastic presentation. We are describing the case of an ovarian paraneoplastic nephrotic syndrome. The kidney biopsy was consistent with MCD. Steroids and immunosuppressive therapy were given with no change in the nephrotic-range proteinuria. A complete resolution of the nephrotic syndrome was soon observed with improvement of her clinical condition after five cycles of chemotherapy with paclitaxel and carboplatin and tumor-debulking surgery. Ovarian carcinoma paraneoplastic nephrotic syndrome secondary to MCD is an extremely rare event, which is important to recognize since it is responsive to the standard chemotherapy.

  10. Large-scale genomic analysis of ovarian carcinomas.

    PubMed

    Gorringe, Kylie L; Campbell, Ian G

    2009-04-01

    Epithelial ovarian cancers are typified by frequent genomic aberrations that have been difficult to unravel. Recently, high-resolution array technologies have provided the first glimpse of the remarkable complexity of these aberrations with some ovarian cancers containing hundreds of copy number breakpoints, micro-deletions and amplifications. Many of these alterations contain cancer-related genes suggesting that the majority is disease-associated and not just the product of random genomic instability. Future developments such as next-generation sequencing and integrated analysis of data from multiple array platforms on large numbers of samples are poised to revolutionize our understanding of this complex disease.

  11. Relation between hyaluronan synthesis and cell morphology in ovarian clear cell carcinomas.

    PubMed

    Kato, Noriko; Shibata, Kasumi; Uchigasaki, Shinya; Kurose, Akira

    2016-04-01

    Ovarian clear cell carcinomas often show a spherule-like mucoid stroma. In ascitic fluid, they form spheroids with a hollow acellular space. In spite of the absence of stromal cells, both the mucoid stroma and hollow spheroids contain abundant extracellular matrix, and one of the major components is hyaluronan. It has been suggested that tumor-derived hyaluronan plays a significant role in the formation of these structures. To clarify this, a hyaluronan inhibition assay was performed on HAC-2, a clear cell carcinoma cell line, in vitro. When hyaluronan synthesis was inhibited by 4-methylumbelliferone, HAC-2 failed to show the spherule-like accumulation of hyaluronan or hollow spheroids. Inhibition of hyaluronan synthesis was associated with the reduction of cell growth. Analysis of 28 archival ascites cytology specimens showed that clear cell carcinomas expressed hyaluronan more frequently than serous carcinomas (11 of 14 vs 3 of 14, respectively, P < 0.05). All of these facts indicate that tumor-derived hyaluronan is essential for the formation of the mucoid stroma or hollow spheroids, and that hyaluronan is also involved in the regulation of cell growth in ovarian clear cell carcinomas. The inhibition of hyaluronan synthesis could be a potential adjunctive therapy for refractory clear cell carcinomas outside the ovary. © 2016 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  12. Expression and clinical role of protein of regenerating liver (PRL) phosphatases in ovarian carcinoma.

    PubMed

    Reich, Reuven; Hadar, Shany; Davidson, Ben

    2011-02-11

    The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was analyzed in 157 tumors by Western blotting. PRL-1 mRNA levels were significantly higher in effusions compared to solid tumors (p < 0.001), and both PRL-1 and PRL-2 were overexpressed in pleural compared to peritoneal effusions (p = 0.001). PRL-3 protein expression was significantly higher in primary diagnosis pre-chemotherapy compared to post-chemotherapy disease recurrence effusions (p = 0.003). PRL-1 mRNA expression in effusions correlated with longer overall survival (p = 0.032), and higher levels of both PRL-1 and PRL-2 mRNA correlated with longer overall survival for patients with pre-chemotherapy effusions (p = 0.022 and p = 0.02, respectively). Analysis of the effect of laminin on PRL-3 expression in ovarian carcinoma cells in vitro showed dose-dependent PRL-3 expression in response to exogenous laminin, mediated by Phospholipase D. In contrast to previous studies associating PRL-3 with poor outcome, our data show that PRL-3 expression has no clinical role in ovarian carcinoma, whereas PRL-1 and PRL-2 expression is associated with longer survival, suggesting that PRL phosphatases may be markers of improved outcome in this cancer.

  13. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma.

    PubMed

    Kurman, R J

    2013-12-01

    A new paradigm for the pathogenesis of ovarian cancer has recently been proposed which helps to explain persistent problems in describing the development and diverse morphology of these neoplasms. The paradigm incorporates recent advances in our understanding of the molecular pathogenesis of epithelial 'ovarian' cancer with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies led to the development of a dualistic model that divides all the various histologic types of epithelial ovarian carcinomas into two broad categories designated 'type I' and 'type II'. The prototypic type I tumor is low-grade serous carcinoma and the prototypic type II tumor is high-grade serous carcinomas (HGSCs). As the serous tumors comprise ∼70% of all epithelial ovarian tumors and account for the majority of deaths, the serous tumors will be the subject of this review. There are marked differences between the low-grade and high-grade serous tumors. Briefly, the former are indolent, present in stage I (tumor confined to the ovary) and develop from well-established precursors, so-called 'atypical proliferative (borderline) tumors,' which are characterized by specific mutations, including KRAS, BRAF and ERBB2; they are relatively genetically stable. In contrast, HGSCs are aggressive, present in the advanced stage, and develop from intraepithelial carcinomas in the fallopian tube. They harbor TP53 mutations in over 95% of cases, but rarely harbor the mutations detected in the low-grade serous tumors. At the time of diagnosis they demonstrate marked chromosomal aberrations but over the course of the disease these changes remain relatively stable. Along with the recent advances in understanding the molecular pathogenesis of these tumors, studies have demonstrated that the long sought for precursor of ovarian HGSC appears to develop from an occult intraepithelial carcinoma in the fimbrial region of the fallopian tube designated 'serous tubal

  14. β-Catenin Expression Pattern in Stage I and II Ovarian Carcinomas

    PubMed Central

    Gamallo, Carlos; Palacios, José; Moreno, Gema; Calvo de Mora, Jorge; Suárez, Asunción; Armas, Alvaro

    1999-01-01

    The immunohistochemical expression pattern of β-catenin has been correlated with β-catenin gene mutations, clinicopathological features, and disease outcome in 69 stage I and II ovarian carcinomas. β-Catenin expression was localized in the nuclei, in addition to the cytoplasm and membrane, in 11 tumors (16%): nine endometrioid carcinomas with widespread nuclear expression and two serous carcinomas with focal nuclear expression. The remaining 58 carcinomas (84%) only had membranous β-catenin expression. All but one of the endometrioid carcinomas with nuclear β-catenin expression had considerable squamous metaplasia, and five of these cases had large areas of endometrioid tumor of low malignant potential. In addition, β-catenin nuclear expression was observed in atypical epithelial cells in endometriotic glands adjacent to an endometrioid carcinoma. Sequencing was performed on 25 tumors and corresponding normal tissue: all 13 endometrioid tumors as well as 12 carcinomas of other histological types (four serous, two clear cell, two mucinous, and two mixed). There were oncogenic mutations in the phosphorylation sequence for GSK-3β in exon 3 of the β-catenin gene in seven endometrioid carcinomas with β-catenin nuclear expression. Three mutations affected codon 32 (D32G, D32Y, and D32Y), one affected codon 33 (S33C), two affected codon 37 (S37C and S37F), and one affected codon 41 (T41A). No mutations were observed in the other 18 carcinomas analyzed, comprising two endometrioid and two serous carcinomas with β-catenin nuclear expression, and 14 carcinomas of different histological types with only membranous expression. In the univariate and multivariate survival analyses, β-catenin nuclear expression was selected as an indicator of good prognosis, because no patient whose tumor expressed β-catenin in the nuclei showed relapses or died, in contrast to the 19 relapses and deaths among patients with tumors that only had β-catenin membranous expression

  15. STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

    PubMed Central

    Wei, Luwei; Yin, Fuqiang; Zhang, Wei; Li, Li

    2017-01-01

    Abstract Cancer stem cells (CSCs) are considered to be the root of carcinoma relapse and drug resistance in ovarian cancer. Hunting for the potential CSC genes and explain their functions would be a feasible strategy to meet the challenge of the drug resistance in ovarian cancer. In this study, we performed bioinformatic approaches such as biochip data extraction and pathway enrichment analyses to elucidate the mechanism of the CSC genes in regulation of drug resistance. Potential key genes, integrins, were identified to be related to CSC in addition to their associations with drug resistance and prognosis in ovarian cancer. A total of 36 ovarian CSC genes involved in regulation of drug resistance were summarized, and potential drug resistance-related CSC genes were identified based on 3 independent microarrays retrieved from the Gene Expression Omnibus (GEO) Profiles. Pathway enrichment of CSC genes associated with drug resistance in ovarian cancer indicated that focal adhesion signaling might play important roles in CSC genes-mediated drug resistance. Integrins are members of the adhesion molecules family, and integrin subunit alpha 1, integrin subunit alpha 5, and integrin subunit alpha 6 (ITGA6) were identified as central CSC genes and their expression in side population cells, cisplatin-resistant SKOV3 (SKOV3/DDP2) cells, and cisplatin-resistant A2780 (A2780/DDP) cells were dysregulated as measured by real-time quantitative polymerase chain reaction. The high expression of ITGA6 in 287 ovarian cancer patients of TCGA cohort was significantly associated with poorer progression-free survival. This study provide the basis for further understanding of CSC genes in regulation of drug resistance in ovarian cancer, and integrins could be a potential biomarker for prognosis of ovarian cancer. PMID:28328815

  16. [Risk factors of endometriosis associated ovarian carcinoma in women aged 45 years and older].

    PubMed

    He, Z X; Wang, S; Li, Z F; Zhu, L; Leng, J H; Lang, J H

    2017-05-25

    Obiective: To explore the risk factors of endometriosis-associated ovarian cancer (EAOC) in women with ovarian endometriosis aged 45 years and older in China. Methods: The medical records of total 1 038 women aged 45 years and older with a surgicopathological diagnosis of ovarian endometriosis treated at Peking Union Medical College Hospital from December 1994 to December 2014 were reviewed. Histology evaluation determined ovarian endometriosis with (n=30) or without (n=1 008) ovarian cancer. Results: (1) There were 30 (2.9%, 30/1 018) cases confirmed as having EAOC. Clear cell carcinoma (63.3%, 17/30) and endometrioid adenocarcinoma (23.3%, 7/30) were commonly observed subtypes and 70.0% of EAOC patients were at stage Ⅰ. (2) Compared women with ovarian endometriosis in the same age group, patients with EAOC were older (50.8 vs 48.5 years, P=0.002). There were more in postmenopausal status at diagnosis of EAOC (P<0.01). There were more found with a mass ≥8 cm (P<0.01). Women with EAOC had higher prevalence of coexisting endometrial disorders (P=0.003). No differences were found in preoperative CA(125) value and infertile or nulliparous women (P>0.05). Conclusions: For women with ovarian endometriosis aged 45 years and older, the subgroup of patients characterized by postmenopausal status and ovarian endometrioma (≥8 cm) have a higher risk of EAOC. Active intervention or intensive follow-up should be considered for this population group, especially for those concurrent with endometrial disorders.

  17. Characterization of human ovarian carcinomas in a SCID mouse model.

    PubMed

    Xu, Y; Silver, D F; Yang, N P; Oflazoglu, E; Hempling, R E; Piver, M S; Repasky, E A

    1999-02-01

    This study characterizes a murine model which is promising for the study of the growth and natural history of ovarian cancer and for testing of new therapies for its treatment. Intact portions of 20 different human ovarian cancer surgical specimens were implanted in over 60 severe combined immunodeficient (SCID) mice using techniques previously developed in our laboratory. Growth of xenografts was evaluated by gross examination and histopathologic analysis. Confirmation of the human origin of the tumor outgrowth was obtained using in situ hybridization analysis. By histological evaluation, all of the patients' tumors showed evidence of invasive growth in at least 1 of the mice implanted with portions of each surgical specimen and these tumors remained morphologically similar to the parent tumors for a long period of time. Furthermore, 65% (13/20) of the xenografts grew rapidly enough (i.e., reached a diameter of 1-2 cm within 2-6 months) to allow passage to subsequent SCID mice. Among the passaged xenografts, 3 eventually developed metastases in a distribution pattern similar to that of naturally occurring ovarian cancer and 2 developed ascites without evidence of further metastatic spread. Upon evaluation of sera from tumor-bearing mice, human antibodies presumably derived from immunoglobulin-secreting cells present in the original tumor specimen were identified. In support of this, human B cells and plasma cells could be seen within the tumor xenograft for more than 6 months following implantation. In summary, transplantation of surgical specimens from ovarian cancer patients into SCID mice results in an attractive model for the study of the natural history of ovarian cancer and may also be useful for analysis or new experimental therapeutic approaches for the treatment of this disease.

  18. Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy

    ClinicalTrials.gov

    2014-12-29

    Fatigue; Malignant Ovarian Mixed Epithelial Tumor; Neuropathy; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Pain; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

  19. Selective cytotoxicity of indirect nonequilibrium atmospheric pressure plasma against ovarian clear-cell carcinoma.

    PubMed

    Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Hori, Masaru; Kikkawa, Fumitaka

    2014-01-01

    Ovarian clear cell carcinoma (CCC) is a histological type of epithelial ovarian cancer that is less responsive to chemotherapy and associated with a poorer prognosis than serous and endometrioid carcinoma. Non-thermal atmospheric pressure plasma which produces reactive species has recently led to an explosion of research in plasma medicine. Plasma treatment can be applied to cancer treatment to induce apoptosis and tumor growth arrest. Furthermore, recent studies have shown that a medium exposed to plasma also has an anti-proliferative effect against cancer in the absence of direct exposure to plasma. In this study, we confirmed whether this indirect plasma has an anti-tumor effect against CCC, and investigated whether this efficacy is selective for cancer cells. Non-thermal atmospheric pressure plasma induced apoptosis in CCC cells, while human peritoneal mesothelial cells remained viable. Non-thermal atmospheric pressure plasma exhibits selective cytotoxicity against CCC cells which are resistant to chemotherapy.

  20. Ovarian stromal tumor with minor sex cord elements with coexistent endometrial carcinoma.

    PubMed

    Kumar, Sunesh; Mathur, Sandeep; Subbaiah, Murali; Singh, Lavleen

    2013-01-01

    Ovarian stromal tumor with minor sex cord elements is a rare tumor. It is composed of predominantly fibrothecomatous tumor with scattered minor sex cord elements in less than 10% of the tumor area. These tumors may be hormonally active and predispose to carcinoma endometrium. A case of ovarian fibroma-thecoma with minor sex cord elements in which coexistent endometrial carcinoma was also discovered is being reported. Though thecoma may be a predisposing factor for endometrial cancer, meticulous histopathological examination of the ovary may reveal additional sources of estrogen like granulosa cell aggregates as in our patient. Such patients would require long-term follow-up to detect any recurrence of granulosa cell tumor.

  1. Weight change therapy as a potential treatment for end-stage ovarian carcinoma

    PubMed Central

    Oshakbayev, Kuat Pernekulovich; Alibek, Kenneth; Ponomarev, Igor Olegovich; Uderbayev, Nurlybek Nurlanovich; Dukenbayeva, Bibazhar Abayevna

    2014-01-01

    Patient: Female, 41 Final Diagnosis: Ovarian carcinoma Symptoms: Ascites • hepatomegaly • weight loss Medication: — Clinical Procedure: — Specialty: Oncology Objective: Unusual or unexpected effect of treatment Background: The aim of this case report is to present the results of treatment of end-stage ovarian carcinoma in a 41-year-old women using weight loss therapy. Case Report: We describe the case of a female aged 41 years with epithelial invasive ovarian cancer of III–IV stage, T3N2M1. Concurrent diseases were: abdominal carcinomatosis; hepatomegaly; ascites; condition after laparocentesis and skin-abdominal fistula; condition after 6 courses of neo-adjuvant polychemotherapy; hypertension II stage, risk factor of 3–4; dyslipidemia; and metabolic syndrome. A weight loss method based on a very-low-calorie diet and physical activity was used. Body weight was reduced from 74 kg to 53 due to loss of adipose tissue after 6 months of therapy. At the same time, the percentages of water and muscle tissue were increased significantly. While overweight was reducing, clinical, laboratory, and instrumental results were improving. As a result of the weight loss therapy, about ≈100 mm-sized ovarian cancer was transformed into smaller-sized ovarian cysts. Conclusions: An analgesic effect was also achieved without use of narcotic or non-narcotic analgesics. These cyto-reversible processes were documented by laboratory and instrumental data. The mechanisms behind these differences remain to be elucidated. Future research with a larger study cohort and longer follow-up is needed to further investigate the role of caloric restriction diet in cancer cell changes in ovarian cancer. PMID:24847411

  2. Metastatic ovarian serous carcinoma presenting as inflammatory breast cancer: a case report.

    PubMed

    Gingell, Dana; Samuel, Amber; Haynik, Denise; McBee, William; Kelley, Joseph; Zorn, Kristin; Bhargava, Rohit

    2010-05-01

    A 42-year-old woman presented with localized irritation, erythema and sharp pain in the one breast. After unsuccessful treatment for mastitis, an oncology consultation was obtained. A breast biopsy revealed an invasive carcinoma and a diagnosis of inflammatory breast cancer was made. The patient was treated with neo-adjuvant chemotherapy and subsequently underwent bilateral mastectomy. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was also performed at the same time due to the presence of a pelvic mass. Morphologic and immunohistochemical examination of the specimens helped to clarify the correct diagnosis of primary ovarian carcinoma with widespread metastases to bilateral breasts.

  3. Acetaminophen Enhances Cisplatin- and Paclitaxel-mediated Cytotoxicity to SKOV3 Human Ovarian Carcinoma

    PubMed Central

    Wu, Y. Jeffrey; Neuwelt, Alexander J.; Muldoon, Leslie L.; Neuwelt, Edward A.

    2013-01-01

    Background Ovarian cancer is commonly treated with cisplatin/paclitaxel but many tumors become resistant. Acetaminophen reduced glutathione and enhanced chemotherapy efficacy in treating hepatic cancer. The objective of this study was to examine if acetaminophen enhances the cytotoxicity of cisplatin/paclitaxel in ovarian cancer. Materials and Methods SKOV3 human ovarian carcinoma cells in vitro and a subcutaneous tumor nude rat model were used and treated with cisplatin/paclitaxel with or without acetaminophen. Results In vitro, acetaminophen enhanced apoptosis induced by cisplatin and paclitaxel with similar effects on glutathione, reactive oxygen species and mitochondrial membrane potential but different effects on nuclear factor erythroid 2-related factor 2 (NRF2) translocation. In vivo, acetaminophen was uniformly distributed in tissue and significantly reduced hepatic glutathione. Acetaminophen enhanced cisplatin chemotherapeutic effect by reducing tumor recurrence Conclusion Our results suggest that acetaminophen as a chemoenhancing adjuvant could improve the efficacy of cisplatin and paclitaxel in treating patients with ovarian carcinoma and other tumor types. PMID:23749887

  4. Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma

    PubMed Central

    Chene, G.; Ouellet, V.; Rahimi, K.; Barres, V.; Meunier, L.; De Ladurantaye, M.; Provencher, D.; Mes-Masson, A. M.

    2015-01-01

    In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC). We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process. PMID:26504831

  5. Expression of WT1, CA 125, and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary.

    PubMed

    Tornos, Carmen; Soslow, Robert; Chen, Shirley; Akram, Muzaffar; Hummer, Amanda J; Abu-Rustum, Nadeen; Norton, Larry; Tan, Lee K

    2005-11-01

    Metastatic breast carcinoma to the ovary is sometimes difficult to differentiate from primary ovarian carcinoma. This problem is often encountered in breast carcinoma patients who develop adnexal masses. ER and PR can be positive in a high percentage of breast and ovarian carcinomas, and therefore cannot be used in the differential diagnosis of these entities. WT1 and CA125 have been identified as possible markers for ovarian cancer. However, no studies have been done that specifically compare the immunophenotype of breast carcinoma metastatic to ovary with that of primary ovarian cancer. Thirty-nine cases of metastatic breast carcinoma to the ovary, 36 primary breast carcinomas, and 42 primary ovarian carcinomas were examined immunohistochemically for the expression of WT1, CA125, carcinoembryonic antigen, MUC2, MUC1, and GCDFP. The percentage of cells stained and the intensity of staining were recorded. Thirty-two ovarian carcinomas (76%) were positive for WT1, including 31 of 33 (94%) serous carcinomas. Most of them had strong and diffuse staining. None of the breast cancers either primary or metastatic to the ovary expressed WT1. Thirty-eight (90%) ovarian carcinomas were positive for CA125, most of them with strong and diffuse staining. Most breast carcinomas were negative for CA125, with only 6 (16%) of the primary ones and 5 (12%) of the metastatic showing weak and focal positivity. All ovarian carcinomas were negative for GCDFP. Five primary breast cancers (14%) and 17 (43%) metastatic to the ovary were positive for GCDFP. Nine (21%) ovarian carcinomas, 8 (22%) primary breast carcinomas, and 13 (33%) metastatic to the ovary were positive for carcinoembryonic antigen. Almost all tumors examined were positive for MUC1 (100% ovarian carcinomas, 100% primary breast carcinomas, and 95% metastatic breast carcinomas to ovary). MUC2 was positive in 10 (24%) ovarian carcinomas, 3 (8%) primary breast cancers, and 12 (30%) metastases to the ovary. The presence of

  6. Modulators of Response to Tumor Necrosis-Factor-Related Apoptosis Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

    DTIC Science & Technology

    2010-04-01

    antibody, MORAb-003. Methods: FRα expression was examined in ovarian cell lines (SKOV3ip1, IGROV, HeyA8, A2780-par, and HIO -180) with fluorescence...IGROVand SKOV3ip1 cell lines both expressed high levels of FRα compared with the non-transformed ( HIO -180) cells. HeyA8 and A2780-par cell lines lacked

  7. Interobserver and intraobserver variability of a two-tier system for grading ovarian serous carcinoma.

    PubMed

    Malpica, Anais; Deavers, Michael T; Tornos, Carmen; Kurman, Robert J; Soslow, Robert; Seidman, Jeffrey D; Munsell, Mark F; Gaertner, Erich; Frishberg, David; Silva, Elvio G

    2007-08-01

    Although grading has been demonstrated to be an important prognostic factor in ovarian serous carcinoma, there is no system universally used to perform this task. A few years ago, we proposed a two-tier system for grading ovarian serous carcinoma that is based primarily on the assessment of nuclear atypia (uniformity vs. pleomorphism) in the worst area of the tumor. Tumor grade in this two-tier system is correlated with survival. After being used by numerous pathologists and trainees at The University of Texas M.D. Anderson Cancer Center (MDACC) for 15 years, we have observed that this system is user-friendly and reproducible. We undertook this study to evaluate the interobserver and intraobserver variability among a group of 7 gynecologic pathologists and 2 general surgical pathologists using this grading system. A total of 80 cases of ovarian serous carcinoma, 40 low-grade and 40 high-grade, were circulated twice among these pathologists. Slides with examples of low-grade and high-grade serous carcinoma were sent with the unknowns. A website was used to provide diagnostic criteria, images of examples of ovarian low-grade and high-grade carcinoma, and a log form to facilitate data entry. Statistical analysis demonstrated an overall kappa statistic among the different observers of 0.909. The intergrader kappa's ranged from 0.717 to 1.000 in the first round of the review and from 0.701 to 1.000 in the second round. Eight of the participants had an intragrader kappa ranging from 0.775 to 1.000 (excellent agreement), whereas a single participant had an intragrader kappa of 0.725 (good agreement). This study demonstrates that the two-tier grading system (the MDACC grading system) for ovarian serous carcinoma on the basis of the assessment of nuclear atypia is easy to learn and is highly reproducible. These findings would support its universal use, which would be beneficial for the standardization of clinical trials and protocols, thus facilitating the understanding of

  8. Intraperitoneal Bortezomib and Carboplatin in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-09-04

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Transitional Cell Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  9. Association of Hormone Receptor Expression with Survival in Ovarian Endometrioid Carcinoma: Biological Validation and Clinical Implications

    PubMed Central

    Rambau, Peter; Kelemen, Linda E.; Steed, Helen; Quan, May Lynn; Ghatage, Prafull; Köbel, Martin

    2017-01-01

    This paper aims to validate whether hormone receptor expression is associated with longer survival among women diagnosed with ovarian endometrioid carcinoma (EC), and whether it identifies patients with stage IC/II tumors with excellent outcome that could be spared from toxic chemotherapy. Expression of estrogen receptor (ER) and progesterone receptor (PR) was assessed on 182 EC samples represented on tissue microarrays using the Alberta Ovarian Tumor Type (AOVT) cohort. Statistical analyses were performed to test for associations with ovarian cancer specific survival. ER or PR expression was present in 87.3% and 86.7% of cases, respectively, with co-expression present in 83.0%. Expression of each of the hormonal receptors was significantly higher in low-grade tumors and tumors with squamous differentiation. Expression of ER (Hazard Ratio (HR) = 0.18, 95% confidence interval 0.08–0.42, p = 0.0002) and of PR (HR = 0.22, 95% confidence interval 0.10–0.53, p = 0.0011) were significantly associated with longer ovarian cancer specific survival adjusted for age, grade, treatment center, stage, and residual disease. However, the five-year ovarian cancer specific survival among women with ER positive stage IC/II EC was 89.0% (standard error 3.3%) and for PR positive tumors 89.9% (standard error 3.2%), robustly below the 95% threshold where adjuvant therapy could be avoided. We validated the association of hormone receptor expression with ovarian cancer specific survival independent of standard predictors in an independent sample set of EC. The high ER/PR co-expression frequency and the survival difference support further testing of the efficacy of hormonal therapy in hormone receptor-positive ovarian EC. The clinical utility to identify a group of women diagnosed with EC at stage IC/II that could be spared from adjuvant therapy is limited. PMID:28264438

  10. Olaparib or Cediranib Maleate and Olaparib Compared With Standard Platinum-Based Chemotherapy in Treating Patients With Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-10-09

    BRCA Rearrangement; Deleterious BRCA1 Gene Mutation; Deleterious BRCA2 Gene Mutation; Endometrial Undifferentiated Carcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Tumor; Ovarian Seromucinous Carcinoma; Ovarian Serous Tumor; Ovarian Transitional Cell Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  11. Suppression of RNA interference on expression of c-myc of SKOV3 ovarian carcinoma cell line.

    PubMed

    Ai, Z-H; Wang, J; Xu, Y-L; Zhu, X-L; Teng, Y-C

    2013-11-01

    To investigate suppression of RNA interference (RNAi) on expression of c-myc of SKOV3 ovarian carcinoma cell line. The c-myc -siRNA was designed and synthesized, then transfected to SKOV3 ovarian carcinoma cell lines. The cell lines were divided into four groups, including the blank control group, the siRNA transfection group, the mock transfection group and the negative control group. The expression level of c-myc mRNA and protein were detected by RT-PCR and Western blotting, respectively. The growth and proliferation of SKOV3 ovarian carcinoma cell lines were observed with CCK-8 assay. After transfected with c-myc -siRNA, the expression level of c-myc mRNA and protein were down-regulated, the growth and proliferation of SKOV3 ovarian carcinoma cell line were inhibited in the siRNA transfection group. There were significant differences between the siRNA transfection group and the blank control group (p < 0.05). The silencing efficiency was 77.78%, the protein suppression rate was 67.78%, and the inhibition ratio was 56.35% by CCK-8 assay in siRNA transfection group. The down-regulation of c-myc expression of SKOV3 ovarian carcinoma cell line by c-myc -siRNA can lead to the suppression of cancer cell proliferation. The small interfering RNAs technique can inhibit the proliferation of carcinoma cell by oncogene silencing.

  12. Ovarian carcinoma: care and survival in a community-based population.

    PubMed

    Yawn, B P; Wollan, P; Klee, M; Barrette, B

    2001-01-01

    Previous studies of the management and costs of ovarian cancer have been based on data from oncology practices. Such studies may exclude patients who are not candidates for treatment and may not account for costs incurred during diagnosis or primary treatment. The purpose of this study was to describe the epidemiology, management, and costs of care of ovarian cancer in a geographically defined population to better reflect the total spectrum of the disease and its care. We conducted a retrospective review of the medical records of all residents of Olmsted County, Minnesota, who received a first diagnosis of epithelial ovarian carcinoma (including postmortem diagnoses) between 1985 and 1997. Of the 107 women with a new diagnosis of ovarian cacinoma, 42 (39%) had stage I or II tumors at the time of diagnosis. The mean age of the patients at the time of diagnosis was 64.7 years, and 20% were nulliparous. The diagnostic assessment for ovarian carcinoma was initiated by a family physician or internist in 50% of cases and by an obstetrician or gynecologist in 16% of cases. One hundred two patients (95%) underwent surgical treatment, and 80 (75%) received primary chemotherapy. The 5-year survival rate was 88% in those with stage I or II tumors and 17% in those with stage III or IV tumors. The mean charges for secondary care were higher than those for primary care ($36,110 vs $32,367; P < 0.05) in those receiving both types of therapy. Fifty percent of those dying of ovarian cancer received hospice care for a mean of 39.0 days before death. Most assessments leading to a diagnosis of ovarian carcinoma were initiated by primary care physicians. In this community-based population, early-stage and low-grade tumors were common (> or = 30%) and were associated with lower costs of care and higher 5-year survival rates. Total treatment costs for those requiring secondary therapy were approximately twice the costs for those requiring primary treatment only, with approximately 50% of

  13. Liposomal daunorubicin overcomes drug resistance in human breast, ovarian and lung carcinoma cells.

    PubMed

    Sadava, David; Coleman, Aaron; Kane, Susan E

    2002-11-01

    Multi-drug resistance due in part to membrane pumps such as P-glycoprotein (Pgp) is a major clinical problem in human cancers. We tested the ability of liposomally-encapsulated daunorubicin (DR) to overcome resistance to this drug. A widely used breast carcinoma cell line originally selected for resistance in doxorubicin (MCF7ADR) was 4-fold resistant to DR compared to the parent MCF7 cells (IC50 79 nM vs. 20 nM). Ovarian carcinoma cells (SKOV3) were made resistant by retroviral transduction of MDR1 cDNA and selection in vinblastine. The resulting SKOV3MGP1 cells were 130-fold resistant to DR compared to parent cells (IC50 5700 nM vs. 44 nM). Small-cell lung carcinoma cells (H69VP) originally selected for resistance to etoposide were 6-fold resistant to DR compared to H69 parent cells (IC50 180 nM vs. 30 nM). In all three cases, encapsulation of DR in liposomes as Daunoxome (Gilead) did not change the IC50 of parent cells relative to free DR. However, liposomal DR overcame resistance in MCF7ADR breast carcinoma cells (IC50 20 nM), SKOV3MGP1 ovarian carcinoma cells (IC50 237 nM) and H69VP small-cell lung carcinoma cells (IC50 27 nM). Empty liposomes did not affect the IC50 for free DR in the three resistant cell lines, nor did empty liposomes affect the IC50 for other drugs that are part of the multi-drug resistance phenotype (etoposide, vincristine) in lung carcinoma cells. These data indicate the possible value of liposomal DR in overcoming Pgp-mediated drug resistance in human cancer.

  14. Growth inhibitory effects of sodium phenylacetate (NSC 3039) on ovarian carcinoma cells in vitro.

    PubMed

    Ferrandina, G; Melichar, B; Loercher, A; Verschraegen, C F; Kudelka, A P; Edwards, C L; Scambia, G; Kavanagh, J J; Abbruzzese, J L; Freedman, R S

    1997-10-01

    The aim of this study was to determine the antiproliferative activity of sodium phenylacetate (NaPa) against ovarian carcinoma cell lines. NaPa induced a dose-dependent inhibition (IC50 from 12 mM to >20 mM) of all ovarian carcinoma cell lines, although the sensitivity of individual lines to NaPa varied. Both cisplatin-sensitive and -resistant cell lines responded to NaPa, and growth-inhibitory activity was also detected against cells freshly isolated from malignant ascites of previously treated patients. The growth inhibitory effects that were produced by NaPa were time dependent, showing a maximum effect at 72 h, and were not associated with cytotoxic action. Growth inhibitory effects of NaPa were also reversible. After 48- and 72-h exposures to NaPa, a reduction in the percentage of cells in the S-phase was detected, with a concomitant recruitment of cells in the G0-G1 phase. Treatment with NaPa after different exposure times did not significantly increase the proportion of cells undergoing apoptosis. NaPa also produced a significant reduction in the percentage of cyclin-D1- and p21/ras-positive cells and in the percentage of cells positive for bcl-2, whereas the percentages of bax/p21-positive cells increased. NaPa produced minimal, if any, alterations of expression of HLA class I and transforming growth factor beta1 antigens. In contrast, the percentage of transforming growth factor beta2-positive cells decreased after exposure to NaPa. The combination of NaPa with cisplatin resulted in an additive inhibitory effect. Our results show, for the first time, that NaPa inhibits the growth of ovarian carcinoma cell lines and the cells from malignant ascites of chemotherapy-treated patients with ovarian carcinoma. The growth-inhibitory properties of NaPa suggest that this molecule could represent a prototype of a new class of compounds with possible therapeutic potential in patients with ovarian carcinoma.

  15. Combining CA 125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma

    PubMed Central

    McIntosh, M.W.; Drescher, C.; Karlan, B.; Scholler, N.; Urban, N.; Hellstrom, K.E.; Hellstrom, I.

    2009-01-01

    Objectives The serum tumor marker CA 125 is elevated in most clinically advanced ovarian carcinomas. Because these elevations may precede clinical detection by a year or more, CA 125 is potentially useful for early detection as part of an ovarian cancer screening program. However, CA 125 is often not elevated in clinically detected cancer and is frequently elevated in women with benign ovarian tumors. CA 125 may be more useful in conjunction with one or more other tumor biomarkers. Additional markers could play a role if, when used with CA 125, they identify some carcinomas missed by CA 125 (i.e., they improve sensitivity), rule out false positives (i.e., improve specificity), or are able to detect the same cancers earlier. Methods We have evaluated a composite marker (CM) that combines CA 125 and a previously described soluble mesothelin related (SMR) marker in sera from 52 ovarian cancer cases, 43 controls with benign ovarian tumors, and 220 normal risk controls who participated in a screening program, including 25 healthy women having two serum samples collected 1 year apart. CA 125, SMR, and CM were evaluated for their ability to identify clinical disease and for their temporal stability, which assesses their ability to obtain even greater sensitivity when used in a longitudinal screening program. Results CM has the best sensitivity, with specificity equal to CA 125. Importantly, CM has temporal stability at least as high as CA 125. Conclusion The CM may outperform CA 125 alone in a longitudinal screening program as well as in a diagnostic setting. PMID:15385104

  16. Expression of HPIP in epithelial ovarian carcinoma: a clinicopathological study

    PubMed Central

    Wang, Yuping; Meng, Fanling; Liu, Yunduo; Chen, Xiuwei

    2017-01-01

    Objectives Hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP) plays an important role in cancer invasion and metastasis. The aim of this study is to investigate the expression of HPIP in epithelial ovarian cancer (EOC). Patients and methods Immunohistochemical method was performed using 42 normal ovarian specimens and 145 specimens with EOC. The correlations of HPIP expression with the clinicopathological factors and prognosis of EOC patients were evaluated. Statistical analyses were performed using the chi-square test, multivariate Cox proportional hazard, and Kaplan–Meier method. Results HPIP expression in EOC was higher than that in normal tissues (P<0.001). HPIP expression was significantly associated with histological grade, International Federation of Gynecology and Obstetrics stage, and lymphatic metastasis of EOC (P<0.05). Patients with high HPIP expression had poorer overall survival and disease-free survival (P<0.001) compared with patients with low HPIP expression. Multivariate Cox analysis demonstrated that HPIP was an independent factor for overall survival and disease-free survival (P<0.05). Conclusion HPIP may be a valuable biomarker for predicting the prognosis of EOC patients and may serve as a potential target for cancer therapy. PMID:28053543

  17. Ovarian carcinoma in a 14-year-old with classical salt-wasting congenital adrenal hyperplasia and bilateral adrenalectomy.

    PubMed

    Pina, Christian; Khattab, Ahmed; Katzman, Philip; Bruckner, Lauren; Andolina, Jeffrey; New, Maria; Yau, Mabel

    2015-05-01

    A 14-year-old female with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency underwent bilateral adrenalectomy at 6 years of age as a result of poor hormonal control. Because the patient was adrenalectomized, extra adrenal androgen production was suspected. Imaging studies including pelvic ultrasound and pelvic magnetic resonance imaging (MRI) were obtained to evaluate for adrenal rest tumors of the ovaries. Abdominal MRI was obtained to evaluate for residual adrenal tissue. A cystic lesion arising from her right ovary suspicious for ovarian neoplasm was noted on pelvic MRI. Right salpingo-oophorectomy was performed and histopathological examination revealed ovarian serous adenocarcinoma, low-grade, and well-differentiated. Tumor marker CA-125 was elevated and additional ovarian cancer staging workup confirmed stage IIIC due to one lymph node positive for carcinoma. The patient then developed a large left ovarian cyst, which led to a complete total abdominal hysterectomy and removal of the left ovary and fallopian tube. Pathology confirmed ovarian serous adenocarcinoma with microscopic focus of carcinoma in the left ovary. After numerous complications, the patient responded well to chemotherapy, CA-125 levels fell and no evidence of carcinoma was observed on subsequent imaging. To our knowledge, this is the first reported case of an ovarian serous adenocarcinoma in a patient with CAH. Although rare, we propose that the ovaries were the origin of androgen production and not residual adrenal tissue. The relationship between CAH and ovarian carcinomas has yet to be established, but further evaluation is needed given the poor survival rate of high-grade serous ovarian carcinoma.

  18. Detection of polyol accumulation in a new ovarian carcinoma cell line, CABA I: a(1)H NMR study.

    PubMed

    Ferretti, A; D'Ascenzo, S; Knijn, A; Iorio, E; Dolo, V; Pavan, A; Podo, F

    2002-04-08

    Ovarian carcinomas represent a major form of gynaecological malignancies, whose treatment consists mainly of surgery and chemotherapy. Besides the difficulty of prognosis, therapy of ovarian carcinomas has reached scarce improvement, as a consequence of lack of efficacy and development of drug-resistance. The need of different biochemical and functional parameters has grown, in order to obtain a larger view on processes of biological and clinical significance. In this paper we report novel metabolic features detected in a series of different human ovary carcinoma lines, by (1)H NMR spectroscopy of intact cells and their extracts. Most importantly, a new ovarian adenocarcinoma line CABA I, showed strong signals in the spectral region between 3.5 and 4.0 p.p.m., assigned for the first time to the polyol sorbitol (39+/-11 nmol/10(6) cells). (13)C NMR analyses of these cells incubated with [1-(13)C]-D-glucose demonstrated labelled-sorbitol formation. The other ovarian carcinoma cell lines (OVCAR-3, IGROV 1, SK-OV-3 and OVCA432), showed, in the same spectral region, intense resonances from other metabolites: glutathione (up to 30 nmol/10(6) cells) and myo-inositol (up to 50 nmol/10(6) cells). Biochemical and biological functions are suggested for these compounds in human ovarian carcinoma cells, especially in relation to their possible role in cell detoxification mechanisms during tumour progression.

  19. Bilateral ovarian carcinomas differ in the expression of metastasis-related genes

    PubMed Central

    Smebye, Marianne Lislerud; Haugom, Lisbeth; Davidson, Ben; Trope, Claes Göran; Heim, Sverre; Skotheim, Rolf Inge; Micci, Francesca

    2017-01-01

    The mechanisms behind bilaterality of ovarian carcinomas are not fully understood, as the two tumors could possibly represent two primary tumors, a primary tumor and a metastasis, or two metastases. The gene expression profiles from bilateral high-grade serous carcinomas (HGSCs) and clear cell carcinomas (CCCs) of the ovary were compared to study the association between the tumors of the two sides. A separate analysis of genes from chromosome 19 was also performed, since this chromosome is frequently rearranged in ovarian carcinomas. Tumors from four patients were included (three pairs of HGSC and one pair of CCC). The gene expression was analyzed at the exon level, and bilateral tumors were compared to identify within-pair differences. Gene expression data were also compared with genomic information on the same tumors. Similarities in gene expression were observed between the tumors within each pair, as expected if the two tumors were clonally related. However, certain genes exhibited differences in expression between the two sides, indicating metastasis involvement. Among the most differently expressed genes, one gene was common to all four pairs: Immunoglobulin J. In all HGSC pairs, serpin peptidase inhibitor, clade B (ovalbumin), member 2, serpin family E member 1 and phospholipase A2, group IIA (platelets, synovial fluid) were also among the differentially expressed genes. The specific analysis of chromosome 19 highlighted expression differences in the zinc finger protein 36 gene. These results indicate that bilateral ovarian tumors represent different stages during progression of a single clonal process. Several of the genes observed to be differently expressed are known to be metastasis-related, and are likely to be also involved in spreading from one side to the other in the bilateral cancer cases examined. PMID:28123539

  20. Expressions of lysophosphatidic acid receptors in the development of human ovarian carcinoma

    PubMed Central

    Si, Jinge; Su, Yuanyuan; Wang, Yifeng; Yan, You-Liang; Tang, Ya-Ling

    2015-01-01

    Aim: To investigate the associations between the expressions of three lysophosphatidic acid (LPA) receptors (LPA1-3) and the development of ovarian carcinoma (OC). Method: Ovarian tissue specimens, including normal ovarian epithelium tissues, benign ovarian tumor tissues and OC tissues were collected from patients who underwent surgical resections between March 2012 and December 2014. Immunohistochemical staining was used to detect LPA receptor expressions in ovarian tissues. Reverse transcription-polymerase chain reaction and Western blotting were used to detect mRNA and protein expression of LPA receptors, respectively. Association analysis between LPA receptors protein expression and clinical pathological characteristics was conducted. The value of LPA2 and LPA3 in discriminating OC was confirmed by receiver-operator characteristic (ROC) curves analysis. Results: The positive expression rates of LPA2 and LPA3 in OC group was obviously higher than normal control and benign groups. The LPA2 and LPA3 mRNA and protein levels in OC group were higher than in normal control and benign groups. LPA2 and LPA3 mRNA expression levels were positively correlated with LPA2 and LPA3 protein expression in OC group. ROC curve analysis revealed that LPA2 yield a specificity of 96.3% and a sensitivity of 97.9%, and LPA3 yield a specificity of 98.5% and a sensitivity of 97.9% for the detection of OC. Conclusion: LPA2 and LPA3 were highly expressed in OC tissues, which may be involved in the development of OC. Further, LPA2 and LPA3 had higher sensitivity and specificity in distinguishing the OC from benign ovarian tumors, which could be potential diagnostic indictors in OC. PMID:26770382

  1. Identification and Characterization of Genomic Amplifications in Ovarian Serous Carcinoma

    DTIC Science & Technology

    2006-01-01

    squamous carcinoma [23], bladder cancer [24], pancreatic cancer [25], chronic lym- phocytic leukemia [26], and gastric cancer [27,28]. Al- though CGH array...amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes...Lisitsyn N, Wigler M: Cloning the differences between two complex ge- nomes. Science 1993, 259: 946 –951. •• 33 Lucito R, Healy J, Alexander J, et al

  2. Development of alpha-emitting radionuclide lead 212 for the potential treatment of ovarian carcinoma

    SciTech Connect

    Rotmensch, J.; Atcher, R.W.; Hines, J.; Grdina, D.; Schwartz, J.S.; Toohill, M.; Herbst, A.L.

    1989-04-01

    alpha-Emitting radionuclides may be an effective alternative treatment against ovarian carcinoma because they have short half-lives and are densely ionizing, with high linear energy transfer to a depth of several cell diameters without requiring cellular oxygenation. One radionuclide that has been generated and tested in our laboratory in vitro and in vivo is lead 212 (/sup 212/Pb). Intraperitoneal instillation of /sup 212/Pb prolonged survival and totally eradicated tumor in 24% of mice inoculated with the extremely virulent Ehrlich ascites-producing tumor. In vitro /sup 212/Pb was two to four times more effective in killing human ovarian cancer cells than x-rays. Irradiation with /sup 212/Pb increased the radiosensitivity and chromosomal aberrations of cells. In dogs, intraperitoneal instillation of 2.6 mCi of ferrous hydroxide tagged with /sup 212/Pb caused no significant toxicity. It appears that alpha-emitting radionucides such as /sup 212/Pb have the potential to be a new and potent treatment of ovarian carcinoma and could be effective in cases that are resistant to conventional chemotherapy or x-ray therapy.

  3. Decreased expression of pyruvate dehydrogenase A1 predicts an unfavorable prognosis in ovarian carcinoma

    PubMed Central

    Li, Yaqing; Huang, Ruixia; Li, Xiaoli; Li, Xiaoran; Yu, Dandan; Zhang, Mingzhi; Wen, Jianguo; Goscinski, Mariusz Adam; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

    2016-01-01

    Pyruvate dehydrogenase A1 (PDHA1) serves as a gate-keeper enzyme link between glycolysis and the mitochondrial citric acid cycle. The inhibition of PDHA1 in cancer cells can result in an increased Warburg effect and a more aggressive phenotype in cancer cells. This study was conducted to investigate the expression of PDHA1 in ovarian cancer and the correlation between PDHA1 expression and the prognosis of patients. The PDHA1 protein expression in 3 ovarian cancer cell lines (OVCAR-3, SKOV-3 and ES-2) and 248 surgically removed ovarian carcinoma samples was immunocytochemically examined. Statistical analyses were performed to evaluate the correlations between PDHA1 expression and the clinicopathological characteristics of the patients as well as the predictive value of PDHA1. The results showed the presence of variable expression of PDHA1 in the three ovarian cancer cell lines. Of the 248 ovarian cancer tissue specimens, 45 cases (18.1%) were negative in tumor cells for PDHA1, 162 cases (65.3%) displayed a low expression level, and 41 cases (16.5%) had a relatively high PDHA1 staining. The expression of PDHA1 was associated with the histological subtype (P=0.004) and FIGO stage (P=0.002). The median OS time in the PDHA1 negative group, low expression group and high expression group were 0.939 years, 1.443 years and 9.900 years, respectively. The median PFS time in the above three groups were 0.287 years, 0.586 years and 9.900 years, respectively. Furthermore, the high expression of PDHA1 in ovarian carcinoma cells was significantly associated with better OS and PFS by statistical analyses. Multivariate analyses showed that PDHA1 expression was also an independent prognostic factor for higher OS in ovarian cancer patients (HR=0.705, 95% CI 0.541-0.918, P=0.01). Our study indicated that the decreased expression of PDHA1 might be an independent prognostic factor in unfavorable outcomes. PMID:27725912

  4. Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma.

    PubMed

    Park, Young-Ae; Choi, Chel Hun; Do, In-Gu; Song, Sang Yong; Lee, Jae Kwan; Cho, Young Jae; Choi, Jung-Joo; Jeon, Hye Kyung; Ryu, Ji Yoon; Lee, Yoo-Young; Kim, Tae-Joong; Bae, Duk-Soo; Lee, Jeong-Won; Kim, Byoung-Gie

    2014-10-01

    The renin-angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is the main effector of RAS, and AGTR2 antagonizes AGTR1. Accumulating evidence supports the role of RAS in the paracrine regulation of tumorigenesis in several cancer types. Although treatment with AGTR1 antagonist (losartan) or AGTR2 agonist (CGP42112A) inhibits tumor progression in several cancer cells, their combined treatment has not been reported. In this study, we estimated the expression of AGTR1 and AGTR2 in epithelial ovarian cancer cells and tissues. Then, we evaluated the anti-cancer effects of combined treatment with losartan and/or CGP42112A in ovarian cancer cells and human umbilical vein endothelial cells (HUVEC). AGTR1 protein was detected in 86% of ovarian cancer tissues, while AGTR2 was not detected in immunohistochemistry. The mRNA expression of AGTR1 obtained from the cancer genome atlas (TCGA) dataset showed that AGTR1 overexpression was correlated with poor survival. Treatment with either losartan or CGP42112A reduced the angiotensin II (Ang II)-mediated cell survival in both ovarian cancer cells and HUVEC. Combined treatment with losartan and CGP42112A synergistically decreased cell survival. As a downstream pathway, phosphorylation of phospholipase C β3 (PLC β3) and expression of vascular endothelial growth factor (VEGF) decreased synergistically in combined treatment. The results suggest that dual regulation of AGTR1 and AGTR2 may be a novel therapeutic strategy for epithelial ovarian carcinoma through inhibition of cancer cell survival as well as anti-angiogenesis. This study investigated the expressions of AGTR1 and AGTR2 in epithelial ovarian carcinoma and the therapeutic potential of AGTR modulation with specific antagonist and/or agonist in epithelial ovarian cancer cells. Treatment of AGTR1 antagonist, losartan and/or AGTR2 agonist, CGP42112A synergistically mediated anti-cancer effects including the decrease of cell

  5. EphB3 protein is associated with histological grade and FIGO stage in ovarian serous carcinomas.

    PubMed

    Gao, Weiwei; Zhang, Qin; Wang, Yan; Wang, Jiandong; Zhang, Shu

    2017-02-01

    Eph (Erythropoietin-producing human hepatocellular carcinoma cell) is the largest subfamily of receptor tyrosine kinases. Eph receptors and their ephrin ligands are involved in embryonic development and physiological processes. Aberrant expression of Eph/ephrin may contribute to a variety of diseases including cancer. EphB3 is a member of Eph receptors and has been found to play roles in carcinogenesis of some types of human cancer. But, its expression and clinical significance in ovarian serous carcinoma have not been well investigated and are unknown. In this study, a set of ovarian tissues including normal fallopian tube, serous borderline tumor, and serous carcinoma were subjected to immunohistochemistry using a specific polyclonal antibody for EphB3. The relationship between EphB3 expression and clinicopathological parameters was statistically analyzed. EphB3 was strongly expressed in all fallopian tube specimens (19/19, 100%). EphB3 was negatively or weekly expressed in 1 of 17 (5.8%) in borderline tumors and 26 of 50 (52.0%) in serous carcinomas, moderately expressed in 7 of 17 (41.2%) in borderline tumors and 14 of 50 (28%) in serous carcinomas, and strongly expressed in 9 17 (52.9%) in borderline tumors and 10 of 50 (20%) in serous carcinomas. EphB3 expression is significantly reduced in serous carcinomas compared with normal fallopian tubes and borderline tumors (p < 0.001). EphB3 expression is negatively associated with histological grade (p < 0.001, rs = -0.613) and FIGO stage (p = 0.001, rs = -0.464) of serous carcinomas. Our results show EphB3 protein lost in ovarian serous carcinoma and is associated with tumor grade and FIGO stage, which indicate EphB3 protein may play a role in carcinogenesis of ovarian serous carcinoma and may be used as a molecular marker for prognosis.

  6. Biomarkers and endosalpingiosis in the ovarian and tubal microenvironment of women at high-risk for pelvic serous carcinoma

    PubMed Central

    Gruessner, Christine; Gruessner, Angelika; Glaser, Katherine; AbuShahin, Nisreen; Laughren, Cynthia; Zheng, Wenxin; Chambers, Setsuko K

    2014-01-01

    Introduction: BRCA mutations increase the risk for development of high-grade pelvic serous carcinomas. Tissue biomarkers distinguishing women at high-risk (HR) for ovarian cancer from those at low-risk (LR) may provide insights into tumor initiation pathways. Methods: A prospective study of 47 HR women (40% BRCA carriers) undergoing risk-reducing salpingo-oophorectomy and 48 LR controls undergoing salpingo-oophorectomy was performed. Ovarian/tubal tissues were harvested. Immunohistochemical analysis of candidate proteins CSF-1, CSF-1R, ErbB4 is presented, with scores separately analyzed in epithelium and stroma, in ampulla, fimbria, ovary, and ovarian endosalpingiosis (ES). Comparison was performed between HR and LR groups. Results: Elevated levels of CSF-1 (p=0.005) or ErbB4 (p=0.005) in the ovarian epithelium, or ErbB4 (p=0.005) in the ovarian stroma, were significantly associated with both the HR status and carrying a BRCA mutation, as was nuclear ErbB4 staining. Ovarian ES, an entity which likely derives from the tubal mucosal epithelium, was also associated with HR (p=0.038) and BRCA mutation status (p=0.011). Among the BRCA carriers only, markers also found association when present in the tube as well as in ovarian ES (p < 0.05). ROCs were generated including in the regression model both CSF-1 and ErbB4 expression levels. A model including CSF-1 in ovarian epithelium, ErbB4 in ovarian stroma, and younger age achieves AUC=0.87 (73% sensitivity, 93% specificity) of detection of the HR status. In BRCA carriers, CSF-1 in ovarian epithelium alone achieves AUC=0.85. Conclusions: Our data suggest that elevated levels of CSF-1/ErbB4 in the adnexae correlate with HR/BRCA carrier status. CSF-1/CSF-1R signaling is active in ovarian cancer progression; our data suggests a role in its initiation. ErbB4, in particular nuclear ErbB4, may have a role in tumor initiation as well. Ovarian ES, an entity which may represent a latent precursor to low-grade pelvic serous

  7. A case report of peritoneal tuberculosis with multiple miliary peritoneal deposits mimicking advanced ovarian carcinoma

    PubMed Central

    Yazdani, Shahla; Sadeghi, Mahmod; Alijanpour, Abolhasan; Naeimi-rad, Mojgan

    2016-01-01

    Background: Peritoneal tuberculosis accounts 1-2% of all forms of tuberculosis. Peritoneal tuberculosis is an important differential diagnosis for ovarian cancer in women with ascites, adnexal mass and elevated cancer antigen 125 (CA125) levels. We report a case of a 32- year -old woman with multiple miliary peritoneal deposits mimicking advanced ovarian carcinoma. Case Presentation: A 32-year-old drug addicted woman presented with menometrorrhagia, fever and shivering, ascites and pelvis mass. Ultrasonography revealed a 53×65 mm cyst in left ovary and ascites. Multiple miliary peritoneal deposits were observed during laparatomy without any mass, histologic examination confirmed tuberculosis of uterus, tubes, omentum, liver and external surfaces of small intestine. Finally, the patient recovered with anti-tuberculosis treatment. Conclusion: These findings highlight considering tuberculosis in the differential diagnosis of any patients with adnexal mass, ascitis and elevated serum CA125 even with negative cytology and bacteriology test results. PMID:26958336

  8. Erythropoietin inhibits apoptosis induced by photodynamic therapy in ovarian cancer cells.

    PubMed

    Solár, Peter; Koval, Ján; Mikes, Jaromír; Kleban, Ján; Solárová, Zuzana; Lazúr, Ján; Hodorová, Ingrid; Fedorocko, Peter; Sytkowski, Arthur J

    2008-08-01

    Recombinant human erythropoietin is widely used to treat anemia associated with cancer and with the myelosuppressive effects of chemotherapy, particularly platinum-based regimens. Erythropoietin is the principal regulator of erythroid cell proliferation, differentiation, and apoptosis. Recently, the antiapoptotic and proliferative effects of erythropoietin on nonhematopoietic cells were also established. We now show the effect of erythropoietin treatment on the response of A2780 and SKOV3 ovarian carcinoma cell lines to photodynamic therapy (PDT) using hypericin. SKOV3 exhibited an increased resistance to hypericin when cells were treated with erythropoietin. This resistance was reversed by treatment of SKOV3 cells with the specific Janus kinase 2 kinase inhibitor AG490 or the tyrosine kinase inhibitor genistein. These results support a role for the specific erythropoietin-induced Janus kinase 2/STAT signal transduction pathway in PDT resistance. Evidence of erythropoietin signaling was obtained by the demonstration of Akt phosphorylation in both A2780 and SKOV3 cells. Erythropoietin-treated SKOV3 cells exhibited decreased apoptosis induced by hypericin, an effect that was blocked by the phosphoinositide 3-kinase/Akt inhibitor wortmannin. These results may have important implications for ovarian cancer patients undergoing PDT and receiving erythropoietin.

  9. Radionuclide bone scan, radiographic bone survey, and alkaline phosphatase: studies of limited value in asymptomatic patients with ovarian carcinoma

    SciTech Connect

    Metler, F.A. Jr.; Christie, J.H.; Crow, N.E. Jr.; Garcia, J.F.; Wicks, J.D.; Bartow, S.A.

    1982-10-15

    Bone scans or skeletal surveys were obtained in 104 patients with ovarian carcinoma. No metastases were identified at staging in the 43 patients with Stage I or II disease. Four patients in the entire series had osseous metastases. Three of the 40 patients with Stage III epithelian ovarian carcinoma has osseous metastases at the time of staging. All of these were Grade III lesions. One Stage I, Grade III patient demonstrated osseous metastases two years after initial diagnosis. None of the four patients with osseous metastases had an elevated alkaline phosphatase; three of the four had bone pain. Based on these results, it is suggested that radiographic bone survey and radionuclide bone scans are not indicated as screening procedures in asymptomatic patients with ovarian carcinoma.

  10. Downregulation of glypican-3 expression increases migration, invasion, and tumorigenicity of human ovarian cancer cells.

    PubMed

    Liu, Ying; Zheng, Dongping; Liu, Mingming; Bai, Jiao; Zhou, Xi; Gong, Baolan; Lü, Jieyu; Zhang, Yi; Huang, Hui; Luo, Wenying; Huang, Guangrong

    2015-09-01

    Glypican-3 (GPC3) is a membrane of heparan sulfate proteoglycan family involved in cell proliferation, adhesion, migration, invasion, and differentiation during the development of the majority of mesodermal tissues and organs. GPC3 is explored as a potential biomarker for hepatocellular carcinoma screening. However, as a tumor-associated antigen, its role in ovarian cancer remains elusive. In this report, the expression levels of GPC3 in the various ovarian cancer cells were determined with quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and GPC3 expression in ovarian cancer UCI 101 and A2780 cells was knocked down by siRNA transfection, and the effects of GPC3 knockdown on in vitro cell proliferation, migration, and invasion were respectively analyzed by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay and Transwell migration assay. Additionally, the effect of GPC3 knockdown on in vivo tumorigenesis were investigated in athymic nude mice. The results indicated that GPC3 knockdown significantly promoted cell proliferation and increased cell migration and invasion by upregulation of matrix metalloproteinase (MMP)-2 and MMP-9 expression and downregulation of tissue inhibitor of metalloproteinase-1 expression. Additionally, GPC3 knockdown also increased in vivo tumorigenicity of UCI 101 and A2780 cells and final tumor weights and volumes after subcutaneous cell injection in the nude mice. The results of immunohistochemical staining and Western blotting both demonstrated a lower expression of GPC3 antigen in the tumors of GPC3 knockdown groups than that of negative control groups. Moreover, transforming growth factor-β2 protein expression in the tumors of GPC3 knockdown groups was significantly increased, which at least contributed to tumor growth in the nude mice. Taken together, these findings suggest that GPC3 knockdown promotes the progression of human ovarian cancer cells by increasing their migration, invasion

  11. Basement membrane protein distribution in LYVE-1-immunoreactive lymphatic vessels of normal tissues and ovarian carcinomas.

    PubMed

    Vainionpää, Noora; Bützow, Ralf; Hukkanen, Mika; Jackson, David G; Pihlajaniemi, Taina; Sakai, Lynn Y; Virtanen, Ismo

    2007-05-01

    The endothelial cells of blood vessels assemble basement membranes that play a role in vessel formation, maintenance and function, and in the migration of inflammatory cells. However, little is known about the distribution of basement membrane constituents in lymphatic vessels. We studied the distribution of basement membrane proteins in lymphatic vessels of normal human skin, digestive tract, ovary and, as an example of tumours with abundant lymphatics, ovarian carcinomas. Basement membrane proteins were localized by immunohistochemistry with monoclonal antibodies, whereas lymphatic capillaries were detected with antibodies to the lymphatic vessel endothelial hyaluronan receptor-1, LYVE-1. In skin and ovary, fibrillar immunoreactivity for the laminin alpha4, beta1, beta2 and gamma1 chains, type IV and XVIII collagens and nidogen-1 was found in the basement membrane region of the lymphatic endothelium, whereas also heterogeneous reactivity for the laminin alpha5 chain was detected in the digestive tract. Among ovarian carcinomas, intratumoural lymphatic vessels were found especially in endometrioid carcinomas. In addition to the laminin alpha4, beta1, beta2 and gamma1 chains, type IV and XVIII collagens and nidogen-1, carcinoma lymphatics showed immunoreactivity for the laminin alpha5 chain and Lutheran glycoprotein, a receptor for the laminin alpha5 chain. In normal lymphatic capillaries, the presence of primarily alpha4 chain laminins may therefore compromise the formation of endothelial basement membrane, as these truncated laminins lack one of the three arms required for efficient network assembly. The localization of basement membrane proteins adjacent to lymphatic endothelia suggests a role for these proteins in lymphatic vessels. The distribution of the laminin alpha5 chain and Lutheran glycoprotein proposes a difference between normal and carcinoma lymphatic capillaries.

  12. Survival of women with ovarian carcinomas and borderline tumors is not affected by estrogen and progesterone receptor status.

    PubMed

    Sallum, Luis Felipe; Sarian, Luis Otavio; Lucci De Angelo Andrade, Liliana; Vassallo, José; Soares, Fernando Augusto; Pinto, Glauce Aparecida; Ferreira, Patrícia Andréia; Derchain, Sophie

    2013-04-01

    To examine the patterns of estrogen receptor (ER) and progesterone receptor (PR) expression in borderline ovarian tumors (BOTs) and ovarian carcinomas. We also assessed the disease-free survival (DFS) and overall survival (OS) in women with ovarian carcinoma, in relation to ER and/or PR expression. We examined ER/PR expression in 38 BOTs and 172 ovarian carcinomas removed from patients treated at the State University of Campinas-UNICAMP (Brazil), from 1993 to 2008 and followed for up to 60 months using tissue microarray-based immunohistochemistry. Twenty-eight (73.7%) mucinous and 10 (26.3%) serous BOTs were included. Ovarian carcinomas consisted mainly of 79 (46.0%) serous, 44 (25.5%) mucinous, 17 (9.8%) endometrioid, 10 (5.8%) clear-cell types. There was no significant difference of the ER/PR expression between BOT and ovarian carcinoma (p=0.55 for ER alone, 0.90 for PR alone, and 0.12 for combined expression). The level of ER/PR expression in BOTs was significantly higher in serous than in mucinous tumors (p<0.01). In carcinomas, ER/PR was higher in serous tumors than in mucinous (p<0.01) and clear cell tumors (p=0.02), and higher in endometrioid tumors than in mucinous tumors (p<0.01). DFS was affected neither by the clinical characteristics nor by combined steroid receptor status. OS was found to be significantly worse (p<0.01) only in women with stages II-IV tumors and those with residual disease after surgery (p<0.01). Overall, serous and endometrioid tumors were predominantly ER/PR positive, whereas mucinous and clear-cell tumors were preponderantly ER/PR negative. DFS and OS were not affected by ER/PR expression.

  13. Survival of women with ovarian carcinomas and borderline tumors is not affected by estrogen and progesterone receptor status

    PubMed Central

    Sallum, Luis Felipe; Sarian, Luis Otavio; Lucci De Angelo Andrade, Liliana; Vassallo, José; Soares, Fernando Augusto; Pinto, Glauce Aparecida; Ferreira, Patrícia Andréia

    2013-01-01

    Objective To examine the patterns of estrogen receptor (ER) and progesterone receptor (PR) expression in borderline ovarian tumors (BOTs) and ovarian carcinomas. We also assessed the disease-free survival (DFS) and overall survival (OS) in women with ovarian carcinoma, in relation to ER and/or PR expression. Methods We examined ER/PR expression in 38 BOTs and 172 ovarian carcinomas removed from patients treated at the State University of Campinas-UNICAMP (Brazil), from 1993 to 2008 and followed for up to 60 months using tissue microarray-based immunohistochemistry. Results Twenty-eight (73.7%) mucinous and 10 (26.3%) serous BOTs were included. Ovarian carcinomas consisted mainly of 79 (46.0%) serous, 44 (25.5%) mucinous, 17 (9.8%) endometrioid, 10 (5.8%) clear-cell types. There was no significant difference of the ER/PR expression between BOT and ovarian carcinoma (p=0.55 for ER alone, 0.90 for PR alone, and 0.12 for combined expression). The level of ER/PR expression in BOTs was significantly higher in serous than in mucinous tumors (p<0.01). In carcinomas, ER/PR was higher in serous tumors than in mucinous (p<0.01) and clear cell tumors (p=0.02), and higher in endometrioid tumors than in mucinous tumors (p<0.01). DFS was affected neither by the clinical characteristics nor by combined steroid receptor status. OS was found to be significantly worse (p<0.01) only in women with stages II-IV tumors and those with residual disease after surgery (p<0.01). Conclusion Overall, serous and endometrioid tumors were predominantly ER/PR positive, whereas mucinous and clear-cell tumors were preponderantly ER/PR negative. DFS and OS were not affected by ER/PR expression. PMID:23653835

  14. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms.

    PubMed

    Tafe, Laura J; Garg, Karuna; Chew, Ivy; Tornos, Carmen; Soslow, Robert A

    2010-06-01

    Carcinomas of the endometrium and ovary with undifferentiated components are uncommon neoplasms that are likely underdiagnosed. They are important to recognize as they have been shown to be clinically aggressive. We identified 32 carcinomas with undifferentiated components as defined by Silva and co-workers, 26 endometrial and 6 of ovarian origin. The patient age ranged from 21 to 76 years (median 55); 40% of patients were ovarian carcinomas with undifferentiated components) presented at advanced stages (FIGO III-IV). Pelvic and para-aortic lymph nodes were the most frequent sites of metastases. Twenty tumors, entirely undifferentiated, consisted of sheets of dyshesive, ovoid cells with uniform, large vesicular nuclei, whereas 12 tumors contained combinations of differentiated endometrioid adenocarcinoma with undifferentiated components. Although most undifferentiated tumors had a monotonous cytologic appearance without prominent stroma, six showed focal nuclear pleomorphism and eight cases had variably sized zones of rhabdoid cells in a background of myxoid stroma. The tumors were frequently misdiagnosed; they received a wide range of diagnoses, including FIGO grade 2 or 3 endometrioid carcinoma, carcinosarcoma, high-grade sarcoma including endometrial stromal sarcoma, neuroendocrine carcinoma, lymphoma, granulosa cell tumor and epithelioid sarcoma. Up to 86% of the cases showed focal, but strong keratin and/or epithelial membrane antigen staining, with CK18 being the most frequently positive keratin stain. They were predominantly negative for neuroendocrine markers, smooth muscle markers and estrogen receptor/progesterone receptor. Mismatch repair protein expression by immunohistochemistry was evaluated in 17 cases, and 8 (47%) were abnormal (7 with loss of MLH1/PMS2 and 1 with MSH6 loss). Follow-up was available for 27 patients, although it was very short in many cases, ranging from 0.5 to 89

  15. CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma.

    PubMed

    Shang, Y; He, J; Wang, Y; Feng, Q; Zhang, Y; Guo, J; Li, J; Li, S; Wang, Y; Yan, G; Ren, F; Shi, Y; Xu, J; Zeps, N; Zhai, Y; He, D; Chang, Z

    2017-07-20

    Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer.

  16. ARID1A Mutations and PI3K/AKT Pathway Alterations in Endometriosis and Endometriosis-Associated Ovarian Carcinomas

    PubMed Central

    Samartzis, Eleftherios P.; Noske, Aurelia; Dedes, Konstantin J.; Fink, Daniel; Imesch, Patrick

    2013-01-01

    Endometriosis is a common gynecological disease affecting 6%–10% of women of reproductive age and is characterized by the presence of endometrial-like tissue in localizations outside of the uterine cavity as, e.g., endometriotic ovarian cysts. Mainly, two epithelial ovarian carcinoma subtypes, the ovarian clear cell carcinomas (OCCC) and the endometrioid ovarian carcinomas (EnOC), have been molecularly and epidemiologically linked to endometriosis. Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) have been found to occur in high frequency in OCCC and EnOC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWI/SNF chromatin remodeling complex and considered as a bona fide tumor suppressor. ARID1A mutations frequently co-occur with mutations, leading to an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, such as mutations in PIK3CA encoding the catalytic subunit, p110α, of PI3K. In combination with recent functional observations, these findings strongly suggest cooperating mechanisms between the two pathways. The occurrence of ARID1A mutations and alterations in the PI3K/AKT pathway in endometriosis and endometriosis-associated ovarian carcinomas, as well as the possible functional and clinical implications are discussed in this review. PMID:24036443

  17. Ovarian high-grade serous carcinoma with a noninvasive growth pattern simulating a serous borderline tumor.

    PubMed

    Imamura, Hiroko; Ohishi, Yoshihiro; Aman, Murasaki; Shida, Kaai; Shinozaki, Tomoko; Yasutake, Nobuko; Sonoda, Kenzo; Kato, Kiyoko; Oda, Yoshinao

    2015-10-01

    Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG-noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT.

  18. Silencing of p130Cas in Ovarian Carcinoma: A Novel Mechanism for Tumor Cell Death

    PubMed Central

    Nick, Alpa M.; Stone, Rebecca L.; Armaiz-Pena, Guillermo; Ozpolat, Bulent; Tekedereli, Ibrahim; Graybill, Whitney S.; Landen, Charles N.; Villares, Gabriel; Vivas-Mejia, Pablo; Bottsford-Miller, Justin; Kim, Hye Sun; Lee, Ju-Seog; Kim, Soo Mi; Baggerly, Keith A.; Ram, Prahlad T.; Deavers, Michael T.; Coleman, Robert L.; Lopez-Berestein, Gabriel

    2011-01-01

    Background We investigated the clinical and biological significance of p130cas, an important cell signaling molecule, in ovarian carcinoma. Methods Expression of p130cas in ovarian tumors, as assessed by immunohistochemistry, was associated with tumor characteristics and patient survival. The effects of p130cas gene silencing with small interfering RNAs incorporated into neutral nanoliposomes (siRNA-DOPC), alone and in combination with docetaxel, on in vivo tumor growth and on tumor cell proliferation (proliferating cell nuclear antigen) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were examined in mice bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) or taxane-resistant (HeyA8-MDR) ovarian tumors (n = 10 per group). To determine the specific mechanisms by which p130cas gene silencing abrogates tumor growth, we measured cell viability (MTT assay), apoptosis (fluorescence-activated cell sorting), autophagy (immunoblotting, fluorescence, and transmission electron microscopy), and cell signaling (immunoblotting) in vitro. All statistical tests were two-sided. Results Of 91 ovarian cancer specimens, 70 (76%) had high p130cas expression; and 21 (24%) had low p130cas expression. High p130cas expression was associated with advanced tumor stage (P < .001) and higher residual disease (>1 cm) following primary cytoreduction surgery (P = .007) and inversely associated with overall survival and progression-free survival (median overall survival: high p130cas expression vs low expression, 2.14 vs 9.1 years, difference = 6.96 years, 95% confidence interval = 1.69 to 9.48 years, P < .001; median progression-free survival: high p130cas expression vs low expression, 1.04 vs 2.13 years, difference = 1.09 years, 95% confidence interval = 0.47 to 2.60 years, P = .01). In mice bearing orthotopically implanted HeyA8 or SKOV3ip1 ovarian tumors, treatment with p130cas siRNA-DOPC in combination with docetaxel chemotherapy resulted in the greatest

  19. Inhibition of Hec1 expression enhances the sensitivity of human ovarian cancer cells to paclitaxel

    PubMed Central

    Mo, Qing-qing; Chen, Ping-bo; Jin, Xin; Chen, Qian; Tang, Lan; Wang, Bei-bei; Li, Ke-zhen; Wu, Peng; Fang, Yong; Wang, Shi-xuan; Zhou, Jian-feng; Ma, Ding; Chen, Gang

    2013-01-01

    Aim: Hec1, a member of the Ndc80 kinetochore complex, is highly expressed in cancers. The aim of this study was to explore the role and mechanism of action of Hec1 with respect to the cytotoxicity of paclitaxel in ovarian cancer. Methods: Thirty ovarian cancer samples and 6 normal ovarian samples were collected. Hec1 expression in these samples was determined with immunohistochemistry. Ovarian cancer cell lines A2780, OV2008, C13K, SKOV3, and CAOV3 and A2780/Taxol were examined. Cell apoptosis and cell cycle analysis were detected with flow cytometric technique. siRNA was used to delete Hec1 in the cells. The expression of related mRNAs and proteins was measured using RT-PCR and Western blot analysis, respectively. Results: Hec1 expression was significantly higher in ovarian cancer samples than in normal ovarian samples, and was associated with paclitaxel-resistance and poor prognosis. Among the 6 ovarian cancer cell lines examined, Hec1 expression was highest in paclitaxel-resistant A2780/Taxol cells, and lowest in A2780 cells. Depleting Hec1 in A2780/Taxol cells with siRNA decreased the IC50 value of paclitaxel by more than 10-fold (from 590±26.7 to 45.6±19.4 nmol/L). Depleting Hec1 in A2780 cells had no significant effect on the paclitaxel sensitivity. In paclitaxel-treated A2780/Taxol cells, depleting Hec1 significantly increased the cleaved PARP and Bax protein levels, and decreased the Bcl-xL protein level. Conclusion: Hec1 overexpression is associated with the progression and poor prognosis of ovarian cancer. Inhibition of Hec1 expression can sensitize ovarian cancer cells to paclitaxel. PMID:23474708

  20. Somatic Activation of rasK Gene in a Human Ovarian Carcinoma

    NASA Astrophysics Data System (ADS)

    Feig, L. A.; Bast, R. C.; Knapp, R. C.; Cooper, G. M.

    1984-02-01

    A tumor isolate from a patient with serous cystadenocarcinoma of the ovary contained an activated rasK gene detected by transfection of NIH/3T3 cells. In contrast, DNA from normal cells of the same patient lacked transforming activity, indicating that activation of this transforming gene was the consequence of somatic mutation in the neoplastic cells. The transforming gene product displayed an electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that differed from the mobilities of rasK transforming proteins in other tumors, indicating that a previously undescribed mutation was responsible for activation of rasK in this ovarian carcinoma.

  1. Lack of acute toxicity associated with a multimodality treatment of stage III ovarian epithelial carcinoma

    SciTech Connect

    Belch, R.Z.; Coughlin, C.T.; Cooney, L.C.; Forcier, R.J.; Maurer, L.H. )

    1990-04-01

    Eleven patients with advanced stage III ovarian epithelial carcinoma were treated primarily according to an aggressive multimodality plan utilizing cytoreductive surgery, chemotherapy (high-dose cisplatin and Cytoxan), and consolidative radiation therapy (abdominopelvic bath plus pelvic boost). The treatment was tolerated remarkably well. There was no evidence of progressive disease during treatment, and all patients showed a positive response. There was a notable lack of significant acute morbidity, with the exception of a severe symptomatic peripheral neuropathy associated with cisplatin doses of 200 mg/m2. This was not evident with doses of cisplatin up to 150 mg/m2.

  2. A survival analysis comparing women with ovarian low-grade serous carcinoma to those with high-grade histology.

    PubMed

    Chen, Ming; Jin, Ying; Bi, Yalan; Yin, Jie; Wang, Yongxue; Pan, Lingya

    2014-01-01

    Ovarian low-grade serous carcinoma (LGSC) and high-grade serous carcinoma have distinct molecular profiles, clinical behaviors, and treatment responses. The survival advantage for patients with low-grade carcinoma compared with patients with high-grade histology remains controversial. We retrospectively reviewed the medical charts of 381 patients with ovarian serous carcinoma at Peking Union Medical College Hospital from 2007 to 2010. Patients were classified into two groups according to MD Anderson two-tier system: 35 (9.2%) cases with LGSC and 346 with high-grade serous carcinoma. Patients with low-grade serous ovarian cancer had a significantly younger age at diagnosis (46 versus 56 years, P=0.046), and their median progression-free survival (PFS) and overall survival values were 35.0 and 54.0 months, respectively. A multivariate analysis showed that, for serous ovarian cancer, the histological grade was a significant prognostic factor for PFS but not for overall survival (P=0.022 and P=0.0566, respectively). When stratified by the existence of a residual disease, patients with low-grade disease who underwent cytoreductive surgery without macroscopic residual disease (>1 cm) had a significantly improved median PFS time (36.0 months) compared with that of patients with high-grade carcinoma who received optimal cytoreductive surgery (16.0 months, P=0.017). Conversely, patients with low-grade and high-grade carcinoma who were left with macroscopic residue (>1 cm) experienced a similarly shorter median PFS (10.0 and 13.0 months, respectively, P=0.871). The International Federation of Gynecology and Obstetrics stage and residual disease were significant prognostic factors of low-grade carcinoma, while positive ascites was associated with a worse PFS value. Our data showed that LGSC is a different entity from high-grade carcinoma and that LGSC was associated with improved PFS after optimal cytoreductive surgery but not suboptimal operation.

  3. Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

    ClinicalTrials.gov

    2017-10-11

    Low Grade Ovarian Serous Adenocarcinoma; Micropapillary Serous Carcinoma; Ovarian Serous Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

  4. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.

    PubMed

    Pennington, Kathryn P; Walsh, Tom; Harrell, Maria I; Lee, Ming K; Pennil, Christopher C; Rendi, Mara H; Thornton, Anne; Norquist, Barbara M; Casadei, Silvia; Nord, Alexander S; Agnew, Kathy J; Pritchard, Colin C; Scroggins, Sheena; Garcia, Rochelle L; King, Mary-Claire; Swisher, Elizabeth M

    2014-02-01

    Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. ©2013 AACR.

  5. Diagnostic value of dual detection of hepatocyte nuclear factor 1 beta (HNF-1β) and napsin A for diagnosing ovarian clear cell carcinoma.

    PubMed

    Li, Qing; Zeng, Xin; Cheng, Xue; Zhang, Jingmin; Ji, Jie; Wang, Jinsong; Xiong, Kemei; Qi, Qiong; Huang, Wenbin

    2015-01-01

    We evaluated the diagnostic value of hepatocyte nuclear factor 1 beta (HNF-1β) and napsin A for diagnosing ovarian clear cell carcinoma. Immunohistochemical EnVision was used to measure HNF-1β and napsin A expression in 38 cases of ovarian clear cell carcinoma, 30 cases of high-grade serous carcinoma, 22 cases of endometrioid adenocarcinoma, and 16 metastatic Krukenberg tumor cases. Then we found that HNF-1β appeared in all ovarian clear cell carcinoma and was less common in high-grade serous and endometrioid adenocarcinoma (P < 0.05). However, no significant difference in HNF-1β between clear cell carcinoma and metastatic Krukenberg tumor was found (P > 0.05). Napsin A was expressed in 97.4% of ovarian clear cell carcinoma, 6.7% high-grade serous carcinoma, 22.7% endometrioid adenocarcinoma, and 0% metastatic Krukenberg tumors. Napsin A in clear cell carcinoma was greater than that found in high-grade serous carcinoma, endometrioid adenocarcinoma, and metastatic Krukenberg tumor (P < 0.05). Sensitivity and specificity of HNF-1β and napsin A for diagnosing ovarian clear cell carcinoma was 100% and 54.4%, and 97.4% and 89.7%, respectively. Sensitivity and specificity of HNF-1β and napsin A for diagnosing ovarian clear cell carcinoma was 97.4% and 91.2%, respectively. So it is concluded that HNF-1β and napsin A are more sensitive than currently used markers for diagnosing ovarian clear cell carcinoma. Moreover, napsin A is more specific than HNF-1β. Combining HNF-1β and napsin A may distinguish clear cell carcinoma from high-grade serous carcinoma, endometrioid adenocarcinoma and metastatic Krukenberg tumors.

  6. [Reversal effect of MDR1 and MDR3 gene silencing on resistance of A2780/taxol cells to paclitaxel].

    PubMed

    Xiao, Lan; Gao, Rui; Lu, Shi; Lu, Mei-Song; Liang, Ming-Lin; Ren, Li-Rong; Wang, Ze-Hua

    2007-06-01

    To investigate the reversal effect of MDR1 and MDR3 gene silencing on resistance of A2780/taxol cells to paclitaxel. shRNA plasmid vector specifically targeting MDR1 and MDR3 genes was transfected into A2780/taxol cells. The early stage cell apoptosis and the effect of intracellular rhodamine 123 (Rh123) accumulation were detected by flow cytometry (FCM). The late stage cell apoptosis rate was detected by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). The 50% inhibition concentration (IC(50)) of paclitaxel on A2780/taxol cells was determined by methyl thiazolyl tetrazolium (MTT) assay. MDR1 and MDR3 mRNA were assessed by RT-PCR, and caspase-3 protein was detected by western blot. After treatment with MDR1 and MDR3 shRNA plasmid vector, early apoptosis rate of A2780/taxol cells was (20.21 +/- 0.56)% and (10.87 +/- 1.24)%, respectively. MDR1 and MDR3 shRNA could increase cellular Rh123 accumulation (116.6 +/- 8.1 and 98.4 +/- 3.8, respectively). The late stage apoptosis rates detected by TUNEL displayed the same tendency as FCM results did. The IC(50) for paclitaxel of A2780/taxol cells was decreased significantly. The mRNA levels of MDR1 and MDR3 in A2780/taxol cells were decreased by (73.3 +/- 0.8)% and (51.6 +/- 0.4)% of control, and the reduction of MDR1 and MDR3 mRNA was in a time-dependent manner. The expression of caspase-3 protein of MDR1 and MDR3 shRNA vector transfected group in A2780/taxol cells was significantly increased [(80.8 +/- 2.6)% and (72.0 +/- 4.7)%, respectively]. MDR1 and MDR3 gene silencing could recover sensitivity of A2780/taxol cells to paclitaxel and induce cell apoptosis, thus reversing cell resistance to paclitaxel.

  7. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.

    PubMed

    Qiu, Wen; Hu, Min; Sridhar, Anita; Opeskin, Ken; Fox, Stephen; Shipitsin, Michail; Trivett, Melanie; Thompson, Ella R; Ramakrishna, Manasa; Gorringe, Kylie L; Polyak, Kornelia; Haviv, Izhak; Campbell, Ian G

    2008-05-01

    There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs.

  8. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

    PubMed Central

    Qiu, Wen; Hu, Min; Sridhar, Anita; Opeskin, Ken; Fox, Stephen; Shipitsin, Michail; Trivett, Melanie; Thompson, Ella R; Ramakrishna, Manasa; Gorringe, Kylie L; Polyak, Kornelia; Haviv, Izhak; Campbell, Ian G

    2013-01-01

    There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs. PMID:18408720

  9. Dasatinib in Treating Patients With Recurrent or Persistent Ovarian, Fallopian Tube, Endometrial or Peritoneal Cancer

    ClinicalTrials.gov

    2017-04-13

    Endometrial Clear Cell Adenocarcinoma; Estrogen Receptor Negative; Ovarian Clear Cell Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma

  10. Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

    PubMed

    King, Claire M; Barbara, Cynthia; Prentice, Andrew; Brenton, James D; Charnock-Jones, D Stephen

    2016-01-01

    Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain--frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.

  11. Clinicopathology of EpCAM and EGFR in Human Epithelial Ovarian Carcinoma

    PubMed Central

    Zheng, Jingying; Zhao, Lijing; Wang, Yi; Zhao, Shuhua; Cui, Manhua

    2017-01-01

    Abstract The objective of this study was to explore the expression of EpCAM and EGFR in human epithelial ovarian cancer (EOC) and their correlation with clinicopathological parameters. The protein expression levels of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) were evaluated by immunohistochemistry in formalin-fixed paraffin-embedded specimens from 30 patients with epithelial ovarian carcinoma and 15 normal ovary tissues. Clinicopathological characteristics were gathered by retrospective review of the patients’ files. The correlation between EpCAM and EGFR expression, as well as their association with clinical pathological parameters were investigated. The SPSS 17.0 package was used to perform statistical analyses. The positive expression rates of EpCAM and EGFR were significantly elevated in epithelial ovarian cancer tissues than in normal ovary tissues. The positive expressions of EpCAM and EGFR in EOC were associated with International Federation of Gynecology and Obstetrics (FIGO) stage and tumor differentiation, lymph node metastasis. Spearman correlation analysis demonstrated a significant positive association between EpCAM and EGFR expression in EOC. The co-expression of EpCAM and EGFR may play an important role in the carcinogenesis of EOC and might provide a promising molecular therapeutic target. PMID:28401199

  12. Intracellular localization and trafficking of fluorescein-labeled cisplatin in human ovarian carcinoma cells.

    PubMed

    Safaei, Roohangiz; Katano, Kuniyuki; Larson, Barrett J; Samimi, Goli; Holzer, Alison K; Naerdemann, Wiltrud; Tomioka, Mika; Goodman, Murray; Howell, Stephen B

    2005-01-15

    We sought to identify the subcellular compartments in which cisplatin [cis-diamminedichloroplatinum (DDP)] accumulates in human ovarian carcinoma cells and define its export pathways. Deconvoluting digital microscopy was used to identify the subcellular location of fluorescein-labeled DDP (F-DDP) in 2008 ovarian carcinoma cells stained with organelle-specific markers. Drugs that block vesicle movement were used to map the traffic pattern. F-DDP accumulated in vesicles and were not detectable in the cytoplasm. F-DDP accumulated in the Golgi, in vesicles belonging to the secretory export pathway, and in lysosomes but not in early endosomes. F-DDP extensively colocalized with vesicles expressing the copper efflux protein, ATP7A, whose expression modulates the cellular pharmacology of DDP. Inhibition of vesicle trafficking with brefeldin A, wortmannin, or H89 increased the F-DDP content of vesicles associated with the pre-Golgi compartments and blocked the loading of F-DDP into vesicles of the secretory pathway. The importance of the secretory pathway was confirmed by showing that wortmannin and H89 increased whole cell accumulation of native DDP. F-DDP is extensively sequestered into vesicular structures of the lysosomal, Golgi, and secretory compartments. Much of the distribution to other compartments occurs via vesicle trafficking. F-DDP detection in the vesicles of the secretory pathway is consistent with a major role for this pathway in the efflux of F-DDP and DDP from the cell.

  13. Cytogenetic damage in lymphocytes of patients undergoing therapy for small cell lung cancer and ovarian carcinoma

    SciTech Connect

    Padjas, Anna; Lesisz, Dominika; Lankoff, Anna; Banasik, Anna; Lisowska, Halina; Bakalarz, Robert; Gozdz, Stanislaw; Wojcik, Andrzej . E-mail: awojcik@pu.kielce.pl

    2005-12-01

    The level of cytogenetic damage in peripheral blood lymphocytes of patients undergoing chemotherapy has been analyzed incisively 20 years ago. The results showed that the highest level of cytogenetic damage was observed at the end of therapy. In recent years, the doses of anticancer drugs were intensified thanks to the discovery of colony stimulating factors. Therefore, it was interesting to analyze the kinetics of micronuclei formation in lymphocytes of patients undergoing modern chemotherapy. The frequencies of micronuclei were measured in lymphocytes of 6 patients with small cell lung cancer treated with a combination of cisplatin and etoposide and 7 patients with ovarian carcinoma treated with a combination of taxol and cisplatin. 3 patients with lung cancer received radiotherapy in addition to chemotherapy. Micronuclei were analyzed in lymphocytes collected before the start of therapy and 1 day before each following cycle of chemotherapy. The micronucleus frequencies were compared with the kinetics of leukocyte counts. The micronucleus frequencies showed an interindividual variability. On average, the frequencies of micronuclei increased during the first half of therapy and declined thereafter, reaching, in some patients with ovarian carcinoma, values below the pre-treatment level. Leukocyte counts decreased strongly at the beginning of therapy with an upward trend at the end. We suggest that the decline of micronuclei was due to repopulation of lymphocytes and acquired drug resistance.

  14. Cytogenetic damage in lymphocytes of patients undergoing therapy for small cell lung cancer and ovarian carcinoma.

    PubMed

    Padjas, Anna; Lesisz, Dominika; Lankoff, Anna; Banasik, Anna; Lisowska, Halina; Bakalarz, Robert; Góźdź, Stanisław; Wojcik, Andrzej

    2005-12-01

    The level of cytogenetic damage in peripheral blood lymphocytes of patients undergoing chemotherapy has been analyzed incisively 20 years ago. The results showed that the highest level of cytogenetic damage was observed at the end of therapy. In recent years, the doses of anticancer drugs were intensified thanks to the discovery of colony stimulating factors. Therefore, it was interesting to analyze the kinetics of micronuclei formation in lymphocytes of patients undergoing modern chemotherapy. The frequencies of micronuclei were measured in lymphocytes of 6 patients with small cell lung cancer treated with a combination of cisplatin and etoposide and 7 patients with ovarian carcinoma treated with a combination of taxol and cisplatin. 3 patients with lung cancer received radiotherapy in addition to chemotherapy. Micronuclei were analyzed in lymphocytes collected before the start of therapy and 1 day before each following cycle of chemotherapy. The micronucleus frequencies were compared with the kinetics of leukocyte counts. The micronucleus frequencies showed an interindividual variability. On average, the frequencies of micronuclei increased during the first half of therapy and declined thereafter, reaching, in some patients with ovarian carcinoma, values below the pre-treatment level. Leukocyte counts decreased strongly at the beginning of therapy with an upward trend at the end. We suggest that the decline of micronuclei was due to repopulation of lymphocytes and acquired drug resistance.

  15. Patterns of First Recurrence in African American Patients with High Grade Epithelial Ovarian Carcinoma.

    PubMed

    Singh, Sareena; Armstrong, Amy; Pettigrew, Gaetan; Resnick, Kimberly

    2016-01-01

    The aim of this study is to compare the distribution of anatomic sites of first recurrence in African American (AA) patients with ovarian carcinoma compared to Caucasians. Patients diagnosed with high-grade epithelial ovarian, fallopian tube or peritoneal carcinoma from 2007 to 2013 were identified. Patterns of recurrence were compared for AA and Caucasian patients. Progression-free survival (PFS) and overall survival (OS) were compared. A total of 238 patients were included - 210 Caucasians and 28 AAs. At a follow-up time of 28 months, AAs were more likely to have multiple anatomic sites of recurrence rather than a single site when compared to Caucasians (63.6 vs. 35.5%, p = 0.01). Time to first recurrence was shorter for AA patients (12 vs. 18 months, p < 0.01). PFS and OS did not differ. AA patients with multiple sites of first recurrence had a significantly shorter OS than Caucasian patients with multiple sites of first recurrence (24 vs. 30 months, p = 0.022). Patterns of first recurrence differ between AAs and Caucasians. AAs have shorter times to first recurrence and are more likely to have multiple anatomic sites involved. AA patients with multiple sites of recurrence have a shorter OS than Caucasian patients with multiple sites. © 2015 S. Karger AG, Basel.

  16. Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells.

    PubMed

    Alvero, Ayesha B; O'Malley, David; Brown, David; Kelly, Graham; Garg, Manish; Chen, Wei; Rutherford, Thomas; Mor, Gil

    2006-02-01

    Previously, it was demonstrated that phenoxodiol induces apoptosis in epithelial ovarian carcinoma (EOC) cells and that it is capable of sensitizing these cells to Fas-mediated apoptosis. The objectives of this study were to determine whether phenoxodiol can also act as chemosensitizer to chemotherapeutic agents and to characterize the molecular mechanism behind its sensitizing effect. Ten EOC cell lines were used in this study. The effect of phenoxodiol on the inhibitory concentration 50% (IC50) of carboplatin, paclitaxel, and gemcitabine was determined by the CellTiter 96 Assay. The in vivo effect of combination treatments with phenoxodiol and the above-mentioned agents was determined in animal xenograft models. Apoptosis was measured using the Caspase-Glo Assay and the apoptotic cascade was characterized by Western blot analyses. The results showed that phenoxodiol is able to sensitize EOC cells to carboplatin, paclitaxel, and gemcitabine both in vitro and in vivo. In addition, it was demonstrated that phenoxodiol is capable of inducing apoptosis by: 1) the activation of the mitochondrial pathway through caspase-2 and Bid signaling, and 2) the proteasomal degradation of the anti-apoptotic protein XIAP. Understanding the components of the apoptotic pathway activated by phenoxodiol, which allows it to sensitize EOC cells to chemotherapeutic agents, will provide valuable information on the characteristic mode of action of a chemosensitizer. This will help in the identification of novel drugs and in the design of better strategies for combination therapy in patients with recurrent ovarian carcinoma. Copyright (c) 2005 American Cancer Society.

  17. Carboplatin, Paclitaxel and Gemcitabine Hydrochloride With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian, Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-10-12

    Clear Cell Adenocarcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Mucinous Adenocarcinoma; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinofibroma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  18. Human lymphatic endothelial cells contribute to epithelial ovarian carcinoma metastasis by promoting lymphangiogenesis and tumour cell invasion

    PubMed Central

    XIE, YIHONG; ZHONG, YANPING; GAO, TING; ZHANG, XINYING; LI, LI; RUAN, HEYUN; LI, DANRONG

    2016-01-01

    The microenvironment of a tumour is an important factor in ovarian cancer metastasis. The present study aimed to simulate the in vivo microenvironment of an ovarian carcinoma using a co-culture system consisting of human lymphatic endothelial cells (HLECs) and human ovarian carcinoma cells with directional high lymphatic metastasis (SKOV3-PM4s) in order to investigate the role of both cell types in ovarian carcinoma metastasis. The SKOV3-PM4s cultured in the HLEC-conditioned medium exhibited increased numbers of pseudopodia and mitotic figures, proliferated at a faster rate and exhibited enhanced invasion and migratory abilities. Furthermore, the HLECs cultured in SKOV3-PM4-conditioned medium exhibited significant morphological alterations and vacuolisation of the cytoplasm, as well as increased invasion, migratory and tube forming abilities. In addition, spontaneous fusion of the SKOV3-PM4s and HLECs was observed in the co-culture system using laser confocal microscopy. The gelatin zymography assay demonstrated that matrix metalloproteinase-2, which was downregulated in the SKOV3-PM4s, was upregulated in the co-culture system. The results of the present study suggested that the invasion ability of the SKOV3-PM4s was increased in the in vitro co-culture system of SKOV3-PM4 and HLECs. Therefore, alterations in the cell microenvironment may represent a novel strategy for ovarian cancer therapy. PMID:27168777

  19. Somatic Mutations Favorable to Patient Survival Are Predominant in Ovarian Carcinomas

    PubMed Central

    Zhang, Wensheng; Edwards, Andrea; Flemington, Erik; Zhang, Kun

    2014-01-01

    Somatic mutation accumulation is a major cause of abnormal cell growth. However, some mutations in cancer cells may be deleterious to the survival and proliferation of the cancer cells, thus offering a protective effect to the patients. We investigated this hypothesis via a unique analysis of the clinical and somatic mutation datasets of ovarian carcinomas published by the Cancer Genome Atlas. We defined and screened 562 macro mutation signatures (MMSs) for their associations with the overall survival of 320 ovarian cancer patients. Each MMS measures the number of mutations present on the member genes (except for TP53) covered by a specific Gene Ontology (GO) term in each tumor. We found that somatic mutations favorable to the patient survival are predominant in ovarian carcinomas compared to those indicating poor clinical outcomes. Specially, we identified 19 (3) predictive MMSs that are, usually by a nonlinear dose-dependent effect, associated with good (poor) patient survival. The false discovery rate for the 19 “positive” predictors is at the level of 0.15. The GO terms corresponding to these MMSs include “lysosomal membrane” and “response to hypoxia”, each of which is relevant to the progression and therapy of cancer. Using these MMSs as features, we established a classification tree model which can effectively partition the training samples into three prognosis groups regarding the survival time. We validated this model on an independent dataset of the same disease (Log-rank p-value <2.3×10-4) and a dataset of breast cancer (Log-rank p-value <9.3×10−3). We compared the GO terms corresponding to these MMSs and those enriched with expression-based predictive genes. The analysis showed that the GO term pairs with large similarity are mainly pertinent to the proteins located on the cell organelles responsible for material transport and waste disposal, suggesting the crucial role of these proteins in cancer mortality. PMID:25390899

  20. Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma.

    PubMed

    Matsuo, Koji; Nishimura, Masato; Komurov, Kakajan; Shahzad, Mian M K; Ali-Fehmi, Rouba; Roh, Ju-Won; Lu, Chunhua; Cody, Dianna D; Ram, Prahlad T; Loizos, Nick; Coleman, Robert L; Sood, Anil K

    2014-01-01

    Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy. PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers. When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P=0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model. These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development. © 2013.

  1. CCNE1 amplification and centrosome number abnormality in serous tubal intraepithelial carcinoma: further evidence supporting its role as a precursor of ovarian high-grade serous carcinoma.

    PubMed

    Kuhn, Elisabetta; Wang, Tian-Li; Doberstein, Kai; Bahadirli-Talbott, Asli; Ayhan, Ayse; Sehdev, Ann Smith; Drapkin, Ronny; Kurman, Robert J; Shih, Ie-Ming

    2016-10-01

    Aberration in chromosomal structure characterizes almost all cancers and has profound biological significance in tumor development. It can be facilitated by various mechanisms including overexpression of cyclin E1 and centrosome amplification. As ovarian high-grade serous carcinoma has pronounced chromosomal instability, in this study we sought to determine whether increased copy number of CCNE1 which encodes cyclin E1 and centrosome amplification (>2 copies) occurs in its putative precursor, serous tubal intraepithelial carcinoma. We found CCNE1 copy number gain/amplification in 8 (22%) of 37 serous tubal intraepithelial carcinomas and 12 (28%) of 43 high-grade serous carcinomas. There was a correlation in CCNE1 copy number between serous tubal intraepithelial carcinoma and high-grade serous carcinoma in the same patients (P<0.001). There was no significant difference in the percentage of CCNE1 gain/amplification between serous tubal intraepithelial carcinoma and high-grade serous carcinoma (P=0.61). Centrosome amplification was recorded in only 5 (14%) of 37 serous tubal intraepithelial carcinomas, and in 10 (40%) of 25 high-grade serous carcinomas. The percentage of cells with centrosome amplification was higher in high-grade serous carcinoma than in serous tubal intraepithelial carcinoma (P<0.001). Induced expression of cyclin E1 increased the percentage of fallopian tube epithelial cells showing centrosome amplification. Our findings suggest that gain/amplification of CCNE1 copy number occurs early in tumor progression and precedes centrosome amplification. The more prevalent centrosome amplification in high-grade serous carcinoma than in serous tubal intraepithelial carcinoma supports the view that serous tubal intraepithelial carcinoma precedes the development of many high-grade serous carcinomas.

  2. New Blocking Antibodies Impede Adhesion, Migration and Survival of Ovarian Cancer Cells, Highlighting MFGE8 as a Potential Therapeutic Target of Human Ovarian Carcinoma

    PubMed Central

    Tibaldi, Lorenzo; Notebaert, Sofie; Dewulf, Melissa; Ngo, Thu Hoa; Zuany-Amorim, Claudia; Amzallag, Nathalie; Bernard-Pierrot, Isabelle; Sastre-Garau, Xavier; Théry, Clotilde

    2013-01-01

    Milk Fat Globule – EGF – factor VIII (MFGE8), also called lactadherin, is a secreted protein, which binds extracellularly to phosphatidylserine and to αvβ3 and αvβ5 integrins. On human and mouse cells expressing these integrins, such as endothelial cells, phagocytes and some tumors, MFGE8/lactadherin has been shown to promote survival, epithelial to mesenchymal transition and phagocytosis. A protumoral function of MFGE8 has consequently been documented for a few types of human cancers, including melanoma, a subtype of breast cancers, and bladder carcinoma. Inhibiting the functions of MFGE8 could thus represent a new type of therapy for human cancers. Here, we show by immunohistochemistry on a collection of human ovarian cancers that MFGE8 is overexpressed in 45% of these tumors, and we confirm that it is specifically overexpressed in the triple-negative subtype of human breast cancers. We have established new in vitro assays to measure the effect of MFGE8 on survival, adhesion and migration of human ovarian and triple-negative breast cancer cell lines. Using these assays, we could identify new MFGE8-specific monoclonal antibodies, which efficiently blocked these three tumor-promoting effects of MFGE8. Our results suggest future use of MFGE8-blocking antibodies as new anti-cancer therapeutics in subgroups of ovarian carcinoma, and triple-negative breast carcinoma patients. PMID:23977342

  3. Cediranib Maleate and Olaparib in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Recurrent Triple-Negative Breast Cancer

    ClinicalTrials.gov

    2017-04-04

    Estrogen Receptor Negative; HER2/Neu Negative; Ovarian Endometrioid Adenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Triple-Negative Breast Carcinoma

  4. Loss of heterozygosity on chromosome 22 in ovarian carcinoma is distal to and is not accompanied by mutations in NF2 at 22q12.

    PubMed Central

    Englefield, P.; Foulkes, W. D.; Campbell, I. G.

    1994-01-01

    Frequent loss of heterozygosity (LOH) has been reported on 22q in ovarian carcinoma, implying the presence of a tumour-suppressor gene. The neurofibromatosis type 2 gene (NF2) at 22q12 is a plausible candidate. Analysis of 9 of the 17 exons of NF2 by single-strand conformational polymorphism (SSCP) in 67 ovarian carcinomas did not detect any somatic mutations, suggesting that NF2 is not involved in the pathogenesis of ovarian carcinoma. LOH data support this conclusion and that the putative tumour-suppressor gene lies distal to NF2, beyond D22S283. Images Figure 1 PMID:7947096

  5. Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma

    PubMed Central

    Hong, Ji Eun; Cho, Young Jae; Ryu, Ji Yoon; Choi, Jung-Joo; Lee, Sang Hoon; Yoon, Gun; Kim, Woo Young; Do, In-Gu; Kim, Min Kyu; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

    2015-01-01

    This study was designed to investigate whether proton pump inhibitors (PPI, V-ATPase blocker) could increase the effect of cytotoxic agents in chemoresistant epithelial ovarian cancer (EOC). Expression of V-ATPase protein was evaluated in patients with EOC using immunohistochemistry, and patient survival was compared based on expression of V-ATPase mRNA from a TCGA data set. In vitro, EOC cell lines were treated with chemotherapeutic agents with or without V-ATPase siRNA or PPI (omeprazole) pretreatment. Cell survival and apoptosis was assessed using MTT assay and ELISA, respectively. In vivo experiments were performed to confirm the synergistic effect with omeprazole and paclitaxel on tumor growth in orthotopic and patient-derived xenograft (PDX) mouse models. Expression of V-ATPase protein in ovarian cancer tissues was observed in 44 patients (44/59, 74.6%). Higher expression of V-ATPase mRNA was associated with poorer overall survival in TCGA data. Inhibition of V-ATPase by siRNA or omeprazole significantly increased cytotoxicity or apoptosis to paclitaxel in chemoresistant (HeyA8-MDR, SKOV3-TR) and clear cell carcinoma cells (ES-2, RMG-1), but not in chemosensitive cells (HeyA8, SKOV3ip1). Moreover, the combination of omeprazole and paclitaxel significantly decreased the total tumor weight compared with paclitaxel alone in a chemoresistant EOC animal model and a PDX model of clear cell carcinoma. However, this finding was not observed in chemosensitive EOC animal models. These results show that omeprazole pretreatment can increase the effect of chemotherapeutic agents in chemoresistant EOC and clear cell carcinoma via reduction of the acidic tumor microenvironment. PMID:26418900

  6. Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy.

    PubMed Central

    Turner, J. H.; Rose, A. H.; Glancy, R. J.; Penhale, W. J.

    1998-01-01

    Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy. Images Figure 1 Figure 2 Figure 3 PMID:9716032

  7. Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5'-untranslated region in human epithelial ovarian carcinoma.

    PubMed

    Suzuki, Fumihiko; Akahira, Jun-Ichi; Miura, Ikumi; Suzuki, Takashi; Ito, Kiyoshi; Hayashi, Shin-Ichi; Sasano, Hironobu; Yaegashi, Nobuo

    2008-12-01

    Evidence exists that sex steroids such as estrogens affect epithelial ovarian cancer. The expression profiles of the estrogen receptors (ER) and ERbeta in particular have not been fully described. Therefore, in our present study, we examined the methylation status of the promoters 0K and 0N, and the expression of ERbeta isoforms in human epithelial ovarian carcinoma. We then correlated methylation status with ER expression status. Twelve ovarian carcinoma cell lines, six primary cultures of ovarian surface epithelial cells (OSE), and 64 cases of ovarian carcinoma tissues were examined. Bisulfite sequencing and quantitative reverse transcription-polymerase chain reaction were used to evaluate methylation status and expression of ERbeta isoforms. The relative abundance of exon 0N, ERbeta1, ERbeta2, and ERbeta4 mRNA was significantly lower in ovarian cancer cell lines and tissues than in their corresponding normal counterparts. However, ERbeta5 mRNA level was relatively higher in the cancers, in clear cell adenocarcinoma in particular, than in the normal ovary. Bisulfite sequencing analysis demonstrated that the two promoters of the ERbeta gene exhibited distinct methylation patterns. Promoter 0N was unmethylated in OSE, rarely methylated in normal ovarian tissues, and extensively methylated in ovarian cancer cell lines and tissues (11/15 cell lines and 18/32 cancer tissues were extensively methylated). The promoter 0K was, however, unmethylated in both normal and malignant ovarian cells and tissues. A significant correlation between promoter 0N hypermethylation and the loss of exon 0N, ERbeta1, ERbeta2, and ERbeta4 mRNA expression was detected in ovarian carcinoma cells and tissues. Treatment of ovarian carcinoma cells with 5-aza-2' deoxycytidine resulted in reexpression of the ERbeta gene. The results of our present study suggest that ERbeta is inactivated mainly through aberrant DNA methylation. This process may play an important role in the pathogenesis of

  8. KRAS/BRAF Analysis in Ovarian Low-Grade Serous Carcinoma Having Synchronous All Pathological Precursor Regions.

    PubMed

    Nakamura, Kohei; Nakayama, Kentaro; Ishibashi, Tomoka; Ishikawa, Noriyoshi; Ishikawa, Masako; Katagiri, Hiroshi; Minamoto, Toshiko; Sato, Emi; Sanuki, Kaori; Yamashita, Hitomi; Iida, Kouji; Sultana, Razia; Kyo, Satoru

    2016-04-26

    Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression.

  9. [Endometrial adenocarcinoma and clear cell carcinoma in a young woman with polycystic ovarian syndrome: a case report].

    PubMed

    Niu, Jing; Liu, Nan; Liu, Guo-Bing

    2016-05-01

    A 26-year-old unmarried woman with irregular menstruation for 4 years was admitted for an intrauterine space-occupying mass. Pathological examination before surgery showed moderately to poorly differentiated endometrial adenocarcinoma. The patient underwent laparoscopically assisted epifascial panhysterectomy with bilateral salpingo-oophorectomy. Pathological examination of the surgical specimens reported moderately to poorly differentiated endometrial adenocarcinoma and stage II clear cell carcinoma. The patient then received chemotherapy and remained alive without evidence of recurrence. Young women with polycystic ovarian syndrome are at high risk of developing endometrial carcinoma, but concurrent clear cell carcinoma is rare. Careful evaluation before and after treatment are essential to improve the patients prognosis.

  10. Ovarian carcinoma cells synthesize both chondroitin sulfate and heparan sulfate cell surface proteoglycans that mediate cell adhesion to interstitial matrix.

    PubMed

    Kokenyesi, R

    Metastatic ovarian carcinoma metastasizes by intra-peritoneal, non-hematogenous dissemination. The adhesion of the ovarian carcinoma cells to extracellular matrix components, such as types I and III collagen and cellular fibronectin, is essential for intra-peritoneal dissemination. The purpose of this study was to determine whether cell surface proteoglycans (a class of matrix receptors) are produced by ovarian carcinoma cells, and whether these proteoglycans have a role in the adhesion of ovarian carcinoma cells to types I and III collagen and fibronectin. Proteoglycans were metabolically labeled for biochemical studies. Both phosphatidylinositol-anchored and integral membrane-type cell surface proteoglycans were found to be present on the SK-OV-3 and NIH:OVCAR-3 cell lines. Three proteoglycan populations of differing hydrodynamic size were detected in both SK-OV-3 and NIH:OVCAR-3 cells. Digestions with heparitinase and chondroitinase ABC showed that cell surface proteoglycans of SK-OV-3 cells had higher proportion of chondroitin sulfate proteoglycans (75:25 of chondroitin sulfate:heparan sulfate ratio), while NIH:OVCAR-3 cells had higher proportion of heparan sulfate proteoglycans (10:90 of chondroitin sulfate:heparan sulfate ratio). RT-PCR indicated the synthesis of a unique assortment of syndecans, glypicans, and CD44 by the two cell lines. In adhesion assays performed on matrix-coated titer plates both cell lines adhered to types I and III collagen and cellular fibronectin, and cell adhesion was inhibited by preincubation of the matrix with heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, or chondroitin glycosaminoglycans. Treatment of the cells with heparitinase, chondroitinase ABC, or methylumbelliferyl xyloside also interfered with adhesion confirming the role of both heparan sulfate and chondroitin sulfate cell surface proteoglycans as matrix receptors on ovarian carcinoma cells.

  11. Detection of polyol accumulation in a new ovarian carcinoma cell line, CABA I: a1H NMR study

    PubMed Central

    Ferretti, A; D'Ascenzo, S; Knijn, A; Iorio, E; Dolo, V; Pavan, A; Podo, F

    2002-01-01

    Ovarian carcinomas represent a major form of gynaecological malignancies, whose treatment consists mainly of surgery and chemotherapy. Besides the difficulty of prognosis, therapy of ovarian carcinomas has reached scarce improvement, as a consequence of lack of efficacy and development of drug-resistance. The need of different biochemical and functional parameters has grown, in order to obtain a larger view on processes of biological and clinical significance. In this paper we report novel metabolic features detected in a series of different human ovary carcinoma lines, by 1H NMR spectroscopy of intact cells and their extracts. Most importantly, a new ovarian adenocarcinoma line CABA I, showed strong signals in the spectral region between 3.5 and 4.0 p.p.m., assigned for the first time to the polyol sorbitol (39±11 nmol/106 cells). 13C NMR analyses of these cells incubated with [1-13C]-D-glucose demonstrated labelled-sorbitol formation. The other ovarian carcinoma cell lines (OVCAR-3, IGROV 1, SK-OV-3 and OVCA432), showed, in the same spectral region, intense resonances from other metabolites: glutathione (up to 30 nmol/106 cells) and myo-inositol (up to 50 nmol/106 cells). Biochemical and biological functions are suggested for these compounds in human ovarian carcinoma cells, especially in relation to their possible role in cell detoxification mechanisms during tumour progression. British Journal of Cancer (2002) 86, 1180–1187. DOI: 10.1038/sj/bjc/6600189 www.bjcancer.com © 2002 Cancer Research UK PMID:11953869

  12. POLD2 and KSP37 (FGFBP2) Correlate Strongly with Histology, Stage and Outcome in Ovarian Carcinomas

    PubMed Central

    Elgaaen, Bente Vilming; Olstad, Ole Kristoffer; Fortunati, Dario; Onsrud, Mathias; Staff, Anne Cathrine; Sauer, Torill; Gautvik, Kaare M.

    2010-01-01

    Background Epithelial ovarian cancer (EOC) constitutes more than 90% of ovarian cancers and is associated with high mortality. EOC comprises a heterogeneous group of tumours, and the causes and molecular pathology are essentially unknown. Improved insight into the molecular characteristics of the different subgroups of EOC is urgently needed, and should eventually lead to earlier diagnosis as well as more individualized and effective treatments. Previously, we reported a limited number of mRNAs strongly upregulated in human osteosarcomas and other malignancies, and six were selected to be tested for a possible association with three subgroups of ovarian carcinomas and clinical parameters. Methodology/Principal Findings The six selected mRNAs were quantified by RT-qPCR in biopsies from eleven poorly differentiated serous carcinomas (PDSC, stage III–IV), twelve moderately differentiated serous carcinomas (MDSC, stage III–IV) and eight clear cell carcinomas (CCC, stage I–IV) of the ovary. Superficial scrapings from six normal ovaries (SNO), as well as biopsies from three normal ovaries (BNO) and three benign ovarian cysts (BBOC) were analyzed for comparison. The gene expression level was related to the histological and clinical parameters of human ovarian carcinoma samples. One of the mRNAs, DNA polymerase delta 2 small subunit (POLD2), was increased in average 2.5- to almost 20-fold in MDSC and PDSC, respectively, paralleling the degree of dedifferentiation and concordant with a poor prognosis. Except for POLD2, the serous carcinomas showed a similar transcription profile, being clearly different from CCC. Another mRNA, Killer-specific secretory protein of 37 kDa (KSP37) showed six- to eight-fold higher levels in CCC stage I compared with the more advanced staged carcinomas, and correlated positively with an improved clinical outcome. Conclusions/Significance We have identified two biomarkers which are markedly upregulated in two subgroups of ovarian carcinomas

  13. Low meprin α expression differentiates primary ovarian mucinous carcinoma from gastrointestinal cancers that commonly metastasise to the ovaries

    PubMed Central

    Heinzelmann‐Schwarz, Viola A; Scolyer, Richard A; Scurry, James P; Smith, Alison N; Gardiner‐Garden, Margaret; Biankin, Andrew V; Baron‐Hay, Sally; Scott, Carolyn; Ward, Robyn L; Fink, Daniel; Hacker, Neville F; Sutherland, Robert L; O'Brien, Philippa M

    2007-01-01

    Background Currently, no specific immunohistochemical markers are available to differentiate primary mucinous epithelial ovarian cancer (MOC) from adenocarcinomas originating at other sites that have metastasised to the ovary, which may have an impact on patient management and prognosis. Aim To investigate the expression of two intestinal markers, galectin 4 and meprin α, in mucinous carcinomas of the ovary and gastrointestinal tract. Methods Using immunohistochemical analysis, the expression of galectin 4 and meprin α was investigated in 10 MOCs and in 38 mucinous adenocarcinomas of colon, pancreas, stomach and appendix, the most common sites of origin of ovarian metastases. Results Total cytoplasmic galectin 4 expression was relatively consistent between the different carcinomas. Membranous meprin α expression was significantly lower in MOCs compared with gastrointestinal carcinomas. Moreover, meprin α expression showed greater discrimination between the ovarian and gastrointestinal carcinomas than the cytokeratins CK7 and CK20, the current standard immunohistochemical markers used to determine the tissue origin of mucinous carcinomas involving the ovaries. Conclusions Meprin α is a useful additional marker in differentiating primary from secondary mucinous adenocarcinomas of the ovary. PMID:16822880

  14. Biochemical composition of malignant ascites determines high aggressiveness of undifferentiated ovarian tumors.

    PubMed

    Mikuła-Pietrasik, Justyna; Uruski, Paweł; Szubert, Sebastian; Moszyński, Rafał; Szpurek, Dariusz; Sajdak, Stefan; Tykarski, Andrzej; Książek, Krzysztof

    2016-08-01

    Although undifferentiated tumors are the most lethal among all ovarian cancer histotypes, the exact reasons for this situation are unclear. This report was aimed at investigating whether the high aggressiveness of undifferentiated ovarian cancer may be associated with a biochemical composition of malignant ascites accumulating in the peritoneal cavity. We analyzed ascites from patients with undifferentiated, high-grade serous, endometrioid and clear-cell ovarian cancers, and from non-cancerous patients with respect to a group of soluble agents involved in cancer cell progression. Moreover, the effect of these fluids on proliferation and migration of ovarian cancer cells (A2780, OVCAR-3 and SKOV-3) was evaluated. The study showed that the level of all tested proteins in malignant ascites was higher than in the benign fluids. Concentration of 9/11 agents (CCL2, CXCL1, CXCL5, CXCL8, CXCL12, HGF, PAI-1, TGF-β1 and VEGF) was the greatest in the fluids from undifferentiated cancer, while the level of remaining 2 (IL-6 and uPA) was the highest in ascites from serous carcinoma. Proliferation of cancer cells was the most effective when they were subjected to ascites from patients with undifferentiated and serous cancer, whereas the migration was the highest in the case of undifferentiated tumors. Our findings indicate that the aggressiveness of undifferentiated ovarian tumors may be associated with the composition of malignant ascites, in particular the concentration of specific proinflammatory, cancer-promoting agents.

  15. Effects and mechanism of RhoC downregulation in suppressing ovarian cancer stem cell proliferation, drug resistance, invasion and metastasis.

    PubMed

    Sang, Xiu-Bo; Sun, Kai-Xuan; Wang, Li-Li; Chen, Shuo; Wu, Dan-Dan; Zong, Zhi-Hong; Zhao, Yang

    2016-12-01

    Cancer stem cells are considered to be the root cause of tumor initiation, metastasis, recurrence and therapeutic resistance. Recent studies have reported that RhoC plays a critical role in regulating cancer stem cells; however, its function in ovarian cancer stem cells (OCSCs) remains unknown. The ovarian cancer cell line A2780, and the paclitaxel-resistant A2780 cell line (A2780-PTX) were obtained. A2780 cells were used to isolate and identify the highly invasive A2780-PM cells, and A2780-PTX cells were used to isolate and identify the highly drug-resistant and highly invasive A2780-PTX-PM cells by Transwell assay. MTT, Transwell and wound healing assays were used to compare the differences in cell proliferation, invasion and migration ability among the four cell lines. Immunofluorescence was used to detect the expression of stem cell markers CD117 and CD133. OCSCs were sorted by flow cytometry. Following si-RhoC transfection of the OCSCs, cell proliferation, drug resistance, invasion and migration ability and RhoC, CD117 and CD133 expression levels were assayed. RT-PCR was used to assess RhoC, CD117, CD133 and matrix metalloproteinase 9 (MMP9) mRNA expression levels. A2780-PM and A2780‑PTX-PM cells exhibited higher cell proliferation, drug resistance, and invasion and migration ability than the A2780 and A2780-PTX cell lines. Furthermore, CD133 and CD117 expression levels were higher in the A2780-PM and A2780‑PTX-PM cells than levels in the A2780 and A2780-PTX cells. Transfection of si-RhoC in OCSCs suppressed the proliferation, drug resistance, invasion, migration and CD117 and CD133 expression levels. Furthermore, the expression levels of RhoC, CD117, CD133, MDR1, and MMP9 mRNA were downregulated in the transfected population. Taken together, our results demonstrated that RhoC downregulation may inhibit the proliferation, drug resistance, invasion and migration of OCSCs, and RhoC may play an important role in the formation of OCSCs.

  16. S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro

    PubMed Central

    Xu, Ya-si; Feng, Jian-guo; Zhang, Dan; Zhang, Bo; Luo, Min; Su, Dan; Lin, Neng-ming

    2014-01-01

    Aim: To investigate the effects of S-allylcysteine (SAC), a water-soluble garlic derivative, on human ovarian cancer cells in vitro. Methods: Human epithelial ovarian cancer cell line A2780 was tested. Cell proliferation was examined with CCK-8 and colony formation assays. Cell cycle was analyzed with flow cytometry. Cell apoptosis was studied using Hoechst 33258 staining and Annexin V/PI staining with flow cytometry. The migration and invasion of A2780 cells were examined with transwell and wound healing assays. The expression of relevant proteins was detected with Western blot assays. Results: SAC (1−100 mmol/L) inhibited the proliferation of A2780 cells in dose- and time-dependent manners (the IC50 value was approximately 25 mmol/L at 48 h, and less than 6.25 mmol/L at 96 h). Furthermore, SAC dose-dependently inhibited the colony formation of A2780 cells. Treatment of A2780 cells with SAC resulted in G1/S phase arrest and induced apoptosis, accompanied by decreased expression of pro-caspase-3, Parp-1 and Bcl-2, and increased expression of active caspase-3 and Bax. SAC treatment significantly reduced the migration of A2780 cells, and markedly decreased the protein expression of Wnt5a, p-AKT and c-Jun, which were the key proteins involved in proliferation and metastasis. Conclusion: SAC suppresses proliferation and induces apoptosis in A2780 ovarian cancer cells in vitro. PMID:24362328

  17. Ovarian low and high grade serous carcinomas: hidden divergent features in the tumor microenvironment

    PubMed Central

    Buttarelli, Marianna; Martinelli, Enrica; Mascilini, Floriana; Petrillo, Marco; Ferrandina, Gabriella; Scambia, Giovanni; Gallo, Daniela

    2016-01-01

    Only recently low-grade serous carcinoma (LGSOC) of the ovary has been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSOC), with significant differences in pathogenesis and clinical and pathologic features. The present study aimed at evaluating whether the different natural histories and patterns of response to therapy demonstrated for LGSOC and HGSOC, along with a diverse genomic landscape, may also reside in the supporting tumor stroma, specifically in the state of differentiation and activation of tumor associated macrophages (TAMs). TAMs play complex roles in tumorigenesis since they are believed to possess both tumor rejecting (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we showed that, when compared to HGSOC (n = 55), LGSOC patients (n = 25) exhibited lower density of tumor-infiltrating CD68+ macrophage, along with an attenuated M2-skewed (CD163+) phenotype. Accordingly, assessment of intratumoral vascularization and of matrix metalloproteinase 9 expression (a key protein involved in tumor invasion and metastasis) revealed lower expression in LGSOC compared to HGSOC patients, in line with emerging evidence supporting a role for TAMs in all aspects of tumor initiation, growth, and development. In conclusion, results from the present study demonstrate that microenvironmental factors contribute greatly to determine clinical and pathological features that differentiate low and high grade serous ovarian carcinomas. This understanding may increase possibilities and opportunities to improve disease control and design new therapeutic strategies. PMID:27462782

  18. FAU regulates carboplatin resistance in ovarian cancer.

    PubMed

    Moss, Esther L; Mourtada-Maarabouni, Mirna; Pickard, Mark R; Redman, Charles W; Williams, Gwyn T

    2010-01-01

    The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell line's sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short-interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin-induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal-Wallis P = 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin-induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real-time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal-Wallis P = 0.0261). These data support a role for FAU in the regulation of platinum-resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer.

  19. Paclitaxel, Cisplatin, and Topotecan With or Without Filgrastim in Treating Patients With Newly Diagnosed Stage III or Stage IV Epithelial Ovarian Cancer

    ClinicalTrials.gov

    2013-01-23

    Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  20. The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness.

    PubMed

    Maggiora, Piera; Lorenzato, Annalisa; Fracchioli, Stefano; Costa, Barbara; Castagnaro, Massimo; Arisio, Riccardo; Katsaros, Dionyssios; Massobrio, Marco; Comoglio, Paolo M; Flavia Di Renzo, Maria

    2003-08-15

    RON is a member of the receptor tyrosine kinase gene family that includes the MET oncogene, whose germline mutations have been causally related to human tumorigenesis. In vitro, RON and MET receptors cross-talk, synergize in intracellular signaling, and cooperate in inducing morphogenic responses. Here we show that the RON and MET oncogenes were expressed in 55% and 56% of human ovarian carcinomas, respectively, and were significantly coexpressed in 42% (P < 0.001). In ovarian carcinoma samples and cell lines we did not find mutations in RON and MET gene kinase domain, nor coexpression of RON and MET receptor ligands (MSP and HGF, respectively). We show that motility and invasiveness of ovarian cancer cells coexpressing MET and RON receptors were elicited by HGF and, to a lesser extent, by MSP. More interestingly, invasion of both reconstituted basement membrane and collagen gel was greatly enhanced by the simultaneous addition of the two ligands. These data suggest that coexpression of the MET and RON receptors confer a selective advantage to ovarian cancer cells and might promote ovarian cancer progression.

  1. Generation and characterization of human monoclonal antibody HMD4 against ovarian carcinoma and the study of radioimmunoimaging in nude mice

    SciTech Connect

    Qian, H.N.; Cui, H.; Feng, J.; Fu, T.Y.; Wei, P.; Fu, Z.Y. )

    1990-01-01

    Lymphocytes from regional lymph nodes of patients with ovarian carcinoma were immortalized by fusing them with a nonsecreting cell line of murine myeloma (Sp2/0-Ag14). By early cloning and recloning a hybrid cell line, named HMD4, was established. It has secreted human IgG for more than 15 months stably. Chromosome analysis corresponded with the characterization of human-mouse hybridoma. Large quantities of ascites were obtained after hybrid cells injection into the primed nude mice. Human IgG of light chain was detected and purified from the ascites. Twenty-six of 43 (60.5%) epithelial ovarian cancers were positively stained with HMD4 by ABC immunoperoxidase methods while nonepithelial ovarian cancers and almost all benign tumors and normal tissues were negative. The molecular weight of the antigen recognized by HMD4 was 55KDa determined by Western blotting. 131I labeled HMD4 was administered intraperitoneally to nude mice bearing human ovarian epithelial adenocarcinoma; 131I labeled normal human IgG and normal murine IgG were used as controls. Measurements of T/NT and T/B ratios of 131I-HMD4 were done. Radioimaging showed HMD4 clearly localized on tumor regions at 48 and 72 hours and the biodistribution and metabolism of the labeled HMD4 corresponded with the images. The above results indicate that HMD4 was specific to ovarian carcinoma, a hopeful clue for clinical applications.

  2. Organometallic Half-Sandwich Dichloridoruthenium(II) Complexes with 7-Azaindoles: Synthesis, Characterization and Elucidation of Their Anticancer Inactivity against A2780 Cell Line

    PubMed Central

    Štarha, Pavel; Hanousková, Lucie; Trávníček, Zdeněk

    2015-01-01

    A series of organometallic half-sandwich dichloridoruthenium(II) complexes of the general formula [Ru(η6-p-cym)(naza)Cl2] (1–8; p-cym = p-cymene; naza = 7-azaindole or its derivatives) was synthesised and fully characterized by elemental analysis, mass spectrometry, and infrared and multinuclear NMR spectroscopy. A single-crystal X-ray structural analysis of [Ru(η6-p-cym)(2Me4Claza)Cl2] (6) revealed a typical piano-stool geometry with an N7-coordination mode of 2-methyl-4-chloro-7-azaindole (2Me4Claza). The complexes have been found to be inactive against human ovarian cancer cell line A2780 up to the highest applied concentration (IC50 > 50.0 μM). An inactivity of the complexes is caused by their instability in water-containing solvents connected with a release of the naza N-donor ligand, as proved by the detailed 1H NMR, mass spectrometry and fluorescence experiments. PMID:26606245

  3. Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16(INK4A) protein.

    PubMed

    Armes, Jane E; Lourie, Rohan; de Silva, Melanie; Stamaratis, Georgia; Boyd, Alison; Kumar, Beena; Price, Gareth; Hyde, Simon; Allen, David; Grant, Peter; Venter, Deon J

    2005-10-01

    Dysfunction of proteins involved in the G1 to S transition of the cell cycle, such as p16(INK4A) and RB1, is common in many cancer types. A screen of p16 protein expression was performed in benign, borderline, and invasive ovarian tumors, together with endometrial cancers, aligned on a tissue microarray. We observed frequent p16 overexpression in serous papillary carcinomas of ovarian and endometrial origin. An extended cohort of ovarian serous papillary carcinomas was examined to further evaluate the frequency of p16 overexpression. Strong, uniform staining in the majority of cancer cells occurred commonly in invasive serous papillary ovarian cancers, particularly in grade 3 carcinomas. RB1 protein expression abnormalities were rare. Our data indicate that abnormalities in the retinoblastoma pathway, as determined by p16 overexpression, are common in serous papillary carcinomas and are probably an early event.

  4. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response.

    PubMed

    Chen, Yu-Li; Chang, Ming-Cheng; Huang, Chia-Yen; Chiang, Ying-Cheng; Lin, Han-Wei; Chen, Chi-An; Hsieh, Chang-Yao; Cheng, Wen-Fang

    2012-06-01

    The alpha-folate receptor (α-FR) is highly-expressed in various non-mucinous tumors of epithelial origin, including ovarian carcinoma. The aim of this study was to investigate the relationship between alpha-folate receptor (α-FR) and the clinico-pathologic features and outcomes of serous ovarian carcinoma patients and the possible mechanism of α-FR to chemo-resistance. Therefore, semi-quantitative reverse-transcription polymerase chain reactions for α-FR expression were performed in the 91 specimens of serous ovarian carcinomas. The expression of α-FR in each ovarian cancer tissue specimen was defined as the ratio of density of α-FR to density of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In vitro apoptotic experiments were tested in the original OVCAR-3 tumor cells and various OVCAR-3 α-FR-transfectants. Patients with an increased α-FR expression level had poorer responses to chemotherapy (per α-FR expression level increase: odds ratio (OR): 8.97 (95% confidence interval (CI): 1.40-57.36), p = 0.021). An increased α-FR expression level was an independently poor prognostic factor for disease free interval (DFI) (per α-FR expression level increase: hazard ratio (HR): 2.45 (95% CI: 1.16-5.18), p = 0.02) and had a negative impact on overall survival (OS) of these serous ovarian cancer patients (per α-FR expression level increase: HR: 3.6 (95% CI: 0.93-13.29), p = 0.03) by multivariate analyses. α-FR inhibited cytotoxic drug-induced apoptosis in our in vitro apoptotic assays. α-FR could induce chemo-resistance via regulating the expression of apoptosis-related molecules, Bcl-2 and Bax. Therefore, α-FR can be a potential biomarker for the prediction of chemotherapeutic responses and clinical prognosis. It also could be the target of ovarian cancer treatment.

  5. Complexity of expression of the intermediate filaments of six new human ovarian carcinoma cell lines: new expression of cytokeratin 20.

    PubMed Central

    Yanagibashi, T.; Gorai, I.; Nakazawa, T.; Miyagi, E.; Hirahara, F.; Kitamura, H.; Minaguchi, H.

    1997-01-01

    Six permanent human ovarian carcinoma cell lines (OVISE, OVTOKO, OVMANA and OVSAYO from clear cell adenocarcinoma, and OVSAHO and OVKATE from serous papillary adenocarcinoma) were established from solid tumours. The cell lines have been in culture for 5-8 years, the passage number varying from 62 to 246. Immunohistochemical analysis has shown that five of the six cell lines express at least six cytokeratin (CK) polypeptides. OVISE and OVSAYO expressed CKs 6, 7, 8, 18, 19 and 15 and/or 16. OVTOKO was positive for CKs 7, 8, 18, 19 and 15 and/or 16. OVSAHO expressed CKs 6, 7, 8, 14, 18, 19 and 15 and/or 16. OVMANA expressed CKs 6, 7, 8, 18, 19, 20 and 15 and/or 16. OVKATE expressed CKs 6, 7, 8, 13, 17, 18, 19, 20 and 15 and/or 16. The expression of CK7, additional expression of vimentin, and clinical and histopathological findings enabled us to confirm that six cell lines had been established from primary ovarian cancers. Two of the six cell lines were positive for CK20, although CK20 was not expressed in the original tumours. The heterotransplanted tumours produced by CK20-positive cells also expressed CK20. This is the first report of ovarian carcinoma cell lines that express CK20 irrespective of their histological type. CK20 has been found in all colon carcinoma cell lines, but only in the mucinous type of ovarian tumours. These new ovarian carcinoma cell lines will therefore provide a relevant experimental system for elucidating the regulatory control mechanisms of intermediate filament expression. Images Figure 1 Figure 2 Figure 3 PMID:9328139

  6. Triple Synchronous Malignancies in Genital Tract; Primary Endometrial, Ovarian and Fallopian Tube Carcinoma: A Case Report

    PubMed Central

    Alkilic, Aysegul; Turgay, Batuhan; Gemici, Ali; Atabekoglu, Cem Somer

    2017-01-01

    Synchronous malignancies, including three or more tumours, are extremely rare. Herein, we present a case of a woman with a concurrent simultaneous endometrial, ovarian and fallopian tubal carcinoma with different histopathological characteristics. A 55-year-old postmenopausal woman with a diagnosis of endometrial adenocarcinoma by pipelle biopsy, underwent surgical staging. Final pathology result was reported as synchronous stage IA grade 2 endometrioid adenocarcinoma of the uterus, stage IA grade 2 mucinous adenocarcinoma of the right ovary and in situ serous cystadenocarcinoma of the right fallopian tube. In the postoperative period, patient followed without adjuvant therapy. To our knowledge, this a very rare case report in the literature of sychronous triple gynaecologic cancers including fallopian tube cancer and with the longest disease free survival time with over 39 months due to better prognosis than metastatic or advanced primitive diseases. PMID:28274004

  7. Intraperitoneal P-32 after negative second-look laparotomy in ovarian carcinoma

    SciTech Connect

    Spencer, T.R. Jr.; Marks, R.D. Jr.; Fenn, J.O.; Jenrette, J.M. 3d.; Lutz, M.H.

    1989-06-15

    Thirty-one patients underwent a negative second-look laparotomy between 1976 and 1986. Fourteen patients received intraperitoneal chromic phosphate (P-32) after a negative second-look laparotomy. There has been no local recurrence (zero of 14) and no deaths attributable to recurrent disease. Local control and disease-free survival are 100%, with a minimum follow-up of 2 years and a mean follow-up of 4 years. Seventeen patients received no further therapy because of patient refusal, poor diffusion, or other contraindications to P-32 installation. Four of 17 patients undergoing negative second-look procedures without the addition of P-32 have subsequently recurred. This difference is highly suggestive (P = .076). There have been no major complications with the addition of P-32. The use of intraperitoneal P-32 after negative second-look laparotomies on ovarian carcinoma is well tolerated and effective in preventing recurrence.

  8. HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy

    PubMed Central

    2009-01-01

    Background The response rate of ovarian mucinous carcinomas to paclitaxel/carboplatin is low, prompting interest in targeted molecular therapies. We investigated HER2 expression and amplification, and the potential for trastuzumab therapy in this histologic subtype of ovarian cancer. Methods HER2 status was tested in 33 mucinous carcinomas and 16 mucinous borderline ovarian tumors (BOT)). Five cases with documented recurrence and with tissue from the recurrence available for testing were analyzed to determine whether HER2 amplification status changed over time. Three prospectively identified recurrent mucinous ovarian carcinomas were assessed for HER2 amplification and patients received trastuzumab therapy with conventional chemotherapy. Results Amplification of HER2 was observed in 6/33 (18.2%) mucinous carcinomas and 3/16 (18.8%) BOT. HER2 amplification in primary mucinous carcinomas was not associated with an increased likelihood of recurrence. The prospectively identified recurrent mucinous carcinomas showed overexpression and amplification of HER2; one patient's tumor responded dramatically to trastuzumab in combination with conventional chemotherapy, while another patient experienced an isolated central nervous system recurrence after trastuzumab therapy. Conclusion HER2 amplification is relatively common in ovarian mucinous carcinomas (6/33, 18.2%), although not of prognostic significance. Trastuzumab therapy is a treatment option for patients with mucinous carcinoma when the tumor has HER2 amplification and overexpression. PMID:20003286

  9. c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations.

    PubMed

    Otte, Anna; Rauprich, Finn; von der Ohe, Juliane; Yang, Yuanyuan; Kommoss, Friedrich; Feuerhake, Friedrich; Hillemanns, Peter; Hass, Ralf

    2015-10-13

    A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth.

  10. Common Polymorphism in Interleukin 6 Influences Survival of Women with Ovarian and Peritoneal Carcinoma.

    PubMed Central

    Garg, Ruchi; Wollan, Melissa; Galic, Vijaya; Garcia, Rochelle; Goff, Barbara A.; Gray, Heidi J.; Swisher, Elizabeth

    2007-01-01

    Objectives The IL6 -174 promoter polymorphism impacts serum cytokine levels through transcriptional regulation. The objective of our study was to determine if -174 IL6 genotype influences survival in ovarian cancer. Methods The IL6 -174 polymorphism was assessed by direct DNA sequencing in lymphocyte DNA from 160 women with invasive ovarian, or peritoneal cancer patients. IL6 levels were measured in ascites and plasma in a subset of cases using colorimetric sandwich ELISA procedure. Overall survival was calculated according to the method of Kaplan and Meier. Cox regression analysis was used to evaluate the significance of individual variables in multivariate analysis. Chi-square or Fishers Exact was used to assess the significance of contingency tables. Results The IL6 -174 genotype frequencies of CC (19%), CG (50%), and GG (31%) were in Hardy-Weinberg equilibrium and were similar to published frequencies in Caucasian controls. There were no associations with IL6 -174 genotype and age, stage or optimal cytoreduction. Stage had a significant impact on survival (p=0.003). The IL6 -174 GG genotype was significantly associated with longer overall survival (median 131 months) compared to CC or CG (median 28 months, p=0.0007). In cox regression analysis using the covariates genotype (p=0.006) and stage (p=0.02), both were independently significant. Furthermore, there was no association found between IL6 levels in ascites or plasma, and genotype, stage, or overall survival. Conclusions The IL6 -174 GG genotype has a strong, independent, and favorable impact on survival for women with ovarian, and peritoneal carcinoma. PMID:17023036

  11. Common polymorphism in interleukin 6 influences survival of women with ovarian and peritoneal carcinoma.

    PubMed

    Garg, Ruchi; Wollan, Melissa; Galic, Vijaya; Garcia, Rochelle; Goff, Barbara A; Gray, Heidi J; Swisher, Elizabeth

    2006-12-01

    The IL6 -174 promoter polymorphism impacts serum cytokine levels through transcriptional regulation. The objective of our study was to determine if -174 IL6 genotype influences survival in ovarian cancer. The IL6 -174 polymorphism was assessed by direct DNA sequencing in lymphocyte DNA from 160 women with invasive ovarian, or peritoneal cancers. IL6 levels were measured in ascites and plasma in a subset of cases using colorimetric sandwich ELISA procedure. Overall survival was calculated according to the method of Kaplan and Meier. Cox regression analysis was used to evaluate the significance of individual variables in multivariate analysis. Chi-square or Fishers Exact was used to assess the significance of contingency tables. The IL6 -174 genotype frequencies of CC (19%), CG (50%), and GG (31%) were in Hardy-Weinberg equilibrium and were similar to published frequencies in Caucasian controls. There were no associations with IL6 -174 genotype and age, stage or optimal cytoreduction. Stage had a significant impact on survival (p=0.003). The IL6 -174 GG genotype was significantly associated with longer overall survival (median 131 months) compared to CC or CG (median 28 months, p=0.0007). In cox regression analysis using the covariates genotype (p=0.006) and stage (p=0.02), both were independently significant. Furthermore, there was no association found between IL6 levels in ascites or plasma, and genotype, stage, or overall survival. The IL6 -174 GG genotype has a strong, independent, and favorable impact on survival for women with ovarian, and peritoneal carcinoma.

  12. TLR4 and NFκB signaling is critical for taxol resistance in ovarian carcinoma cells.

    PubMed

    Sun, Nian-Kang; Huang, Shang-Lang; Chang, Ting-Chang; Chao, Chuck C-K

    2017-08-03

    We report here that toll-like receptor 4 (TLR4) and ABCB1 are upregulated in SKOV3 ovarian carcinoma cells that acquired resistance to the anticancer drug taxol. Silencing of TLR4 using short-hairpin RNA sensitized taxol-resistant SKOV3 cells to taxol (4.6 fold), whereas ectopic expression of TLR4 in parental, taxol-sensitive SKOV3 cells or TLR4-null HEK293 cells induced taxol resistance (∼2 fold). A sub-lethal dose of taxol induced ABCB1 protein expression in taxol-resistant SKOV3 cells. Inactivation of TLR4 using chemical inhibitors (CLI-095 and AO-I) downregulated ABCB1 protein expression and enhanced the cytotoxic activity of taxol in taxol-resistant SKOV3 cells. While the sensitization effect of TLR4 inactivation was also detected in TOV21G ovarian cancer cells, which express moderate level of TLR4, ectopic expression of ABCB1 prevented the sensitization effect in these cells. Notably, the NFκB pathway was significantly activated by taxol, and inhibition of this pathway suppressed TLR4-regulated ABCB1 expression. Furthermore, taxol-induced NFκB signaling was reduced following TLR4 silencing in taxol-resistant SKOV3 cells. Consistent with these results, ectopic expression of TLR4 in taxol-sensitive SKOV3 cells enhanced ABCB1 expression and conferred resistance to taxol. The protective effect of exogenous TLR4 expression against taxol was reduced by treatment with NFκB inhibitor in these cells. These results demonstrate that taxol activates the TLR4-NFκB pathway which in turn induces ABCB1 gene expression. This cellular pathway thus represents a novel target to limit resistance to taxol in ovarian cancer cells. © 2017 Wiley Periodicals, Inc.

  13. Resistance of ovarian carcinoma cells to docetaxel is XIAP dependent and reversible by phenoxodiol.

    PubMed

    Sapi, Eva; Alvero, Ayesha B; Chen, Wei; O'Malley, David; Hao, Xiao-Ying; Dwipoyono, Bambang; Garg, Manish; Kamsteeg, Marijke; Rutherford, Thomas; Mor, Gil

    2004-01-01

    Although several pathways have been proposed to explain chemoresistance, all lead to some specific defect in the mechanism of apoptosis. The objective of this study was to characterize the molecular mechanisms of drug resistance to docetaxel in epithelial ovarian cancer cells (EOC) and the use of phenoxodiol as a chemosensitizer. Four established and 12 primary cultures of ovarian carcinoma cell lines (EOC) were treated with docetaxel (5-500 ng/ml) for 24 and/or 48 h. In all the studied cell lines, the best response was seen using 500 ng/ml of docetaxel. Sensitive cell lines were identified as those with IC50 < 100 ng/ml for 48 h while resistant cell lines were identified as those with IC50 > 100 ng/ml. The morphological features of apoptosis and the activation of caspases were seen only in the sensitive cell lines determined by Hoechst staining and Caspase Glo assay. Although X-linked inhibitor of apoptosis protein (XIAP) was expressed in all EOC cells, it was only inactivated in chemosensitive cells. We confirmed the role of XIAP in docetaxel resistance by downregulation of XIAP expression using RNA interference (RNAi) as well as by pretreatment with phenoxodiol. Our results indicate that 1) docetaxel induces its cytotoxic effect through the activation of apoptosis; 2) caspase activation relies on the removal of XIAP; and 3) phenoxodiol restores sensitivity in docetaxel-resistant EOC cells. We demonstrate that phenoxodiol, by interfering with XIAP activity, functions as a chemosensitizer to docetaxel and could provide a more effective treatment for refractory ovarian cancer.

  14. Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.

    PubMed

    Bhagat, Rahul; Kumar, Sandeep Sriram; Vaderhobli, Shilpa; Premalata, Chennagiri S; Pallavi, Venkateshaiah Reddihalli; Ramesh, Gawari; Krishnamoorthy, Lakshmi

    2014-09-01

    Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.

  15. Characterization of Chemically Induced Ovarian Carcinomas in an Ethanol-Preferring Rat Model: Influence of Long-Term Melatonin Treatment

    PubMed Central

    Chuffa, Luiz Gustavo A.; Fioruci-Fontanelli, Beatriz A.; Mendes, Leonardo O.; Fávaro, Wagner J.; Pinheiro, Patricia Fernanda F.; Martinez, Marcelo; Martinez, Francisco Eduardo

    2013-01-01

    Ovarian cancer is the fourth most common cause of cancer deaths among women, and chronic alcoholism may exert co-carcinogenic effects. Because melatonin (mel) has oncostatic properties, we aimed to investigate and characterize the chemical induction of ovarian tumors in a model of ethanol-preferring rats and to verify the influence of mel treatment on the overall features of these tumors. After rats were selected to receive ethanol (EtOH), they were surgically injected with 100 µg of 7,12-dimethyl-benz[a]anthracene (DMBA) plus sesame oil directly under the left ovarian bursa. At 260 days old, half of the animals received i.p. injections of 200 µg mel/100 g b.w. for 60 days. Four experimental groups were established: Group C, rats bearing ovarian carcinomas (OC); Group C+EtOH, rats voluntarily consuming 10% (v/v) EtOH and bearing OC; Group C+M, rats bearing OC and receiving mel; and Group C+EtOH+M, rats with OC consuming EtOH and receiving mel. Estrous cycle and nutritional parameters were evaluated, and anatomopathological analyses of the ovarian tumors were conducted. The incidence of ovarian tumors was higher in EtOH drinking animals 120 days post-DMBA administration, and mel efficiently reduced the prevalence of some aggressive tumors. Although mel promoted high EtOH consumption, it was effective in synchronizing the estrous cycle and reducing ovarian tumor mass by 20%. While rats in the C group displayed cysts containing serous fluid, C+EtOH rats showed solid tumor masses. After mel treatment, the ovaries of these rats presented as soft and mobile tissues. EtOH consumption increased the incidence of serous papillary carcinomas and sarcomas but not clear cell carcinomas. In contrast, mel reduced the incidence of sarcomas, endometrioid carcinomas and cystic teratomas. Combination of DMBA with EtOH intake potentiated the incidence of OC with malignant histologic subtypes. We concluded that mel reduces ovarian masses and the incidence of adenocarcinomas in

  16. Architectural patterns of ovarian/pelvic high-grade serous carcinoma.

    PubMed

    Bromley, Amy B; Altman, Alon D; Chu, Pamela; Nation, Jill G; Nelson, Gregg S; Ghatage, Praful; Kalloger, Steve E; Han, Guangming; Köbel, Martin

    2012-09-01

    We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using χ tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high-grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum-based chemotherapy.

  17. The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization

    PubMed Central

    Adhikary, Till; Wortmann, Annika; Hoffmann, Nathalie; Bieringer, Tim; Nist, Andrea; Stiewe, Thorsten; Jansen, Julia M.; Wagner, Uwe; Müller-Brüsselbach, Sabine; Müller, Rolf

    2016-01-01

    Macrophages occur as resident cells of fetal origin or as infiltrating blood monocyte-derived cells. Despite the critical role of tumor-associated macrophages (TAMs) in tumor progression, the contribution of these developmentally and functionally distinct macrophage subsets and their alteration by the tumor microenvironment are poorly understood. We have addressed this question by comparing TAMs from human ovarian carcinoma ascites, resident peritoneal macrophages (pMPHs) and monocyte-derived macrophages (MDMs). Our study revealed striking a similarity between TAMs and pMPHs, which was considerably greater that the resemblance of TAMs and MDMs, including their transcriptomes, their inflammation-related activation state, the presence of receptors mediating immune functions and the expression of tumor-promoting mediators. Consistent with these results, TAMs phagocytized bacteria, presented peptide antigens and activated cytotoxic T cells within their pathophysiological environment. These observations support the notion that tumor-promoting properties of TAMs may reflect, at least to some extent, normal features of resident macrophages rather than functions induced by the tumor microenvironment. In spite of these surprising similarities between TAMs and pMPHs, bioinformatic analyses identified a TAM-selective signature of 30 genes that are upregulated relative to both pMPHs and MDMs. The majority of these genes is linked to extracellular matrix (ECM) remodeling, supporting a role for TAMs in cancer cell invasion and ovarian cancer progression. PMID:27659538

  18. Peroperative radioimmunodetection of ovarian carcinoma using a hand-held gamma detection probe.

    PubMed Central

    Ind, T. E.; Granowska, M.; Britton, K. E.; Morris, G.; Lowe, D. G.; Hudson, C. N.; Shepherd, J. H.

    1994-01-01

    Radioimmunoscintigraphy (RIS) can be used in the preoperative localisation of ovarian carcinoma to demonstrate uptake of radiolabelled monoclonal antibodies into neoplastic tissue. The tissue uptake of radiotracer was evaluated at laparotomy in 16 patients with suspected ovarian cancer who had preoperative RIS using technetium-99m-labelled monoclonal antibodies SM3 and H17E2. A gamma detection probe (gamma DP) was used to measure uptake in possible tumour deposits at operation and also the uptake in tissues resected for histology. The percentage uptake of the initial injected dose of radiotracer was also measured in resected tissues. Activity was found to be significantly higher in malignant than in non-neoplastic tissue by all three methods of evaluation. The gamma DP used peroperatively yielded a 82% sensitivity with a 72% specificity for an uptake ratio of 1.5:1. When tissue was examined immediately after resection, for a 100% specificity the sensitivity was 64%. In vitro measurements of monoclonal antibody uptake by tissue similarly gave a 65% sensitivity with a 100% specificity. Peroperative and immediate post-operative measurements of tissue radioactivity can be performed quickly and conveniently, and in some cases may be of benefit in the localisation of tumour at laparotomy and in providing extra information when tissue is examined by frozen section. PMID:7981086

  19. Coexistence of borderline ovarian epithelial tumor, primary pelvic hydatid cyst, and lymphoepithelioma-like gastric carcinoma.

    PubMed

    Gungor, Tayfun; Altinkaya, Sunduz Ozlem; Sirvan, Levent; Lafuente, Roberto Alvarez; Ceylaner, Serdar

    2011-06-01

    Borderline ovarian tumors (BOTs) represent a heterogeneous group of ovarian epithelial neoplasms. Despite a favorable prognosis, 10-20% of BOTs exhibit progressively worsening clinic. Primary involvement of pelvic organs with echinococcus is very rare. Lymphoepithelioma-like gastric carcinoma is a rare neoplasm of the stomach. A 58-year-old woman referred with abdominal swelling and gastric complaints. Imaging studies revealed a huge cystic mass with multiple septations and solid component, another cystic mass with an appearance of cyst hydatid in the pelvis, and thickening of the small curvature of stomach. Gastroscopy revealed an ulcer with a suspicious malignant appearance, and histology of the endoscopic specimen showed severe chronic inflammation and lymphocytic infiltration. No other involvement of hydatid cyst was detected. In the exploration, there was a 25cm cystic lesion with solid components arising from right ovary, another 6cm cyst over the former, 7cm cystic lesion arising from left ovary, and 10cm mass near the small curvature of the stomach. Excision of the masses; total gastrectomy with esophagojejunal anastomosis; total abdominal hysterectomy; bilateral salpingo-oophorectomy; omentectomy; appendectomy; splenectomy; and pelvic, paraaortic, and coeliac lympadenectomy were performed. Final pathology revealed lymphoepithelioma-like gastric carcinoma, bilateral serous BOT, and hydatid cyst. Hydatid cyst should always be considered in the differential diagnosis of abdominopelvic masses in endemic regions of the world. Preoperative diagnosis of primary pelvic hydatid disease is difficult and awareness of its possibility is very important especially in patients residing in or coming from endemic areas. Copyright © 2011. Published by Elsevier B.V.

  20. Invasion patterns in stage I endometrioid and mucinous ovarian carcinomas: a clinicopathologic analysis emphasizing favorable outcomes in carcinomas without destructive stromal invasion and the occasional malignant course of carcinomas with limited destructive stromal invasion.

    PubMed

    Chen, Shirley; Leitao, Mario M; Tornos, Carmen; Soslow, Robert A

    2005-07-01

    Stage I, low-grade endometrioid and mucinous ovarian carcinomas have an excellent prognosis. Published data have suggested that destructive stromal invasion, a relatively uncommon finding in these tumors, is a poor prognostic factor. We investigated this by studying all FIGO stage I, grades 1 and 2 (of 3) endometrioid and mucinous ovarian carcinomas that were surgically staged at the Memorial Sloan-Kettering Cancer Center from 1980 to 2000. We undertook a careful review of all available slides using current diagnostic criteria and correlated histopathologic indices with clinical outcome data. Cases studied included 13 endometrioid ovarian carcinomas (stage IA, eight; stage IC, five) and six intestinal mucinous ovarian carcinomas (stage IA, three; stage IC, three). All of the tumors contained areas of expansile invasion, greater than that acceptable for microinvasion, and were thus diagnosed as carcinomas instead of borderline tumors. Nevertheless, nearly all demonstrated borderline tumor (noninvasive) components. Six tumors contained at least one focus of destructive stromal invasion (two endometrioid and four mucinous ovarian carcinomas). Four additional cases showed a focus suspicious for but not diagnostic of destructive invasion ('indeterminate for destructive invasion') (two endometrioid and two mucinous ovarian carcinomas). Follow-up data were available for 17 patients. The median follow-up was 81 months (range, 9-161 months). In all, 14 patients were alive with no evidence of disease (expansile invasion alone, eight; destructive stromal invasion, four; and indeterminate for destructive invasion, two). Three patients died of their disease (destructive stromal invasion, two; and indeterminate for destructive invasion, one). The size, number, and nuclear grade of destructive stromal invasion foci did not appear to have an impact on survival in this relatively limited number of patients. Outcome data in patients with stage I, low-grade endometrioid and mucinous

  1. OVARIAN LOW-GRADE AND HIGH-GRADE SEROUS CARCINOMA: Pathogenesis, Clinicopathologic and Molecular Biologic Features, and Diagnostic Problems

    PubMed Central

    Vang, Russell; Shih, Ie-Ming; Kurman, Robert J.

    2009-01-01

    Ovarian serous carcinomas have been graded using various systems. Recently, a 2-tier system in which tumors are subdivided into low-grade and high-grade has been proposed. This approach is simplistic, reproducible, and based on biologic evidence indicating that both tumors develop via different pathways. Low-grade serous carcinomas exhibit low-grade nuclei with infrequent mitotic figures. They evolve from adenofibromas or borderline tumors, have frequent mutations of the KRAS, BRAF, or ERBB2 genes, and lack TP53 mutations (Type I pathway). The progression to invasive carcinoma is a slow step-wise process. Low-grade tumors are indolent and have better outcome than high-grade tumors. In contrast, high-grade serous carcinomas have high-grade nuclei and numerous mitotic figures. Identification of a precursor lesion in the ovary has been elusive and therefore the origin of ovarian carcinoma has been described as de novo. More recently, studies have suggested that a proportion appear to originate from intraepithelial carcinoma in the fallopian tube. The development of these tumors is rapid (Type II pathway). The vast majority are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2. Although both types of serous carcinomas evolve along different pathways, rare high-grade serous carcinomas seem to arise through the Type I pathway. Immunohistochemical stains for p53, p16, and Ki-67 for distinction of low- from high-grade tumors are of limited value but can be helpful in selected instances. This review provides an update on the pathogenesis and clinicopathologic features of these two types of serous carcinomas and addresses some of the diagnostic problems that are encountered in routine practice. PMID:19700937

  2. Pembrolizumab, Bevacizumab, and Cyclophosphamide in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-08-25

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  3. Mutation of NRAS is a Rare Genetic Event in Ovarian Low-Grade Serous Carcinoma.

    PubMed

    Xing, Deyin; Rahmanto, Yohan Suryo; Zeppernick, Felix; Hannibal, Charlotte G; Kjaer, Susanne K; Vang, Russell; Shih, Ie-Ming; Wang, Tian-Li

    2017-09-02

    Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of serous borderline tumor (SBT) to invasive low grade serous carcinoma (LGSC) remains largely unknown. While mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression. In this study, we analyzed NRAS exon 3 mutational status in 98 cases that were diagnosed with SBT/atypical proliferative serous tumor (SBT/APST), non-invasive LGSC (niLGSC), or invasive LGSC (iLGSC). Of the latter, NRAS Q61R (CAA to CGA) mutations were detected in only 2 of 56 (3.6%) cases. The same mutation was not detected in any of the SBT/APSTs or niLGSCs. Mutational analysis for hotspots in KRAS and BRAF demonstrated a wildtype pattern of KRAS and BRAF in one of the NRAS-mutated cases. Interestingly, another LGSC case with NRAS mutation harbored a concurrent BRAF V600L mutation. These findings indicate that, although recurrent NRAS mutations are present, their low prevalence indicates that NRAS plays a limited role in the development of LGSC. Further studies to identify other oncogenic drivers of LGSC progression is warranted. Copyright © 2017. Published by Elsevier Inc.

  4. Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma.

    PubMed

    Chen, Xiaoxiang; Zhang, Jing; Zhang, Zhihong; Li, Hongxia; Cheng, Wenjun; Liu, Jinsong

    2013-11-01

    Although epithelial ovarian cancer cells are eliminated by debulking surgery and chemotherapy during initial treatment, it is believed that only a subset of cancer cells, that is, cancer stem cells, may be an important source of tumor recurrence and drug resistance. This review highlights our current understanding of high-grade serous carcinoma, ovarian cancer stem cells, common methods for enrichment of ovarian cancer stem cells, mechanisms involved in drug resistance, and potential strategies for overcoming drug resistance, with associated potential controversies and pitfalls. We also review the potential relationship between epithelial-to-mesenchymal transition and cancer stem cells and how we can induce cancer cells to differentiate into benign stromal fibroblasts in response to certain chemotherapy drugs.

  5. Poor prognosis of ovarian cancer with large cell neuroendocrine carcinoma: case report and review of published works.

    PubMed

    Asada, Kayo; Kawana, Kei; Teshima, Shinichi; Saito, Ako; Kawabata, Masakiyo; Fujii, Tomoyuki

    2014-03-01

    Large cell neuroendocrine carcinoma (LCNEC) is well-reported to result in unfavorable prognoses in many organ cancers while being rarely reported in gynecologic cancer, especially ovarian and endometrial cancers. Here we report a case of ovarian cancer with LCNEC which spread to distant organs within 1 year of primary surgery despite the fact that the post-surgical stage was Ia. The case received platinum-based chemotherapy as an adjuvant therapy after her curative surgery. However, LCNEC in the case was resistant to the chemotherapy. In our review of published works, ovarian cancer cases with LCNEC show poor prognoses regardless of adjuvant chemotherapy following complete resection. Median overall survival was 10 months in stage I cases. Development of chemotherapy sensitive for LCNEC is needed.

  6. MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53

    PubMed Central

    Makii, Chinami; Oda, Katsutoshi; Ikeda, Yuji; Sone, Kenbun; Hasegawa, Kosei; Uehara, Yuriko; Nishijima, Akira; Asada, Kayo; Koso, Takahiro; Fukuda, Tomohiko; Inaba, Kanako; Oki, Shinya; Machino, Hidenori; Kojima, Machiko; Kashiyama, Tomoko; Mori-Uchino, Mayuyo; Arimoto, Takahide; Wada-Hiraike, Osamu; Kawana, Kei; Yano, Tetsu; Fujiwara, Keiichi; Aburatani, Hiroyuki; Osuga, Yutaka; Fujii, Tomoyuki

    2016-01-01

    MDM2, a ubiquitin ligase, suppresses wild type TP53 via proteasome-mediated degradation. We evaluated the prognostic and therapeutic value of MDM2 in ovarian clear cell carcinoma. MDM2 expression in ovarian cancer tissues was analyzed by microarray and real-time PCR, and its relationship with prognosis was evaluated by Kaplan-Meier method and log-rank test. The anti-tumor activities of MDM2 siRNA and the MDM2 inhibitor RG7112 were assessed by cell viability assay, western blotting, and flow cytometry. The anti-tumor effects of RG7112 in vivo were examined in a mouse xenograft model. MDM2 expression was significantly higher in clear cell carcinoma than in ovarian high-grade serous carcinoma (P = 0.0092) and normal tissues (P = 0.035). High MDM2 expression determined by microarray was significantly associated with poor progression-free survival and poor overall survival (P = 0.0002, and P = 0.0008, respectively). Notably, RG7112 significantly suppressed cell viability in clear cell carcinoma cell lines with wild type TP53. RG7112 also strongly induced apoptosis, increased TP53 phosphorylation, and stimulated expression of the proapoptotic protein PUMA. Similarly, siRNA knockdown of MDM2 induced apoptosis. Finally, RG7112 significantly reduced the tumor volume of xenografted RMG-I clear cell carcinoma cells (P = 0.033), and the density of microvessels (P = 0.011). Our results highlight the prognostic value of MDM2 expression in clear cell carcinoma. Thus, MDM2 inhibitors such as RG7112 may constitute a class of potential therapeutics. PMID:27659536

  7. Lack of ceramide generation and altered sphingolipid composition are associated with drug resistance in human ovarian carcinoma cells

    PubMed Central

    Prinetti, Alessandro; Millimaggi, Danilo; D'Ascenzo, Sandra; Clarkson, Matilda; Bettiga, Arianna; Chigorno, Vanna; Sonnino, Sandro; Pavan, Antonio; Dolo, Vincenza

    2005-01-01

    PTX (Paclitaxel®) is an antimitotic agent used in the treatment of a number of major solid tumours, particularly in breast and ovarian cancer. This study was undertaken to gain insight into the molecular alterations producing PTX resistance in ovarian cancer. PTX treatment is able to induce apoptosis in the human ovarian carcinoma cell line, CABA I. PTX-induced apoptosis in CABA I cells was accompanied by an increase in the cellular Cer (ceramide) levels and a decrease in the sphingomyelin levels, due to the activation of sphingomyelinases. The inhibition of acid sphingomyelinase decreased PTX-induced apoptosis. Under the same experimental conditions, PTX had no effect on Cer and sphingomyelin levels in the stable PTX-resistant ovarian carcinoma cell line, CABA-PTX. The acquisition of the PTX-resistant phenotype is accompanied by unique alterations in the complex sphingolipid pattern found on lipid extraction. In the drug-resistant cell line, the levels of sphingomyelin and neutral glycosphingolipids were unchanged compared with the drug-sensitive cell line. The ganglioside pattern in CABA I cells is more complex compared with that of CABA-PTX cells. Specifically, we found that the total ganglioside content in CABA-PTX cells was approximately half of that in CABA I cells, and GM3 ganglioside content was remarkably higher in the drug-resistant cell line. Taken together our findings indicate that: i) Cer generated by acid sphingomyelinase is involved in PTX-induced apoptosis in ovarian carcinoma cells, and PTX-resistant cells are characterized by their lack of increased Cer upon drug treatment, ii) PTX resistance might be correlated with an alteration in metabolic Cer patterns specifically affecting cellular ganglioside composition. PMID:16356169

  8. Adjuvant intraperitoneal chromic phosphate therapy for women with apparent early ovarian carcinoma who have not undergone comprehensive surgical staging

    SciTech Connect

    Soper, J.T.; Berchuck, A.; Clarke-Pearson, D.L. )

    1991-08-15

    Forty-nine women with apparent Stage 1 and 2 ovarian carcinoma received intraperitoneal phosphate 32 as the only adjuvant therapy after primary surgery. In addition to bilateral salpingo-oophorectomy, 40 (82%) had analysis of peritoneal cytology, and 35 (71%) underwent omentectomy. Random peritoneal biopsies and retroperitoneal lymph node sampling were not done in any of these patients. The overall and disease-free survival rates were 86% and 75%, respectively, with no significant differences by stage, histologic grade, histologic type, or low-risk versus high-risk subsets recognized in patients who received comprehensive surgical staging. Seven (58%) of 12 patients had lymph node metastasis as the first site of recurrence, including two of three with late recurrences. Significant morbidity related to intraperitoneal chromic phosphate (32P) occurred in one (2%) woman. These results emphasize the need for comprehensive surgical staging of women with apparent early ovarian carcinoma to aid in the selection of appropriate initial adjuvant therapy.

  9. Diagnostic and Prognostic Significance of Ki-67 Immunohistochemical Expression in Surface Epithelial Ovarian Carcinoma

    PubMed Central

    Krishna, Shruthi Mysore; Vimala, Manjunath Gubbanna

    2017-01-01

    Introduction The Surface Epithelial Ovarian Carcinoma (SEOC) at the moment of diagnosis, the disease is extended beyond the structures of the pelvis. Ki-67 is one of the prognostic marker which determines the growth fraction of a tumour and its over expression is associated with malignancy, tumour aggression, reserved prognosis and metastasis. Aim To evaluate the proliferative activity using Ki-67 immuno-staining in SEOC and to correlate with histological subtype, grade, Federation of Gynecology and Obstetrics (FIGO) stage, CA125 levels for diagnostic and prognostic purpose. Materials and Methods The study was conducted in JSS Medical College and Hospital, JSS University, Mysuru. It was a descriptive cross-sectional study involving 40 cases of SEOC over a period of two years. The proliferation expression related to Ki-67 antigen was evaluated by immunohistochemical monoclonal MIB-1 antibody. In each case, the Ki-67 labeling index (Ki-67 LI) was articulated as percentage of positively stained cells using high power objective of the microscope (x400). Results Among the 40 carcinomas, 26 were serous, five mucinous, four each of clear cell and undifferentiated and one transitional cell carcinoma. A total of 75% were high grade tumours. High Ki-67 LI was associated with high grade tumours (69.9%), high grade serous tumours (65.34%) and advanced FIGO staging (70.6%) with the p-value of <0.001. CA 125 levels did not have a significant correlation with Ki-67 LI. Conclusion Ki-67 is an exceptionally a cost effective marker to determine the growth fraction of a tumour cell population. In SEOC histological grade and FIGO stage when combined with Ki-67 LI in histopathology report would help in diagnostic differentiation of subtypes, prognostication, deciding the need for adjuvant chemotherapy and in predicting survival analysis. PMID:28384868

  10. Systemic mastocytosis in a patient with ovarian germ cell carcinoma and mast cell leukemia

    SciTech Connect

    Sun, G.; Hajianpour, M.J.; Hajianpour, A.K.

    1994-09-01

    We report a 12-year-old female with a history of mixed germ cell carcinoma of the right ovary who developed a generalized skin rash after oophorectomy and chemotherapy. She also presented with periodic episodes of flushing, anemia, tachycardia, shortness of breath, high fever, hepatosplenomegaly, nausea, abdominal cramping with diarrhea, and a papuloerythematous skin rash. There was no evidence of secondary carcinoma. Skin biopsy revealed nonspecific inflammatory cells with negative staining for mast cells. Peripheral blood smear showed an increased number of mast cells, thrombocytopenia and normal white cells count. Bone marrow showed hypercellularity with 38% of the nucleated cells being mast cells. Bone marrow chromosome analysis revealed hyperdiploidy in 30% of the cells: 58-64,XX, +1, +2, +5, +6, +7, +8, +14, +16, +18, +19, +19, +20, +21, +22. She expired two months after the occurrence of systemic mastocytosis. Systemic mastocytosis has been reported in association with hematopoietic disorders and with germ cell tumors. The association between mediastinal germ cell tumors and hematological malignancies has also been observed. To our knowledge, combination of most cell leukemia, systemic mastocytosis, and ovarian germ cell carcinoma has not been observed. It is know that mutations at the locus of either proto-oncogene c-kit receptor or its ligand, mast/stem cell factor (SCF) may impair the development of three stem cell populations: hematopoietic stem cells, germ cells and melanoblasts. There have been also extensive investigations on the expression and modulation of the SCF/c-kit interaction in various malignancies. Further molecular studies in patients with germ cell tumor/hematopoietic malignancy syndrome are required to delineate underlying mechanisms.

  11. Diagnostic and Prognostic Significance of Ki-67 Immunohistochemical Expression in Surface Epithelial Ovarian Carcinoma.

    PubMed

    Mahadevappa, Asha; Krishna, Shruthi Mysore; Vimala, Manjunath Gubbanna

    2017-02-01

    The Surface Epithelial Ovarian Carcinoma (SEOC) at the moment of diagnosis, the disease is extended beyond the structures of the pelvis. Ki-67 is one of the prognostic marker which determines the growth fraction of a tumour and its over expression is associated with malignancy, tumour aggression, reserved prognosis and metastasis. To evaluate the proliferative activity using Ki-67 immuno-staining in SEOC and to correlate with histological subtype, grade, Federation of Gynecology and Obstetrics (FIGO) stage, CA125 levels for diagnostic and prognostic purpose. The study was conducted in JSS Medical College and Hospital, JSS University, Mysuru. It was a descriptive cross-sectional study involving 40 cases of SEOC over a period of two years. The proliferation expression related to Ki-67 antigen was evaluated by immunohistochemical monoclonal MIB-1 antibody. In each case, the Ki-67 labeling index (Ki-67 LI) was articulated as percentage of positively stained cells using high power objective of the microscope (x400). Among the 40 carcinomas, 26 were serous, five mucinous, four each of clear cell and undifferentiated and one transitional cell carcinoma. A total of 75% were high grade tumours. High Ki-67 LI was associated with high grade tumours (69.9%), high grade serous tumours (65.34%) and advanced FIGO staging (70.6%) with the p-value of <0.001. CA 125 levels did not have a significant correlation with Ki-67 LI. Ki-67 is an exceptionally a cost effective marker to determine the growth fraction of a tumour cell population. In SEOC histological grade and FIGO stage when combined with Ki-67 LI in histopathology report would help in diagnostic differentiation of subtypes, prognostication, deciding the need for adjuvant chemotherapy and in predicting survival analysis.

  12. Collagen type XVIII/endostatin is differentially expressed in primary and metastatic colorectal cancers and ovarian carcinomas

    PubMed Central

    Guenther, U; Herbst, H; Bauer, M; Isbert, C; Buhr, H-J; Riecken, E-O; Schuppan, D

    2001-01-01

    Collagen type XVIII (C18) is a nonfibrillar collagen of basement membranes. Its C-terminal fragment, endostatin, has been identified as an inhibitor of angiogenesis. C18 is predominantly expressed by hepatocytes of normal, cirrhotic and neoplastic liver. We compared the patterns of C18 RNA-expression in colonic adenocarcinoma metastases, which represent the most frequently occurring liver tumours, to normal colon mucosa, to primary colon cancers and to ovarian cancers which are often morphologically similar to colonic cancer or metastasis. Two C18-specific RNA-probes were generated to perform in situ hybridization combined with immunohistochemistry for cytokeratin, vimentin and the endothelial marker CD31, in order to characterize the C18-expressing cells. C18/endostatin protein was localized by immunohistology. In colorectal carcinomas and their liver metastases high levels of C18 transcripts were observed in endothelial cells and fibroblasts/myofibroblasts, whereas C18 RNA was virtually absent from carcinoma cells. Ovarian carcinomas displayed high C18 RNA expression both in carcinoma and stromal cells, indicating that induction of C18 transcription in tumour stromal cells is independent of the ability of carcinoma cells to express C18. While the role of tumour cell derived C18 in cancer growth regulation remains unknown, stimulation of proteolysis of the locally strongly expressed C18 to endostatin could offer an attractive approach for a targeted antineoplastic therapy. © 2001 Cancer Research Campaign   http://www.bjcancer.com PMID:11720442

  13. High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression.

    PubMed

    Roh, Michael H; Yassin, Yosuf; Miron, Alexander; Mehra, Karishma K; Mehrad, Mitra; Monte, Nicolas M; Mutter, George L; Nucci, Marisa R; Ning, Geng; Mckeon, Frank D; Hirsch, Michelle S; Wa, Xian; Crum, Christopher P

    2010-10-01

    High-grade endometrioid and serous carcinomas of the ovary and fallopian tube are responsible for the majority of cancer deaths and comprise a spectrum that includes early or localized (tubal intraepithelial carcinoma) and advanced (invasive or metastatic) disease. We subdivided a series of these tumors into three groups, (1) classic serous, (2) mixed serous and endometrioid and (3) endometrioid carcinomas and determined: (1) the frequencies of coexisting tubal intraepithelial carcinoma, (2) frequency of a dominant ovarian mass suggesting an ovarian origin and (3) immuno-localization of WT-1, p53, PTEN, PAX2 and p16(ink4). All tumors were analyzed for p53 mutations. Thirty six, 25 and 8% of groups 1-3 were associated with tubal intraepithelial carcinoma (P=0.09) and 34, 45 and 62% predominated in one ovary (P=0.028), respectively. Differences in frequencies of diffuse p53 immunostaining (85-93%), WT-1 (70-98%) and p16(ink4) positivity (69-75%) were not significant for all groups. Greater than 95% reduction in PAX2 and PTEN occurred in 67-75 and 5-12%, respectively; however, PAX2 and PTEN staining intensity, when present, was often heterogeneous, highlighting different tumor populations. PAX2 and PTEN expression were markedly reduced or absent in 12 of 12 and 4 of 12 tubal intraepithelial carcinomas. In summary, high-grade müllerian carcinomas share identical frequencies of altered or reduced expression of p53, PTEN and PAX2, all of which can be appreciated in tubal intraepithelial carcinomas. Because only a subset of these tumors appears to arise in the fallopian tube, attention to expression of these biomarkers in the ovary and other müllerian sites might facilitate the identification of other carcinogenic pathways. PAX2 and PTEN, in addition to p53 and p16(ink4), comprise a potentially important gene combination in high-grade pelvic carcinogenesis.

  14. DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

    PubMed Central

    Kamieniak, M M; Muñoz-Repeto, I; Rico, D; Osorio, A; Urioste, M; García-Donas, J; Hernando, S; Robles-Díaz, L; Ramón y Cajal, T; Cazorla, A; Sáez, R; García-Bueno, J M; Domingo, S; Borrego, S; Palacios, J; van de Wiel, M A; Ylstra, B; Benítez, J; García, M J

    2013-01-01

    Background: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours. Methods: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features. Results: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours. Conclusion: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors. PMID:23558894

  15. Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis.

    PubMed

    Mo, Qingqing; Zhang, Yu; Jin, Xin; Gao, Yue; Wu, Yuan; Hao, Xing; Gao, Qinglei; Chen, Pingbo

    2016-11-01

    Paclitaxel is a mitotic inhibitor used in ovarian cancer chemotherapy. Unfortunately, due to the rapid genetic and epigenetic changes in adaptation to stress induced by anticancer drugs, cancer cells are often able to become resistant to single or multiple anticancer agents. However, it remains largely unknown how paclitaxel resistance happens. In this study, we generated a cell line of acquired resistance to paclitaxel therapy, A2780T, which is cross-resistant to other antimitotic drugs, such as PLK1 inhibitor or AURKA inhibitor. Immunoblotting revealed significant alterations in cell-cycle-related and apoptotic-related proteins involved in key signaling pathways. In particular, phosphorylation of p38, which activates H2AX, was significantly decreased in A2780T cells compared to the parental A2780 cells. Geldanamycin (GA), an inhibitor of Hsp90, sustained activation of the p38/H2AX axis, and A2780T cells were shown to be more sensitive to GA compared to A2780 cells. Furthermore, treatment of A2780 and A2780T cells with GA significantly enhanced sensitivity to paclitaxel. Meanwhile, GA cooperated with paclitaxel to suppress tumor growth in a mouse ovarian cancer xenograft model. In conclusion, GA may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by inactivation of p38/H2AX axis.

  16. Binding of nuclear caveolin-1 to promoter elements of growth-associated genes in ovarian carcinoma cells

    SciTech Connect

    Sanna, Elena; Miotti, Silvia . E-mail: silvia.miotti@istitutotumori.mi.it; Mazzi, Mimma; De Santis, Giuseppina; Canevari, Silvana; Tomassetti, Antonella

    2007-04-15

    Caveolin-1 (cav-1), a member of a protein family associated mainly with cell membrane microdomains in many cell types, acts as a tumor suppressor in ovarian carcinoma cells. Biochemical analyses demonstrated that cav-1 was also localized in the nuclei of ovarian carcinoma cells, endogenously (SKOV3) or ectopically (IGtC3) expressing cav-1. By confocal analyses, the same cell lines as well as IGROV1 and SKOV3 cells transiently transfected with green fluorescent protein-cav-1 fusion protein showed nuclear punctate speckled pattern. Subnuclear distribution analysis revealed cav-1 mainly associated with the nuclear matrix, but also slightly with chromatin. Cav-1 was found in nuclear high-molecular weight complexes and by confocal analysis was found to co-localized with the inner nuclear membrane protein emerin. Cyclin D1 and folate receptor promoters were modulated by cav-1 in SKOV3 cells as demonstrated by transient transfection with or silencing of cav-1. Chromatin immunoprecipitation and supershift assays indicated that nuclear cav-1 can bind in vitro and in vivo to promoter sequences of both cyclin D1 and folate receptor genes. These data suggest that in ovarian carcinoma cells cav-1, localized in transcriptionally inactive chromatin, exerts a functional activity mediated, at least in part, by directly binding to sequences of genes involved in proliferation.

  17. Functional effect of point mutations in the alpha-folate receptor gene of CABA I ovarian carcinoma cells.

    PubMed

    Mangiarotti, F; Miotti, S; Galmozzi, E; Mazzi, M; Sforzini, S; Canevari, S; Tomassetti, A

    2001-01-01

    The alpha-folate receptor (alpha FR) is overexpressed in 90% of nonmucinous ovarian carcinomas. In addition to the known role of alpha FR binding and mediating the internalization of folates, functional interaction of alpha FR with signaling molecules was recently shown. To identify a model to study the role of alpha FR in ovarian carcinoma, we characterized the alpha FR gene in the ovarian carcinoma cell line CABA I in comparison to a reference line, IGROV1. In CABA I cells, Northern blot analysis revealed an alpha FR transcript of the expected length and FACS analysis indicated receptor expression on the cell membrane; however, RNase protection assay revealed no specific signals. Southern blot and genomic PCR analysis suggested the presence of a rearrangement(s) involving the 5' region of the gene in CABA I cells as compared to IGROV1 cells. Cloning and sequencing of CABA I alpha FR cDNA revealed several point mutations. The partitioning of alpha FR in membrane microdomains from CABA I cells and its association with regulatory molecules was comparable to that of IGROV1 cells. By contrast, the alpha FR expressed on the CABA I cell membrane bound folic acid with lower affinity, and ectopic expression of the corresponding cDNA in CHO cells confirmed impaired folic acid binding. Thus, CABA I cells may provide a tool to delineate functional domains of the alpha FR.

  18. Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop.

    PubMed

    Coffman, Lan G; Choi, Yun-Jung; McLean, Karen; Allen, Benjamin L; di Magliano, Marina Pasca; Buckanovich, Ronald J

    2016-02-09

    The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.

  19. Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop

    PubMed Central

    Coffman, Lan G.; Choi, Yun-Jung; McLean, Karen; Allen, Benjamin L.; di Magliano, Marina Pasca; Buckanovich, Ronald J.

    2016-01-01

    The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer. PMID:26755648

  20. Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma.

    PubMed

    Arakawa, Noriaki; Kobayashi, Hiroshi; Yonemoto, Naohiro; Masuishi, Yusuke; Ino, Yoko; Shigetomi, Hiroshi; Furukawa, Naoto; Ohtake, Norihisa; Miyagi, Yohei; Hirahara, Fumiki; Hirano, Hisashi; Miyagi, Etsuko

    2016-01-01

    There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC. Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set. The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set. TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC.

  1. Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma

    PubMed Central

    Arakawa, Noriaki; Kobayashi, Hiroshi; Yonemoto, Naohiro; Masuishi, Yusuke; Ino, Yoko; Shigetomi, Hiroshi; Furukawa, Naoto; Ohtake, Norihisa; Miyagi, Yohei; Hirahara, Fumiki; Hirano, Hisashi; Miyagi, Etsuko

    2016-01-01

    Background There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC. Methods Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set. Results The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set. Conclusions TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC. PMID:27798689

  2. Establishment of Primary Cell Culture From Ascitic Fluid and Solid Tumor Obtained From Epithelial Ovarian Carcinoma Patients.

    PubMed

    Kar, Rajarshi; Chawla, Diwesh; Gupta, Bindiya; Mehndiratta, Mohit; Wadhwa, Neelam; Agarwal, Rachna

    2017-08-16

    Ovarian cancer is the seventh leading cause of cancer death worldwide. This is mainly due to late diagnosis and high rate of relapse and resistance following chemotherapy. In the present study, we describe simple and cost-effective method to establish primary culture from ascitic fluid and solid tumor obtained from epithelial ovarian carcinoma patient, which may provide a better tool for in vitro testing of drug sensitivity and designing individualized treatment protocol. Complete Dulbecco modified Eagle medium (DMEM) was prepared by supplementing DMEM with 10% fetal bovine serum and antibiotics (ciprofloxacin and amphotericin B). Establishment of primary culture of ovarian cancer cells from ascites fluid and solid tumor was done by using complete DMEM media. Primary cultures of ovarian cancer cells were established from ascitic fluid and solid tumor tissue. Of the 7 ascitic fluid samples, we were able to establish 5 primary cultures of ovarian cancer cells. All the 7 samples were diagnosed as serous papillary adenocarcinoma. Some fibroblasts were also attached to culture flask on day 4; they were removed by exposing them to trypsin for a brief period. On day 7, grape-like clusters were visualized under inverted microscope. The cells became confluent on the 10th and 11th day and showed cobblestone appearance, which is a hallmark of ovarian cancer cells. Senescent irregularly shaped cells that have ceased dividing were seen after 8 to 10 passages. This study highlights the fact that establishing primary cultures from ascitic fluid or solid tumor tissue may help us to understand the molecular profile of the cancer cells, which allow us to select the best chemotherapeutic agent for ovarian cancer patients and thus take a step toward patient-tailored therapy so that patients are not exposed to drugs to which they are not likely to respond.

  3. Radiosensitivity of human ovarian carcinoma and melanoma cells to γ-rays and protons.

    PubMed

    Keta, Otilija; Todorović, Danijela; Popović, Nataša; Korićanac, Lela; Cuttone, Giacomo; Petrović, Ivan; Ristić-Fira, Aleksandra

    2014-06-29

    Proton radiation offers physical advantages over conventional radiation. Radiosensitivity of human 59M ovarian cancer and HTB140 melanoma cells was investigated after exposure to γ-rays and protons. Irradiations were performed in the middle of a 62 MeV therapeutic proton spread out Bragg peak with doses ranging from 2 to 16 Gy. The mean energy of protons was 34.88 ±2.15 MeV, corresponding to the linear energy transfer of 4.7 ±0.2 keV/µm. Irradiations with γ-rays were performed using the same doses. Viability, proliferation and survival were assessed 7 days after both types of irradiation while analyses of cell cycle and apoptosis were performed 48 h after irradiation. Results showed that γ-rays and protons reduced the number of viable cells for both cell lines, with stronger inactivation achieved after irradiation with protons. Surviving fractions for 59M were 0.91 ±0.01 for γ-rays and 0.81 ±0.01 for protons, while those for HTB140 cells were 0.93 ±0.01 for γ-rays and 0.86 ±0.01 for protons. Relative biological effectiveness of protons, being 2.47 ±0.22 for 59M and 2.08 ±0.36 for HTB140, indicated that protons provoked better cell elimination than γ-rays. After proton irradiation proliferation capacity of the two cell lines was slightly higher as compared to γ-rays. Proliferation was higher for 59M than for HTB140 cells after both types of irradiation. Induction of apoptosis and G2 arrest detected after proton irradiation were more prominent in 59M cells. The obtained results suggest that protons exert better antitumour effects on ovarian carcinoma and melanoma cells than γ-rays. The dissimilar response of these cells to radiation is related to their different features.

  4. Downregulation of connective tissue growth factor by three-dimensional matrix enhances ovarian carcinoma cell invasion.

    PubMed

    Barbolina, Maria V; Adley, Brian P; Kelly, David L; Shepard, Jaclyn; Fought, Angela J; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D; Stack, M Sharon

    2009-08-15

    Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancies, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intraperitoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hr of 3D collagen culture) coupled with confirmatory real-time reverse-transcriptase polymerase chain reaction, multiple 3D cell culture matrices, Western blot, immunostaining, adhesion, migration and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion- mimicking conditions (3D Type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n = 41), but was present in 100% of normal ovarian epithelium samples (n = 7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using alpha6beta1 and alpha3beta1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion.

  5. Downregulation of Connective Tissue Growth Factor by Three-Dimensional Matrix Enhances Ovarian Carcinoma Cell Invasion

    PubMed Central

    Barbolina, Maria V.; Adley, Brian P.; Kelly, David L.; Shepard, Jaclyn; Fought, Angela J.; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D.; Sharon Stack, M

    2010-01-01

    Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancy, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intra-peritoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hours of 3-dimensional collagen culture) coupled with confirmatory real-time RT-PCR, multiple three-dimensional cell culture matrices, Western blot, immunostaining, adhesion, migration, and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion-mimicking conditions (3-dimensional type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n=41), but was present in 100% of normal ovarian epithelium samples (n=7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced, collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using α6β1 and α3β1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion. PMID:19382180

  6. Quantification of the concentration gradient of biomarkers between ovarian carcinoma interstitial fluid and blood

    PubMed Central

    Haslene-Hox, Hanne; Madani, Amina; Berg, Kaja C.G.; Woie, Kathrine; Salvesen, Helga B.; Wiig, Helge; Tenstad, Olav

    2014-01-01

    Background Tumor interstitial fluid (TIF) rather than plasma should be used in cancer biomarker discovery because of the anticipated higher concentration of locally produced proteins in the tumor microenvironment. Nevertheless, the actual TIF-to-plasma gradient of tumor specific proteins has not been quantified. We present the proof-of-concept for the quantification of the postulated gradient between TIF and plasma. Methods TIF was collected by centrifugation from serous (n = 19), endometrioid (n = 9) and clear cell (n = 3) ovarian carcinomas with early (n = 15) and late stage (n = 16) disease in grades 1 (n = 2), 2 (n = 8) and 3 (n = 17), and ELISA was used for the determination of CA-125, osteopontin and VEGF-A. Results All three markers were significantly up-regulated in TIF compared with plasma (p < 0.0001). The TIF-to-plasma ratio of the ovarian cancer biomarker CA-125 ranged from 1.4 to 24,300 (median = 194) and was inversely correlated to stage (p = 0.0006). The cancer related osteopontin and VEGF-A had TIF-to-plasma ratios ranging from 1 to 62 (median = 15) and 2 to 1040 (median = 59), respectively. The ratios were not affected by tumor stage, indicative of more widespread protein expression. Conclusion We present absolute quantitative data on the TIF-to-plasma gradient of selected proteins in the tumor microenvironment, and demonstrate a substantial and stage dependent gradient for CA-125 between TIF and plasma, suggesting a relation between total tumor burden and tissue-to-plasma gradient. General significance We present novel quantitative data on biomarker concentration in the tumor microenvironment, and a new strategy for biomarker selection, applicable in future biomarker studies. PMID:26673827

  7. Sequential combination of flavopiridol with Taxol synergistically suppresses human ovarian carcinoma growth.

    PubMed

    Song, Yue; Xin, Xing; Zhai, Xingyue; Xia, Zhijun; Shen, Keng

    2015-01-01

    The purpose is to investigate the effects of the sequential combination treatment of Taxol and flavopiridol on human ovarian carcinoma in vitro and in vivo. Cell viabilities were determined using the cell counting kit and by flow cytometry. RT-PCR, TUNEL, and immunoblotting assays were used to detect cellular apoptotic activities following treatments. Tumor growth and microvessel density (MVD) detection of mice bearing SKOV3 cells were studied. Taxol or flavopiridol alone was cytotoxic against SKOV3 cells in vitro with a viability rate of 38.2 ± 1.3 % for 1 µmol/L Taxol and 44.3 ± 5.9 % for 300 nM flavopiridol. Sequential combination treatment with Taxol and flavopiridol resulted in a viability rate of 9.1 ± 0.8 %. The apoptotic rate of SKOV3 cells was 15.7 ± 1.7, 9.4 ± 0.4 and 51.1 ± 2.5 % for Taxol, flavopiridol, and combination of Taxol and flavopiridol, respectively. Significant synergisms were observed in SKOV3 cells in vitro, following the sequential combination of Taxol for 24 h followed by flavopiridol for 24 h, which resulted in the most substantial cell death and the highest apoptotic rate. All treatments showed significant suppression of tumor growth at the end point of the in vivo study. All treatments significantly reduce the value of MVD. Sequential combination treatment with Taxol and flavopiridol exerted synergistic cytotoxic activities against SKOV3 cells in vitro and significantly suppress the tumor growth of mice bearing SKOV3 cells. It should be further explored as a potential clinically useful regimen against ovarian cancer.

  8. Regulation of copper transporter 2 expression by copper and cisplatin in human ovarian carcinoma cells.

    PubMed

    Blair, Brian G; Larson, Christopher A; Adams, Preston L; Abada, Paolo B; Safaei, Roohangiz; Howell, Stephen B

    2010-06-01

    Down-regulation of copper transporter 1 (CTR1) reduces uptake and sensitivity, whereas down-regulation of CTR2 enhances both. Cisplatin (DDP) triggers the rapid degradation of CTR1 and thus limits its own accumulation. We sought to determine the effect of DDP and copper on the expression of CTR2. Changes in CTR1 and CTR2 mRNA and protein levels in human ovarian carcinoma 2008 cells and ATOX1(+/+) and ATOX1(-/-) mouse embryo fibroblasts in response to exposure to DDP and copper were measured by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and deconvolution microscopy. DDP triggered rapid degradation of CTR1 in 2008 human ovarian cancer cells. However, it increased the expression of CTR2 mRNA and protein levels. Expression of CTR2 was heavily modulated by changes in intracellular copper concentration; copper depletion produced rapid disappearance of CTR2, whereas excess copper increased the level of CTR2 protein. This increase was associated with an increase in CTR2 mRNA and prolongation of the CTR2 half-life. Consistent with prior observations that short hairpin RNA interference-mediated knockdown of CTR2 enhanced DDP uptake and tumor cell kill, reduction of CTR2 by copper starvation also enhanced DDP uptake and cytotoxicity. Comparison of the ability of copper and DDP to modulate the expression of CTR1 in ATOX1(+/+) and ATOX1(-/-) indicated that ATOX1 participates in the regulation of CTR2 expression. Unlike CTR1, the expression of CTR2 is increased rather than decreased by DDP. Therefore, these two copper transporters have opposite effects on DDP sensitivity. CTR2 expression is regulated by copper availability via the copper-dependent regulator ATOX1.

  9. Regulation of Copper Transporter 2 Expression by Copper and Cisplatin in Human Ovarian Carcinoma Cells

    PubMed Central

    Blair, Brian G.; Larson, Christopher A.; Adams, Preston L.; Abada, Paolo B.; Safaei, Roohangiz

    2010-01-01

    Down-regulation of copper transporter 1 (CTR1) reduces uptake and sensitivity, whereas down-regulation of CTR2 enhances both. Cisplatin (DDP) triggers the rapid degradation of CTR1 and thus limits its own accumulation. We sought to determine the effect of DDP and copper on the expression of CTR2. Changes in CTR1 and CTR2 mRNA and protein levels in human ovarian carcinoma 2008 cells and ATOX1(+/+) and ATOX1(−/−) mouse embryo fibroblasts in response to exposure to DDP and copper were measured by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and deconvolution microscopy. DDP triggered rapid degradation of CTR1 in 2008 human ovarian cancer cells. However, it increased the expression of CTR2 mRNA and protein levels. Expression of CTR2 was heavily modulated by changes in intracellular copper concentration; copper depletion produced rapid disappearance of CTR2, whereas excess copper increased the level of CTR2 protein. This increase was associated with an increase in CTR2 mRNA and prolongation of the CTR2 half-life. Consistent with prior observations that short hairpin RNA interference-mediated knockdown of CTR2 enhanced DDP uptake and tumor cell kill, reduction of CTR2 by copper starvation also enhanced DDP uptake and cytotoxicity. Comparison of the ability of copper and DDP to modulate the expression of CTR1 in ATOX1(+/+) and ATOX1(−/−) indicated that ATOX1 participates in the regulation of CTR2 expression. Unlike CTR1, the expression of CTR2 is increased rather than decreased by DDP. Therefore, these two copper transporters have opposite effects on DDP sensitivity. CTR2 expression is regulated by copper availability via the copper-dependent regulator ATOX1. PMID:20194531

  10. Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

    PubMed Central

    Choi, Jae Yoon; Han, Hyun Ho; Kim, Young Tae; Lee, Joo Hyun; Kim, Baek Gil; Kang, Suki

    2017-01-01

    Purpose Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart. Materials and Methods Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed. Results Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either. Conclusion We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis. PMID:27873496

  11. Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma12

    PubMed Central

    Moreno-Smith, Myrthala; Lee, Sun Joo; Lu, Chunhua; Nagaraja, Archana S; He, Guangan; Rupaimoole, Rajesha; Han, Hee Dong; Jennings, Nicholas B; Roh, Ju-Won; Nishimura, Masato; Kang, Yu; Allen, Julie K; Armaiz, Guillermo N; Matsuo, Koji; Shahzad, Mian M K; Bottsford-Miller, Justin; Langley, Robert R; Cole, Steve W; Lutgendorf, Susan K; Siddik, Zahid H; Sood, Anil K

    2013-01-01

    Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth. PMID:23633922

  12. EphA2 Immunoconjugate as Molecularly Targeted Chemotherapy for Ovarian Carcinoma

    PubMed Central

    Lee, Jeong-Won; Han, Hee Dong; Shahzad, Mian M. K.; Kim, Seung Wook; Mangala, Lingegowda S.; Nick, Alpa M.; Lu, Chunhua; Langley, Robert R.; Schmandt, Rosemarie; Kim, Hye-Sun; Mao, Shenlan; Gooya, John; Fazenbaker, Christine; Jackson, Dowdy; Tice, David A.; Landen, Charles N.; Coleman, Robert L.

    2009-01-01

    proliferation (eg, 1C1-mcMMAF vs control, mean = 44.1% vs 55.8% proliferating cells; difference = 11.7%, 95% CI = 2.45% to 20.9%; P = .01) and increased apoptosis of tumor cells (eg, 1C1-mcMMAF vs control, mean = 8.6% vs 0.9% apoptotic cells; difference = 7.7%, 95% CI = 3.8% to 11.7%; P < .001) and of mouse endothelial cells (eg, 1C1-mcMMAF vs control, mean 2.8% vs 0.4% apoptotic endothelial cells; difference = 2.4%, 95% CI = 1.4% to 4.6%; P = .034). Conclusion The 1C1-mcMMAF immunoconjugate had antitumor activity in preclinical models of ovarian carcinoma. PMID:19641174

  13. Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-grade and High-grade Carcinomas

    PubMed Central

    Kuo, Kuan-Ting; Guan, Bin; Feng, Yuanjian; Mao, Tsui-Lien; Chen, Xu; Jinawath, Natini; Wang, Yue; Kurman, Robert J.; Shih, Ie-Ming; Wang, Tian-Li

    2009-01-01

    Ovarian serous carcinoma, the most common and lethal type of ovarian cancer, was thought to develop from two distinct molecular pathways. High-grade (HG) serous carcinomas contain frequent TP53 mutations while low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway. However, the molecular alterations involved in the progression from SBT to LG carcinoma remain largely unknown. As well, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well-studied. To further address these two issues, we assessed DNA copy number changes among affinity-purified tumor cells from 37 ovarian serous neoplasms including SBT, LG and HG tumors using high density 250K SNP arrays. Chromosomal instability index as measured by changes in DNA copy number was significantly higher in HG than in LG serous carcinomas. Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT. This region contains several candidate tumor suppressors including miR-34a. In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions including homozygous deletions were identified. Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4% and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas. Except the CDKN2A/B region, these homozygous deletions were not present in either SBT or LG tumors. Our study provides a genome-wide homozygous deletion profiles in HG serous carcinomas, serving as a molecular foundation to study tumor suppressors in ovarian cancer. PMID:19383911

  14. Cisplatin and Paclitaxel in Treating Patients With Stage IIB, Stage IIC, Stage III, or Stage IV Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cavity Cancer

    ClinicalTrials.gov

    2014-12-29

    Chemotherapeutic Agent Toxicity; Endometrial Adenocarcinoma; Fallopian Tube Carcinoma; Gastrointestinal Complication; Malignant Ovarian Mixed Epithelial Tumor; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage II Ovarian Cancer; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  15. Prognostic significance of cell cycle proteins and genomic instability in borderline, early and advanced stage ovarian carcinomas.

    PubMed

    Blegen, H.; Einhorn, N.; Sjövall, K.; Roschke, A.; Ghadimi, B. M.; McShane, L. M.; Nilsson, B.; Shah, K.; Ried, T.; Auer, G.

    2000-11-01

    Disturbed cell cycle-regulating checkpoints and impairment of genomic stability are key events during the genesis and progression of malignant tumors. We analyzed 80 epithelial ovarian tumors of benign (n = 10) and borderline type (n = 18) in addition to carcinomas of early (n = 26) and advanced (n = 26) stages for the expression of Ki67, cyclin A and cyclin E, p21WAF-1, p27KIP-1 and p53 and correlated the results with the clinical course. Genomic instability was assessed by DNA ploidy measurements and, in 35 cases, by comparative genomic hybridization. Overexpression of cyclin A and cyclin E was observed in the majority of invasive carcinomas, only rarely in borderline tumors and in none of the benign tumors. Similarly, high expression of p53 together with undetectable p21 or loss of chromosome arm 17p were frequent events only in adenocarcinomas. Both borderline tumors and adenocarcinomas revealed a high number of chromosomal gains and losses. However, regional chromosomal amplifications were found to occur 13 times more frequently in the adenocarcinomas than in the borderline tumors. The expression pattern of low p27 together with high Ki67 was found to be an independent predictor of poor outcome in invasive carcinomas. The results provide a link between disturbed cell cycle regulatory proteins, chromosomal aberrations and survival in ovarian carcinomas.

  16. Metformin Hydrochloride, Carboplatin, and Paclitaxel in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-01-24

    Ovarian Papillary Serous Carcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer

  17. Induction of apoptosis in ovarian carcinoma cells by AHPN/CD437 is mediated by retinoic acid receptors.

    PubMed

    Holmes, W F; Dawson, M I; Soprano, R D; Soprano, K J

    2000-10-01

    Retinoids have great promise in the area of cancer therapy and chemoprevention. These natural and synthetic derivatives of vitamin A have been shown to play an important role in regulating cell differentiation and proliferation. While all-trans-retinoic acid (ATRA) has been demonstrated to inhibit the growth of several ovarian tumor cell lines, other ovarian carcinoma cell lines have been found to be resistant to retinoid dependent growth suppression. Interestingly, a novel synthetic retinoid, CD437 or AHPN, has been demonstrated to inhibit the growth of both ATRA-sensitive (CA-OV3) and ATRA-resistant (SK-OV3) ovarian tumor cell lines as well as to induce apoptosis. The overall goal of this research was to understand the mechanism by which AHPN/CD437 induces apoptosis in ovarian tumor cell lines. Since a number of studies have demonstrated the importance of nuclear receptors (RARs and RXRs) in mediating cellular responses to retinoids, we wished to determine the role of RARs in mediating the AHPN/CD437 response. We modulated RAR level and function by overexpressing either wild type RAR-gamma or a pan dominant negative mutant of all RAR subtypes called RAR-beta (R269Q), or through the use of an RAR-gamma antagonist, MM11253. We found that inhibition of RAR function reduced but did not eliminate induction of apoptosis in both CA-OV3 and SK-OV3 cells by AHPN/CD437. Likewise, overexpression of wild type RAR-gamma was found to increase apoptosis after treatment with AHPN/CD437. Our results suggest that in ovarian carcinomas, AHPN/CD437 induced apoptosis is mediated at least in part via an RAR pathway.

  18. Prognostic impact of HER3 based on protein and mRNA expression in high-grade serous ovarian carcinoma.

    PubMed

    Unger, Ulrike; Denkert, Carsten; Braicu, Ioana; Sehouli, Jalid; Dietel, Manfred; Loibl, Sibylle; Darb-Esfahani, Silvia

    2017-02-01

    HER3 is a member of the epidermal growth factor family and was predominantly described as a negative prognostic factor in various solid tumors as well as in ovarian cancer. In this study, we investigated HER3 on protein and mRNA expression in histologically defined subtypes of ovarian cancer looking for an influence on patient's survival. Altogether, we examined HER3 in ovarian high-grade serous (HGSC, n = 320), low-grade serous (LGSC, n = 55), endometrioid (EC, n = 33), and clear cell (CCC, n = 48) carcinomas using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR (qRT-PCR). Univariate and multivariate analyses were performed to explore the association between HER3 and overall survival (OS) as well as progression-free survival (PFS). In HGSC, high HER3 mRNA expression was a favorable prognostic factor for PFS (P = 0.008) and OS (P = 0.052), while for high HER3 protein expression, a trend towards better survival was seen (OS P = 0.064; PFS P = 0.099). A subgroup of HGSC with negative HER3 staining and negative HER3 mRNA levels showed most unfavorable OS and PFS (P = 0.002 and P = 0.004, respectively). Using the multivariate Cox regression model, HER3 was predictive for prolonged PFS (HR, 0.48; 95% CI, 0.26-0.88; P = 0.018). All in all, we cannot confirm the reported negative prognostic impact of HER3 expression in high-grade serous ovarian carcinoma and moreover find a rather positive prognostic implication of HER3 in this major ovarian cancer histological subtype.

  19. [Paraneoplastic cerebellar degeneration associated with ovarian cancer: anti-Yo immunoreactivity in autoptic cerebellum and ovarian carcinoma].

    PubMed

    Bartos, A; Stourac, P; Rusina, R; Sejdová, M; Velenská, Z

    2002-10-01

    Paraneoplastic cerebellar degeneration is a rare disorder caused likely by autoimmune mechanisms in malignant oncologic diseases, and the most common tumors are ovarian, breast, lung cancer, and m. Hodgkin. An immune reaction is supposed to be directed against identical antigens of cerebellum and tumor, and paraneoplastic antibodies called anti-Yo, anti-Hu, anti-Ri, or anti-Tr are often detected in blood and cerebrospinal fluid. The course of paraneoplastic cerebellar degeneration as a complication of ovarian cancer is described. The relationship between the malignancy and pathologic changes in cerebellum was confirmed by positive immunohistochemical and immunofluorescence reaction between a patient's anti-Yo-positive serum and her own Purkinje's and ovarian cancer cells.

  20. The essential roles of CCR7 in epithelial-to-mesenchymal transition induced by hypoxia in epithelial ovarian carcinomas.

    PubMed

    Cheng, Shaomei; Han, Lin; Guo, Jingyan; Yang, Qing; Zhou, Jianfang; Yang, Xiangshan

    2014-12-01

    The chemokine receptor CCR7 and its ligands CCL19/21 mediate the tumor mobility, invasion, and metastasis (Wu et al. Curr Pharm Des. 15:742-57, 2009). Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Here, we addressed the roles of CCR7 in epithelial ovarian carcinoma tissues and hypoxia-induced serous papillary cystic adenocarcinoma (SKOV-3) EMT. The expression level of CCR7 protein was analyzed by immunohistochemistry in 30 specimens of epithelial ovarian carcinomas. Western blot was used to investigate the expression of hypoxia-induced CCR7, HIF-1α, and EMT markers (N-cadherin, Snail, MMP-9). In addition, wound healing and Transwell assay were introduced to observe the capacity of migration and invasiveness. Our data showed CCR7 expression was observed in 22 cases of tissues and closely associated with lymph node metastasis and FIGO stage (III + IV). At 6, 12, 24, and 36 h following hypoxia, CCR7 and HIF-1α proteins were both obviously upregulated in a time-dependent method, compared with normal oxygen. In vitro, SKOV-3 expressed N-cadherin, Snail, and MMP-9 once either CCL21 stimulation or hypoxia induction, while hypoxia accompanied with CCL21 induction exhibited strongest upregulation of N-cadherin, Snail, and MMP-9 proteins. Besides, wound healing and Transwell assay further identified that hypoxia with CCL21 stimulation can remarkably promote cell migration and invasiveness. Taken together, CCR7 can constitutively express in epithelial ovarian carcinomas and be induced rapidly in response to hypoxia, which indeed participates in EMT development and prompts the cell migration and invasion. Thus, this study suggested that the epithelial ovarian cancer invasion and metastasis can be inhibited by antagonizing CCR7.

  1. OVCA1 inhibits the proliferation of epithelial ovarian cancer cells by decreasing cyclin D1 and increasing p16.

    PubMed

    Kong, Fandou; Tong, Rui; Jia, Lingyu; Wei, Wei; Miao, Xiaoyan; Zhao, Xinyu; Sun, Wenping; Yang, Guang; Zhao, Chunyan

    2011-08-01

    OVCA1, a tumor suppressor gene, is deleted or lower expressed in about 80% of ovarian cancer. Over expression of OVCA1 in human ovarian cancer A2780 cells inhibits cell proliferation and arrests cells in G1 stage. However, the fact that the molecular mechanism of OVCA1 inhibits cell growth is presently elusive. Here we investigated the potential signaling pathway induced by over-expression of OVCA1. Our results show that over-expression of human OVCA1 in ovarian cancer cells A2780 leads to down-regulation of cyclin D1, and up-regulation of p16, but no effect on the expression of NF-κB. It indicates that OVCA1 could inhibit the proliferation of ovarian cancer cell A2780 by p16/cyclin D1 pathway, but not by NF-κB.

  2. Predictive factors of ovarian carcinoma for women with ovarian endometrioma aged 45 years and older in China.

    PubMed

    He, Zheng-Xing; Shi, Hong-Hui; Fan, Qing-Bo; Zhu, Lan; Leng, Jin-Hua; Sun, Da-Wei; Li, Zhan-Fei; Shen, Keng; Wang, Shu; Lang, Jing-He

    2017-07-17

    To explore the risk factors of endometriosis-associated ovarian cancer (EAOC) in women with ovarian endometriosis (OEM) aged 45 years and above in China. This study reviewed the medical records of 1038 women in total who were aged 45 years and above, surgical-pathologically diagnosed with ovarian endometriosis, and were treated at Peking Union Medical College Hospital between December 1996 and December 2016. Histology evaluation was used to determine whether the ovarian endometriosis specimen was with (n = 30) or without (n = 1008) ovarian cancer. 2.9% (30/1038) of women with the surgical-pathological diagnosis of ovarian endometriosis were found to have EAOC. Those patients with EAOC were prone to be in the postmenopausal status at the time of the diagnosis (OR 5.50, 95%CI 2.54-11.90, P < .001) and larger size of tumor (≥8 cm, OR 7.19, 95% CI 3.34-15.50, P < .001), and higher prevalence of coexisting with endometrial disorders (OR 4.11, 95%CI 1.73-9.73, P = .003). This study showed that patients of an older age when diagnosed with OEM, were at a higher risk of developing EAOC, respectively measuring of 1.7% (13/751) at 45-49 years, 5.6% (12/215) at 50-54 years, and 10.0%(5/50) at 55-59 years (P < 0.001). This study showed that for women aged 45 years and above who were diagnosed with OEM, the independent risk factors of EAOC were menopausal status, tumor size of 8 cm or greater in diameter, and coexisting endometrial disorders. Therefore, intensive follow-ups or active interventions should be considered for them.

  3. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

    PubMed Central

    Köbel, M; Madore, J; Ramus, S J; Clarke, B A; Pharoah, P D P; Deen, S; Bowtell, D D; Odunsi, K; Menon, U; Morrison, C; Lele, S; Bshara, W; Sucheston, L; Beckmann, M W; Hein, A; Thiel, F C; Hartmann, A; Wachter, D L; Anglesio, M S; Høgdall, E; Jensen, A; Høgdall, C; Kalli, K R; Fridley, B L; Keeney, G L; Fogarty, Z C; Vierkant, R A; Liu, S; Cho, S; Nelson, G; Ghatage, P; Gentry-Maharaj, A; Gayther, S A; Benjamin, E; Widschwendter, M; Intermaggio, M P; Rosen, B; Bernardini, M Q; Mackay, H; Oza, A; Shaw, P; Jimenez-Linan, M; Driver, K E; Alsop, J; Mack, M; Koziak, J M; Steed, H; Ewanowich, C; DeFazio, A; Chenevix-Trench, G; Fereday, S; Gao, B; Johnatty, S E; George, J; Galletta, L; Goode, E L; Kjær, S K; Huntsman, D G; Fasching, P A; Moysich, K B; Brenton, J D; Kelemen, L E

    2014-01-01

    Background: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. Methods: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. Results: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94). Conclusions: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1

  4. Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer.

    PubMed

    Henry, C E; Llamosas, E; Djordjevic, A; Hacker, N F; Ford, C E

    2016-05-30

    Ovarian cancer survival remains poor despite recent advances in our understanding of genetic profiles. Unfortunately, the majority of ovarian cancer patients have recurrent disease after chemotherapy and lack other treatment options. Wnt signalling has been extensively implicated in cancer progression and chemoresistance. Therefore, we investigated the previously described Wnt receptors ROR1 and ROR2 as regulators of epithelial-to-mesenchymal transition (EMT) in a clinically relevant cell line model. The parental A2780- and cisplatin-resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance. Proliferation, adhesion, migration and invasion were measured after transient overexpression of ROR1 and ROR2 in the parental A2780 cell line, and silencing of ROR1 and ROR2 in the A2780-cis cell line. Here we show that ROR1 and ROR2 expression is increased in A2780-cis cells, alongside β-catenin-independent Wnt targets. Knockdown of ROR1 and ROR2 significantly inhibited cell migration and invasion and simultaneous knockdown of ROR1 and ROR2 significantly sensitised cells to cisplatin, whilereas ROR overexpression in the parental cell line increased cell invasion. Therefore, ROR1 and ROR2 have the potential as novel drug targets in metastatic and recurrent ovarian cancer patients.

  5. Pegylated Liposomal Doxorubicin Hydrochloride With Atezolizumab and/or Bevacizumab in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-01-31

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; High Grade Fallopian Tube Serous Adenocarcinoma; High Grade Ovarian Serous Adenocarcinoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Primary Peritoneal High Grade Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  6. Belinostat and Carboplatin in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Carboplatin or Cisplatin

    ClinicalTrials.gov

    2014-06-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer

  7. Fractalkine receptor CX(3)CR1 is expressed in epithelial ovarian carcinoma cells and required for motility and adhesion to peritoneal mesothelial cells.

    PubMed

    Kim, Mijung; Rooper, Lisa; Xie, Jia; Kajdacsy-Balla, Andre A; Barbolina, Maria V

    2012-01-01

    Epithelial ovarian carcinoma (EOC) is a deadly disease, and little is known about the mechanisms underlying its metastatic progression. Using human specimens and established cell lines, we determined that the G-protein-coupled seven-transmembrane fractalkine receptor (CX(3)CR1) is expressed in primary and metastatic ovarian carcinoma cells. Ovarian carcinoma cells robustly migrated toward CX(3)CL1, a specific ligand of CX(3)CR1, in a CX(3)CR1-dependent manner. Silencing of CX(3)CR1 reduced migration toward human ovarian carcinoma ascites fluid by approximately 70%. Importantly, adhesion of ovarian carcinoma cells to human peritoneal mesothelial cells was dependent on CX(3)CL1/CX(3)CR1 signaling. In addition, CX(3)CL1 was able to induce cellular proliferation. Together, our data suggest that the fractalkine network may function as a major contributor to the progression of EOC, and further attention to its role in the metastasis of this deadly malignancy is warranted.

  8. Genital Schistosomiasis: A Report on Two Cases of Ovarian Carcinomas Containing Viable Eggs of Schistosoma mansoni

    PubMed Central

    Gonçalves Amorim, Andressa; Alves Barbosa Pagio, Fernanda; Neves Ferreira, Rodrigo; Chambô Filho, Antônio

    2014-01-01

    Schistosomiasis is a parasitic infection that is highly prevalent worldwide, with a variety of species being responsible for causing the disease. In Brazil, however, the only identified species is Schistosoma mansoni. The adult parasites inhabit the blood vessels of the hepatic portal system of the main host. The disease may range from being asymptomatic to provoking liver damage or portal hypertension. Furthermore, ectopic schistosomiasis may develop, and several hypotheses have been raised to explain the occurrence of the disease. This paper describes two cases, one in a 39-year-old woman and the other in a 47-year-old woman. Both had similar symptoms of pain and abdominal distension caused by a large abdominal/pelvic mass. Histopathology of the ovary showed a mucinous cystadenocarcinoma of the intestinal type in the first patient and a papillary serous carcinoma in the second, with both tumors containing viable eggs of Schistosoma mansoni. The neoplasms probably serve as a migratory route for the adult parasites and the embolization of eggs. Nevertheless, there is insufficient evidence to confirm the malignization of a benign lesion due to the presence of Schistosoma mansoni. Few cases have been reported in the international literature on the association between ovarian schistosomiasis and neoplasms. PMID:25587473

  9. Primary treatment of stage III ovarian carcinoma with sequential chemotherapy and whole abdominal radiation therapy.

    PubMed

    Reid, G C; Roberts, J A; Hopkins, M P; Schoeppel, S L; Perez-Tamayo, C; Drescher, C; Chamberlain, D; Morley, G W

    1993-06-01

    A prospective phase II clinical treatment trial of 13 patients with previously untreated optimal surgically resected (< or = 1 cm stage III ovarian carcinoma was conducted at the University of Michigan Hospitals. The treatment regimen after surgical resection consisted of chemotherapy followed by whole abdomen and pelvic radiation therapy. Chemotherapy consisted of four cycles of 50 mg/m2 cisplatin and 1000 mg/m2 cytoxan. This was followed by whole abdomen radiation therapy with a planned total dose of 30 Gy to the whole abdomen and then a 20-Gy boost to the pelvis. Six of 13 patients received a paraaortic radiation boost. There was minimal acute toxicity, but delayed toxicity was encountered with 38% of patients developing a bowel obstruction. Nine patients had reassessment laparotomy: 5 second-look laparotomies and 4 laparotomies for bowel obstruction. Two of these 9 patients died of septic complications after surgery. Nine patients died with disease, 1 patient is alive with advanced disease, and only 3 patients are alive with no evidence of disease. Actuarial 3-year survival and progression-free interval was 26 and 20%, respectively. Primary treatment consisting of sequential chemotherapy and whole abdomen radiation in the dose and scheme utilized did not improve the survival over what could be expected utilizing one of these treatments alone. It was associated with increased delayed toxicity.

  10. ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma.

    PubMed

    Yanagida, Satoshi; Taniue, Kenzui; Sugimasa, Hironobu; Nasu, Emiko; Takeda, Yasuko; Kobayashi, Mana; Yamamoto, Tadashi; Okamoto, Aikou; Akiyama, Tetsu

    2013-01-01

    Mammalian genomes encode numerous antisense non-coding RNAs, which are assumed to be involved in the regulation of the sense gene expression. However, the mechanisms of their action and involvement in the development of diseases have not been well elucidated. The ANA/BTG3 protein is an antiproliferative protein whose expression is downregulated in prostate and lung cancers. Here we show that an antisense transcript of the ANA/BTG3 gene, termed ASBEL, negatively regulates the levels of ANA/BTG3 protein, but not of ANA/BTG3 mRNA and is required for proliferation and tumorigenicity of ovarian clear cell carcinoma. We further show that knockdown of ANA/BTG3 rescues growth inhibition caused by ASBEL knockdown. Moreover, we demonstrate that ASBEL forms duplexes with ANA/BTG3 mRNA in the nucleus and suppresses its cytoplasmic transportation. Our findings illustrate a novel function for an antisense transcript that critically promotes tumorigenesis by suppressing translation of the sense gene by inhibiting its cytoplasmic transportation.

  11. Microenvironmental regulation of chemokine (C-X-C-motif) receptor 4 in ovarian carcinoma.

    PubMed

    Barbolina, Maria V; Kim, Mijung; Liu, Yueying; Shepard, Jaclyn; Belmadani, Abdelhak; Miller, Richard J; Shea, Lonnie D; Stack, M Sharon

    2010-05-01

    The majority of women diagnosed with epithelial ovarian carcinoma (EOC) succumb due to complications of metastatic disease, suggesting that antimetastatic therapies may improve patient survival. EOC metastasis involves intraperitoneal shedding of cells from the primary tumor, followed by adhesion and localized penetration of the submesothelial matrix to anchor metastatic implants. Accumulation of malignant ascites is also common. Thus, a unique microenvironmental niche is established, which includes malignant cells and a plethora of soluble factors secreted by-or in response to-tumor cells. As cells penetrating the submesothelial surface encounter an interstitial collagen-rich extracellular matrix, we have used three-dimensional type I collagen gels to model early events resulting from intraperitoneal anchoring. In this study, we show a novel pathway of CXCR4 upregulation through beta1 integrin - and NFkappaB-dependent signaling pathways in response to three-dimensional type I collagen. We also show the involvement of CXCR4-SDF1 axis in collagen invasion and proliferation, relevant to the metastatic EOC. Our data show that CXCR4 expression in human EOCs, as well as SDF1 presence in the ascites, is correlated with disease progression and metastasis. These data emphasize the importance of the CXCR4-SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis.

  12. Microenvironmental Regulation of Chemokine (C-X-C-motif) Receptor 4 in Ovarian Carcinoma

    PubMed Central

    Barbolina, Maria V.; Kim, Mijung; Liu, Yueying; Shepard, Jaclyn; Belmadani, Abdelhak; Miller, Richard J.; Shea, Lonnie D.; Stack, M. Sharon

    2010-01-01

    The majority of women diagnosed with epithelial ovarian carcinoma (EOC) succumb due to complications of metastatic disease, suggesting that anti-metastatic therapies may improve patient survival. EOC metastasis involves intra-peritoneal shedding of cells from the primary tumor, followed by adhesion and localized penetration of the submesothelial matrix to anchor metastatic implants. Accumulation of malignant ascites is also common. Thus, a unique microenvironmental niche is established, which includes malignant cells and a plethora of soluble factors secreted by – or in response to – tumor cells. As cells penetrating the sub-mesothelial surface encounter an interstitial collagen-rich ECM, we have used 3-dimensional type I collagen (3DCI) gels to model early events resulting from intra-peritoneal anchoring. In this study we demonstrate a novel pathway of CXCR4 upregulation through β1-integrin- and NFκB- dependent signaling pathways in response to 3DCI. We also demonstrate the involvement of CXCR4-SDF1 axis in collagen invasion and proliferation, relevant to the metastatic EOC. Our data show that CXCR4 expression in human EOCs, as well as SDF1 presence in the ascites, is correlated with disease progression and metastasis. These data emphasize the importance of CXCR4 – SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis. PMID:20460402

  13. Intravital fiber-optic fluorescence imaging for monitoring ovarian carcinoma progression and treatment response

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Celli, Jonathan P.; Evans, Conor L.; Zhong, Wei; Rizvi, Imran; Mai, Zhiming; Mertz, Jerome; Yun, Seok H.; Hasan, Tayyaba

    2009-06-01

    Our laboratory has constructed a custom fluorescence microendoscope for detecting and monitoring tumor nodules in a mouse model of metastatic ovarian carcinoma (OVCA). The microendoscope is being applied for tumor recognition and for quantifying tumor burden reduction following photodynamic therapy (PDT). Benzoporphyrin derivative monoacid ring A (BPD-MA), a photosensitizing agent for PDT, is administered to the mice and imaged with the microendoscope prior to PDT. BPD-MA fluorescence is a convenient means for locating tumor sites and quantifying tumor burden (despite the fact that BPD-MA is a non-targeted contrast agent). The miniature, flexible microendoscope probe is delivered via a 14-gauge catheter for imaging metastases along the outer surfaces of the internal organs and the inner walls of the peritoneal cavity. The minimal invasiveness of this approach facilitates frequent imaging of the mice in order to monitor cancer progression and treatment response. We present promising data for intravital imaging of treatment response following PDT and new developments in the microendoscope instrumentation for improved image quality.

  14. Analysis of second-harmonic-generation microscopy in a mouse model of ovarian carcinoma

    PubMed Central

    Watson, Jennifer M.; Rice, Photini F.; Marion, Samuel L.; Brewer, Molly A.; Davis, John R.; Rodriguez, Jeffrey J.; Utzinger, Urs; Hoyer, Patricia B.

    2012-01-01

    Abstract. Second-harmonic-generation (SHG) imaging of mouse ovaries ex vivo was used to detect collagen structure changes accompanying ovarian cancer development. Dosing with 4-vinylcyclohexene diepoxide and 7,12-dimethylbenz[a]anthracene resulted in histologically confirmed cases of normal, benign abnormality, dysplasia, and carcinoma. Parameters for each SHG image were calculated using the Fourier transform matrix and gray-level co-occurrence matrix (GLCM). Cancer versus normal and cancer versus all other diagnoses showed the greatest separation using the parameters derived from power in the highest-frequency region and GLCM energy. Mixed effects models showed that these parameters were significantly different between cancer and normal (P<0.008). Images were classified with a support vector machine, using 25% of the data for training and 75% for testing. Utilizing all images with signal greater than the noise level, cancer versus not-cancer specimens were classified with 81.2% sensitivity and 80.0% specificity, and cancer versus normal specimens were classified with 77.8% sensitivity and 79.3% specificity. Utilizing only images with greater than of 75% of the field of view containing signal improved sensitivity and specificity for cancer versus normal to 81.5% and 81.1%. These results suggest that using SHG to visualize collagen structure in ovaries could help with early cancer detection. PMID:22894485

  15. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma

    PubMed Central

    Andersen, Rikke; Donia, Marco; Westergaard, Marie Christine Wulff; Pedersen, Magnus; Hansen, Morten; Svane, Inge Marie

    2015-01-01

    Personalized cancer immunotherapy based on infusion of T cells holds the promise to specifically target a patient’s individual tumor. Accumulating evidence indicates that the T cells mediating these tumor regressions after cancer immunotherapies may primarily target patient-specific mutations expressed by the patients’ tumors and that the presence of these “neo-antigen” specific T-cells may be related to a high number of mutations in the tumor. In melanoma, treatment with autologous tumor-infiltrating lymphocytes (TILs) can mediate durable complete responses. Previous trials investigating TIL therapy in solid tumors other than melanoma have shown limited success, however none of these early trials used current preparative chemotherapy regimens, and the methods for in vitro lymphocyte expansion have changed considerably. New advances and understandings in T cell based immunotherapies have stimulated the interest in developing this approach for other indications. Here, we summarize the early clinical data in the field of adoptive cell transfer therapy (ACT) using tumor-infiltrating lymphocytes for patients with renal cell carcinoma (RCC) and ovarian cancer (OC). In addition we describe the major advances in the characterization and application of TIL therapy for patients with RCC and OC. PMID:26308285

  16. Analysis of second-harmonic-generation microscopy in a mouse model of ovarian carcinoma.

    PubMed

    Watson, Jennifer M; Rice, Photini F; Marion, Samuel L; Brewer, Molly A; Davis, John R; Rodriguez, Jeffrey J; Utzinger, Urs; Hoyer, Patricia B; Barton, Jennifer K

    2012-07-01

    Second-harmonic-generation (SHG) imaging of mouse ovaries ex vivo was used to detect collagen structure changes accompanying ovarian cancer development. Dosing with 4-vinylcyclohexene diepoxide and 7,12-dimethylbenz[a]anthracene resulted in histologically confirmed cases of normal, benign abnormality, dysplasia, and carcinoma. Parameters for each SHG image were calculated using the Fourier transform matrix and gray-level co-occurrence matrix (GLCM). Cancer versus normal and cancer versus all other diagnoses showed the greatest separation using the parameters derived from power in the highest-frequency region and GLCM energy. Mixed effects models showed that these parameters were significantly different between cancer and normal (P<0.008). Images were classified with a support vector machine, using 25% of the data for training and 75% for testing. Utilizing all images with signal greater than the noise level, cancer versus not-cancer specimens were classified with 81.2% sensitivity and 80.0% specificity, and cancer versus normal specimens were classified with 77.8% sensitivity and 79.3% specificity. Utilizing only images with greater than of 75% of the field of view containing signal improved sensitivity and specificity for cancer versus normal to 81.5% and 81.1%. These results suggest that using SHG to visualize collagen structure in ovaries could help with early cancer detection.

  17. Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma

    PubMed Central

    Hsu, I-Ling; Chou, Cheng-Yang; Wu, Yi-Ying; Wu, Jia-En; Liang, Chen-Hsien; Tsai, Yao-Tsung; Ke, Jhen-Yu; Chen, Yuh-Ling; Hsu, Keng-Fu; Hong, Tse-Ming

    2016-01-01

    Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na+/K+-ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression levels of FXYD2 were significantly higher in advanced-stage of OCCC and positively correlated with patients' prognoses. Silencing of FXYD2 expression in OCCC cells inhibited Na+/K+-ATPase enzyme activity and suppressed tumor growth via induction of autophagy-mediated cell death. We found that high FXYD2 expression in OCCC was transcriptionally regulated by the transcriptional factor HNF1B. Furthermore, up-regulation of FXYD2 expression significantly increased the sensitivity of OCCC cells to cardiac glycosides, the Na+/K+-ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo. Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC. PMID:26910837

  18. Clonal evolution of high-grade serous ovarian carcinoma from primary to recurrent disease.

    PubMed

    Castellarin, Mauro; Milne, Katy; Zeng, Thomas; Tse, Kane; Mayo, Michael; Zhao, Yongjun; Webb, John R; Watson, Peter H; Nelson, Brad H; Holt, Robert A

    2013-03-01

    High-grade serous carcinoma (HGSC) is the most common and fatal form of ovarian cancer. While most tumours are highly sensitive to cytoreductive surgery and platinum- and taxane-based chemotherapy, the majority of patients experience recurrence of treatment-resistant tumours. The clonal origin and mutational adaptations associated with recurrent disease are poorly understood. We performed whole exome sequencing on tumour cells harvested from ascites at three time points (primary, first recurrence, and second recurrence) for three HGSC patients receiving standard treatment. Somatic point mutations and small insertions and deletions were identified by comparison to constitutional DNA. The clonal structure and evolution of tumours were inferred from patterns of mutant allele frequencies. TP53 mutations were predominant in all patients at all time points, consistent with the known founder role of this gene. Tumours from all three patients also harboured mutations associated with cell cycle checkpoint function and Golgi vesicle trafficking. There was convergence of germline and somatic variants within the DNA repair, ECM, cell cycle control, and Golgi vesicle pathways. The vast majority of somatic variants found in recurrent tumours were present in primary tumours. Our findings highlight both known and novel pathways that are commonly mutated in HGSC. Moreover, they provide the first evidence at single nucleotide resolution that recurrent HGSC arises from multiple clones present in the primary tumour with negligible accumulation of new mutations during standard treatment.

  19. Downregulation of vimentin expression increased drug resistance in ovarian cancer cells.

    PubMed

    Huo, Yi; Zheng, Zhiguo; Chen, Yuling; Wang, Qingtao; Zhang, Zhenyu; Deng, Haiteng

    2016-07-19

    Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the present study, we found that the expression of vimentin was downregulated in drug-resistant ovarian cancer cell lines A2780-DR and HO-8910 as compared to their respective control cells. Overexpression of vimentin in A2780-DR cells markedly increased their sensitivity to cisplatin, whereas knockdown of vimentin in A2780, HO-8910-PM and HO-8910 cells increased the resistance to cisplatin, demonstrating that vimentin silencing enhanced cisplatin resistance in ovarian cancer cells. Quantitative proteomic analysis identified 95 differentially expressed proteins between the vimentin silenced A2780 cells (A2780-VIM-KN) and the control cells, in which downregulation of endocytic proteins and the upregulation of exocytotic proteins CHMP2B and PDZK1 were proposed to contribute the decreased cisplatin accumulation in vimentin knockdown cells. Silencing of vimentin induced upregulation of cancer stem cell markers and both A2780-DR and A2780-VIM-KN cells were more facile to form spheroids than control cells under serum-free culture condition. Our results also revealed that vimentin knockdown increased the 14-3-3 mediated retention of Cdc25C in the cytoplasm, leading to inactivation of Cdk1 and the prolonged G2 phase arrest that allowed the longer period of time for cells to repair cisplatin-damaged DNA. Taken together, we demonstrated that vimentin silencing enhanced cells' resistance to cisplatin via prolonged G2 arrest and increased exocytosis, suggesting that vimentin is a potential target for treatment of drug resistant ovarian cancer.

  20. Downregulation of vimentin expression increased drug resistance in ovarian cancer cells

    PubMed Central

    Huo, Yi; Zheng, Zhiguo; Chen, Yuling; Wang, Qingtao; Zhang, Zhenyu; Deng, Haiteng

    2016-01-01

    Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the present study, we found that the expression of vimentin was downregulated in drug-resistant ovarian cancer cell lines A2780-DR and HO-8910 as compared to their respective control cells. Overexpression of vimentin in A2780-DR cells markedly increased their sensitivity to cisplatin, whereas knockdown of vimentin in A2780, HO-8910-PM and HO-8910 cells increased the resistance to cisplatin, demonstrating that vimentin silencing enhanced cisplatin resistance in ovarian cancer cells. Quantitative proteomic analysis identified 95 differentially expressed proteins between the vimentin silenced A2780 cells (A2780-VIM-KN) and the control cells, in which downregulation of endocytic proteins and the upregulation of exocytotic proteins CHMP2B and PDZK1 were proposed to contribute the decreased cisplatin accumulation in vimentin knockdown cells. Silencing of vimentin induced upregulation of cancer stem cell markers and both A2780-DR and A2780-VIM-KN cells were more facile to form spheroids than control cells under serum-free culture condition. Our results also revealed that vimentin knockdown increased the 14-3-3 mediated retention of Cdc25C in the cytoplasm, leading to inactivation of Cdk1 and the prolonged G2 phase arrest that allowed the longer period of time for cells to repair cisplatin-damaged DNA. Taken together, we demonstrated that vimentin silencing enhanced cells' resistance to cisplatin via prolonged G2 arrest and increased exocytosis, suggesting that vimentin is a potential target for treatment of drug resistant ovarian cancer. PMID:27322682

  1. Characterization of ovarian clear cell carcinoma using target drug-based molecular biomarkers: implications for personalized cancer therapy.

    PubMed

    Li, Mengjiao; Li, Haoran; Liu, Fei; Bi, Rui; Tu, Xiaoyu; Chen, Lihua; Ye, Shuang; Cheng, Xi

    2017-02-10

    It has long been appreciated that different subtypes (serous, clear cell, endometrioid and mucinous) of epithelial ovarian carcinoma (EOC) have distinct pathogenetic pathways. However, clinical management, especially chemotherapeutic regimens, for EOC patients is not subtype specific. Ovarian clear cell carcinoma (CCC) is a rare histological subtype of EOC, which exhibits high rates of recurrence and low chemosensitivity. We assessed potential therapeutic targets for ovarian CCC patients through analyzing the variation of drug-based molecular biomarkers expression between ovarian CCC and high-grade serous carcinoma (HGSC). Seven candidate drug-based molecular biomarkers, human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), phosphatase and tensin homolog deleted on chromosome ten (PTEN), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2) and programmed death-ligand 1 (PD-L1) were measured in 96 ovarian CCC and 113 HGSC by immunohistochemistry in paraffin embedded tissues. The relationship between these biomarkers and clinicopathological factors were explored. The expression level of four of the seven drug-based molecular biomarkers was markedly different between HGSC and CCC. High expression levels of HER2 and PD-L1 were more commonly observed in CCC patients (12.6% vs 2.7%, 21.1% vs 11.6%, P = 0.006, 0.064, respectively), while loss of BRCA1 and BRCA2 expression were more frequently occurred in HGSC patients (72.6% vs 54.3%, 89.4% vs 79.8%, P = 0.007, 0.054, respectively). Survival analysis showed that five of seven biomarkers had prognostic values but varied between subtypes. Furthermore, EGFR expressed frequently in CCC patients with endometriosis than in HGSC patients (44.4% vs 8.3%, P = 0.049). AURKA and PD-L1 correlated with the resistance to platinum-based chemotherapy in CCC patients (P = 0.043, 0.028, respectively) while no similar

  2. Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma.

    PubMed

    Milea, Anca; George, Sophia H L; Matevski, Donco; Jiang, Haiyan; Madunic, Mary; Berman, Hal K; Gauthier, Mona L; Gallie, Brenda; Shaw, Patricia A

    2014-07-01

    Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical

  3. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.

    PubMed

    Köbel, Martin; Piskorz, Anna M; Lee, Sandra; Lui, Shuhong; LePage, Cecile; Marass, Francesco; Rosenfeld, Nitzan; Mes Masson, Anne-Marie; Brenton, James D

    2016-10-01

    TP53 mutations are ubiquitous in high-grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low-grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged-amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain-of-function (GOF or nonsynonymous), loss-of-function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low-grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.

  4. Silencing dishevelled-1 sensitizes paclitaxel-resistant human ovarian cancer cells via AKT/GSK-3β/β-catenin signalling.

    PubMed

    Zhang, Kun; Song, Haixing; Yang, Ping; Dai, Xiaozhen; Li, Ya; Wang, Lan; Du, Jun; Pan, Kejian; Zhang, Tao

    2015-04-01

    Expression of dishevelled-1 (DVL1) has recently been linked to cancer progression, however, its role in resistance to cancer therapy is unclear. In this study, we aimed to explore the function of DVL1 in paclitaxel-resistant human ovarian cancer cells. The MTT assay was used to assess effects of DVL1 silencing on sensitivity of cells that were otherwise resistant to paclitaxel (Taxol). Western blotting and immunofluorescence staining were used to examine effects of DVL1 on AKT/GSK-3β/β-catenin signalling. Dishevelled-1 was found to be over-expressed in a paclitaxel-resistant cell line derived from human ovarian cancer cell line A2780 (A2780/Taxol line) as well as parental A2780 cells. Down-regulation of DVL1 (using the inhibitor 3289-8625 or siRNA (siDVL1) against DVL1) sensitized A2780/Taxol cells to paclitaxel. Over-expression of DVL1 in A2780 cells increased protein levels of P-gp, BCRP and Bcl-2, which are known targets of β-catenin. Silencing DVL1 in A2780/Taxol cells also reduced levels of these proteins, and led to accumulation of β-catenin. In addition, DVL1 aberrantly activated AKT/GSK-3β/β-catenin signalling. Inactivation of AKT signalling attenuated DVL1-mediated inhibition of GSK-3β and accumulation of β-catenin, in both A2780 and A2780/Taxol cells. Taken together, these results suggest that silencing DVL1 sensitized A2780/Taxol cells to paclitaxel, by down-regulating AKT/GSK-3β/β-catenin signalling, providing a novel strategy for chemosensitization of ovarian cancer to paclitaxel-induced cytotoxicity. © 2015 John Wiley & Sons Ltd.

  5. Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

    DTIC Science & Technology

    2016-12-01

    to identify PARPi sensitivity. Large-scale disarray in chromosome structure is common in HRR-deficient cancers and may be quantitated by several...duplication of chromosomal regions, also known as genomic loss of heterozygosity (LOH).4−6 Half of all high-grade serous ovarian carcinomas are estimated...frequent in older ovarian cancer patients. Genes Chromosomes Cancer 2013; 52: 794−801. 6 Marquard AM, Eklund AC, Joshi T, et al. Pan-cancer analysis of

  6. EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas.

    PubMed

    Etemadmoghadam, Dariush; Azar, Walid J; Lei, Ying; Moujaber, Tania; Garsed, Dale W; Kennedy, Catherine J; Fereday, Sian; Mitchell, Chris; Chiew, Yoke-Eng; Hendley, Joy; Sharma, Raghwa; Harnett, Paul R; Li, Jason; Christie, Elizabeth L; Patch, Ann-Marie; George, Joshy; Au-Yeung, George; Mir Arnau, Gisela; Holloway, Timothy P; Semple, Timothy; Pearson, John V; Waddell, Nicola; Grimmond, Sean M; Köbel, Martin; Rizos, Helen; Lomakin, Ivan B; Bowtell, David D L; deFazio, Anna

    2017-08-15

    Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res; 77(16); 4268-78. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma.

    PubMed

    Diamandis, Eleftherios P; Okui, Akira; Mitsui, Shinichii; Luo, Liu-Ying; Soosaipillai, Antoninus; Grass, Linda; Nakamura, Terukazu; Howarth, David J C; Yamaguchi, Nozomi

    2002-01-01

    Human kallikrein 11 (hK11) is a putative serine protease of the human kallikrein gene family. Currently, no methods are available for measuring hK11 in biological fluids and tissues. Our aim was to develop immunological reagents and assays for measuring hK11 and examine if the concentration of this kallikrein is altered in disease states. We produced recombinant hK11 protein in a baculovirus system and used it to develop monoclonal and polyclonal antibodies against hK11. We then developed an immunofluorometric procedure for measuring hK11 in biological fluids and tissue extracts with high sensitivity and specificity. We further quantified hK11 in various biological fluids and in serum of patients with various cancers. The hK11 immunofluorometric assay is highly sensitive (detection limit, 0.1 microg/l) and specific (no detectable cross-reactivity for other homologous kallikreins). We established the tissue expression pattern of hK11 at the protein level and found the highest levels in the prostate, followed by stomach, trachea, skin, and colon. We have immunohistochemically localized hK11 in epithelial cells of various organs. We further detected hK11 in amniotic fluid, milk of lactating women, cerebrospinal fluid, follicular fluid, and breast cancer cytosols. However, highest levels were seen in prostatic tissue extracts and seminal plasma. hK11 in seminal plasma and prostatic extracts is present at approximately 300-fold lower levels than prostate-specific antigen and at approximately the same levels as hK2. hK11 expression in breast cancer cell lines is up-regulated by estradiol. Elevated serum levels of hK11 were found in 70% of women with ovarian cancer and in 60% of men with prostate cancer. This is the first reported immunological assay for hK11. Analysis of this biomarker in serum may aid in the diagnosis and monitoring of ovarian and prostatic carcinoma.

  8. Radiosensitivity of human ovarian carcinoma and melanoma cells to γ-rays and protons

    PubMed Central

    Keta, Otilija; Todorović, Danijela; Popović, Nataša; Korićanac, Lela; Cuttone, Giacomo; Petrović, Ivan

    2014-01-01

    Introduction Proton radiation offers physical advantages over conventional radiation. Radiosensitivity of human 59M ovarian cancer and HTB140 melanoma cells was investigated after exposure to γ-rays and protons. Material and methods Irradiations were performed in the middle of a 62 MeV therapeutic proton spread out Bragg peak with doses ranging from 2 to 16 Gy. The mean energy of protons was 34.88 ±2.15 MeV, corresponding to the linear energy transfer of 4.7 ±0.2 keV/µm. Irradiations with γ-rays were performed using the same doses. Viability, proliferation and survival were assessed 7 days after both types of irradiation while analyses of cell cycle and apoptosis were performed 48 h after irradiation. Results Results showed that γ-rays and protons reduced the number of viable cells for both cell lines, with stronger inactivation achieved after irradiation with protons. Surviving fractions for 59M were 0.91 ±0.01 for γ-rays and 0.81 ±0.01 for protons, while those for HTB140 cells were 0.93 ±0.01 for γ-rays and 0.86 ±0.01 for protons. Relative biological effectiveness of protons, being 2.47 ±0.22 for 59M and 2.08 ±0.36 for HTB140, indicated that protons provoked better cell elimination than γ-rays. After proton irradiation proliferation capacity of the two cell lines was slightly higher as compared to γ-rays. Proliferation was higher for 59M than for HTB140 cells after both types of irradiation. Induction of apoptosis and G2 arrest detected after proton irradiation were more prominent in 59M cells. Conclusions The obtained results suggest that protons exert better antitumour effects on ovarian carcinoma and melanoma cells than γ-rays. The dissimilar response of these cells to radiation is related to their different features. PMID:25097591

  9. Profile of differentially expressed miRNAs in high-grade serous carcinoma and clear cell ovarian carcinoma, and the expression of miR-510 in ovarian carcinoma.

    PubMed

    Zhang, Xinchen; Guo, Gordon; Wang, Guang; Zhao, Jinyao; Wang, Bo; Yu, Xiaotang; Ding, Yanfang

    2015-12-01

    Improved insight into the molecular and genetic profile of different types of epithelial ovarian cancer (EOC) is required for understanding the carcinogenesis of EOC and may potentially be exploited by future targeted therapies. The aim of the present study was to identify a unique microRNA (miRNA) patterns and key miRNAs, which may assist in predicting progression and prognosis in high‑grade serous carcinoma (HGSC) and clear cell carcinoma (CCC). To identify unique miRNA patterns associated with HGSC and CCC, a miRNA microarray was performed using Chinese tumor bank specimens of patients with HGSC or CCC in a retrospective analysis. The expression levels of four deregulated miRNAs were further validated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) in an external cohort of 42 cases of HGSC and 36 cases of CCC. Kaplan‑Meier analysis was performed to analyze the correlation between the expression levels of the four miRNAs and patient prognosis. Among these validated miRNAs, miR‑510 was further examined in another cohort of normal ovarian tissues, as well as the HGSC, low‑grade serous carcinoma (LGSC) and CCC specimens using RT‑qPCR and in situ hybridization. The results revealed that, of the 768 miRNAs analyzed in the microarray, 33 and 50 miRNAs were significantly upregulated and downregulated, respectively, with at least a 2‑fold difference in HGSC, compared with CCC. The quantitative analysis demonstrated that miR‑510 and miR‑129‑3p were significantly downregulated, and that miR‑483‑5p and miR‑miR‑449a were significantly upregulated in CCC, compared with HGSC (P<0.05), which was consistent with the microarray results. Kaplan‑Meier analysis revealed low expression levels of miR‑510 and low expression levels of miR‑129‑3p, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymphatic metastasis and that HGSC was significantly associated with the poorer overall

  10. PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells.

    PubMed

    Arrighetti, Noemi; Cossa, Giacomo; De Cecco, Loris; Stucchi, Simone; Carenini, Nives; Corna, Elisabetta; Gandellini, Paolo; Zaffaroni, Nadia; Perego, Paola; Gatti, Laura

    2016-11-01

    The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of this study was to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response. MiR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential. Predicted targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. We found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha. Overall, our results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Grape seed procyanidin reversal of p-glycoprotein associated multi-drug resistance via down-regulation of NF-κB and MAPK/ERK mediated YB-1 activity in A2780/T cells.

    PubMed

    Zhao, Bo-xin; Sun, Ya-bin; Wang, Sheng-qi; Duan, Lian; Huo, Qi-lu; Ren, Fei; Li, Guo-feng

    2013-01-01

    The expression and function of P-glycoprotein (P-gp) is associated with the phenotype of multi-drug resistance (MDR), leading chemotherapy failure of patients suffered with cancer. Grape seed procyanidin(GSP) is a natural polyphenol supplement with anti-inflammatory effect. Present study assessed a new use of GSP on the MDR reversal activity and its possible molecular mechanisms in MDR1-overpressing paclitaxel resistant ovarian cancer cells. Our results showed GSP significantly enhanced the cytotoxicity of paclitaxel and adriamycin in paclitaxel resistant A2780/T cells but its parental A2780 cells. Furthermore, GSP strongly inhibited P-gp expression by blocking MDR1 gene transcription, as well as, increased the intracellular accumulation of the P-gp substrate rhodamine-123 in A2780/T cells. Nuclear factor-κB(NF-κB) activity, IκB degradation level and NF-κB/p65 nuclear translocation induced by lipopolysaccharide (LPS) and receptor activator for nuclear factor-κB ligand (RANKL) were markedly inhibited by pre-treatment with GSP. Meanwhile, GSP inhibited MAPK/ERK pathway by decreasing the phosphorylation of ERK1/2, resulting in reduced the Y-box binding protein 1 (YB-1) activation with blocking its nuclear translocation. Moreover, the up-regulation of P-gp expression, the activation of AKT/NF-κB and MAPK/ERK pathway induced by LPS was attenuated by GSP administration. Compared with PDTC and U1026, inhibitor of NF-κB and MAPK/ERK respectively, GSP showed the same tendency of down-regulating NF-κB and MAPK/ERK mediated YB-1 activities. Thus, GSP reverses P-gp associated MDR by inhibiting the function and expression of P-gp through down-regulation of NF-κB activity and MAPK/ERK pathway mediated YB-1 nuclear translocation, offering insight into the mechanism of reversing MDR by natural polyphenol supplement compounds. GSP could be a new potential MDR reversal agent used for combination therapy with chemotherapeutics in clinic.

  12. Problems arising in the diagnosis of primary ovarian transitional cell carcinoma after the occurrence of a transitional cell carcinoma of the bladder: a report of a difficult case and a critical review of literature.

    PubMed

    Raspollini, Maria Rosaria; Paglierani, Milena; Taddei, Gian Luigi

    2009-03-01

    Transitional cell carcinoma (TCC) of the ovary is a recently recognized subtype of ovarian surface epithelial-stromal cancer that morphologically resembles a TCC of the bladder. The most frequent metastases to ovaries come from the gastrointestinal tract and from breast carcinoma, but metastatic TCCs from the urinary tract to the ovary have been reported. TCC of the bladder is the sixth most common cancer in European and North American countries and its incidence has been increasing. We recently observed a woman, who previously had undergone endoscopic resection of a TCC of the bladder. She was affected by an ovarian bilateral tumor with features of malignant transitional cell tumor, characterized by papillae with multilayered transitional epithelium infiltrating the ovarian stroma. In this study, we showed the utility of WT1 and a panel of immunohistochemical markers in the difficult differential diagnosis between bladder and ovarian TCC.

  13. Proteomic identification of fucosylated haptoglobin alpha isoforms in ascitic fluids and its localization in ovarian carcinoma tissues from Mexican patients

    PubMed Central

    2014-01-01

    Background Ovarian cancer is the most lethal gynecologic disease due to delayed diagnosis, and ascites production is a characteristic of patients in advanced stages. The aim of this study was to perform the proteomic analysis of ascitic fluids of Mexican patients with ovarian carcinoma, in order to detect proteins with a differential expression pattern in the continuing search to identify biomarkers for this disease. Methods Samples were collected from 50 patients from the Instituto Nacional de Cancerología of México under informed consent and with approval of the bioethics and scientific committees. After elimination of abundant proteins (Albumin/IgGs) samples were processed for 2D electrophoresis and further protein identification by Mass Spectrometry (MALDI-TOF). Molecules of interest were followed by western blot and lectin binding assays, and their tissue location by histo-immunofluorescence and confocal analysis. Results and discussion An area with a differential expression pattern among samples was located in the 2D gels. Identified proteins were 6 alpha 1 isoforms and 1 alpha 2 isoform of Haptoglobin, and 2 isoforms of Transthyretin. While Transthyretin isoforms were constitutively expressed in all samples, clear differences in the expression pattern of Haptoglobin alpha isoforms were found. Moreover, increased levels of fucosylation of Haptoglobin alpha isoforms analyzed in 40 samples by Aleuria aurantia lectin binding by 1D overlay assay showed a positive correlation with advanced stages of the disease. Tissue detection of Haptoglobin and its fucosylated form, by histo-immunofluorescence in biopsies of ovarian cancer, also showed a correlation with ovarian cancer progression. Moreover, results show that fucosylated Haptoglobin is produced by tumor cells. Conclusions Increased numbers of highly fucosylated Haptoglobin alpha isoforms in ascitic fluids and the presence of fucosylated Haptoglobin in tumor tissues of ovarian cancer Mexican patients

  14. Cediranib Maleate and Olaparib or Standard Chemotherapy in Treating Patients With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-04-13

    Deleterious BRCA1 Gene Mutation; Deleterious BRCA2 Gene Mutation; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  15. Calcified metastases from ovarian carcinoma highlighted by F-18 FDG PET/CT: report of two cases.

    PubMed

    Hu, Si-Long; Zhou, Zheng-Rong; Zhang, Ying-Jian

    2012-08-01

    Two cases of postoperative female patients with ovarian serous papillary carcinoma were referred for F-18 Fluorodeoxyglucose (F-18 FDG) PET/CT to evaluate suspicious recurrence and/or metastasis. One patient presented with multiple extensive calcified lesions with increased FDG uptake in the abdominopelvic cavity and the series of PET/CT scans showed progression of disease after chemotherapy. The other patient presented with three calcified masses with intensive uptake of FDG located in the left pelvis, the right subphrenic region, and the right supradiaphragmatic area, respectively. These suggest that F-18 FDG PET/CT can be useful in identifying malignant calcification and assessing therapeutic response of calcified malignancy.

  16. ARID1A gene silencing reduces the sensitivity of ovarian clear cell carcinoma to cisplatin

    PubMed Central

    Lyu, Changshuai; Zhang, Yinglan; Zhou, Xingnan; Lang, Jinghe

    2016-01-01

    In ovarian clear cell carcinoma (OCCC), the mutation rate of the AT-rich interaction domain 1A (ARID1A) gene is 46–57%. However, the effects of ARID1A gene silencing by small interfering RNA (siRNA) on the sensitivity of OCCC to cisplatin have not been investigated. Thus, this study aimed to elucidate the association between ARID1A gene silencing and drug resistance in OCCC. Three pairs of ARID1A gene siRNA fragments (siRNA-1, siRNA-2 and siRNA-3) were designed and transiently transfected into ES2 OCCC cells using RNAi Max reagent. Western blotting results demonstrated that the transfection reduced ARID1A protein expression levels, with the siRNA-3 group having the lowest levels. The IC50 value, determined using a Cell Counting kit-8 assay, was significantly increased by siRNA-3 transfection compared with that in blank control and negative control groups. The cell survival rate following treatment with 50 µM cisplatin for 48 h was significantly increased in the siRNA-3 group compared with the blank control and negative control groups. Flow cytometric analysis revealed that the apoptosis rate for cisplatin-treated cells was significantly lower in cells with siRNA-3 transfection than in those without, and the apoptosis rate in siRNA-3-transfected cells was lower than that in the negative control group. Western blot analysis showed that the expression level of AKT in cisplatin-treated cells was significantly decreased compared with that in the negative control group, and the AKT expression level in cisplatin-treated cells was significantly higher with siRNA-3 transfection than without. Therefore, the results demonstrated that ARID1A siRNA efficiently decreased ARID1A expression, which reduced cisplatin chemosensitivity and cell apoptosis in ES2 OCCC cells via the regulation of AKT expression. PMID:28105136

  17. Salvage Chemotherapy for Patients With Recurrent or Persistent Ovarian Clear Cell Carcinoma

    PubMed Central

    Bai, Huimin; Sha, Guihua; Cao, Dongyan; Yang, Jiaxin; Chen, Jie; Wang, Yue; Lang, Jinghe; Shen, Keng; Zhang, Zhenyu

    2015-01-01

    Abstract The purpose of this study was to evaluate the effects of salvage chemotherapy on recurrent or persistent ovarian clear cell carcinoma (CCC) with the goal of identifying a more rational treatment regimen for this lethal disease. The medical records of patients with CCC were retrospectively reviewed to select patients that were subsequently treated for recurrent or persistent disease. Of the 164 women with recurrent or persistent CCC, 485 chemotherapy courses with 1766 cycles were administered. Overall, the clinical benefit rate (CBR) was 39.4%, and the mean progression-free survival (PFS) was 4.5 months. Grade 3/4 toxicities occurred in 94 courses (19.4%). The CBR for TC was 45.1%, with a PFS of 3.7 months. Compared to that of TC, the CBRs for PC and CC were significantly lower (P = 0.020 and 0.021, respectively). The CBRs and PFS for PAF-C were slightly higher (P = 0.518 and 0.077, respectively), but showed a significantly higher adverse event rate (AER, P = 0.039). The CBR for bevacizumab was 50% with an extraordinarily long PFS (49.8 months). Gemcitabine and oxaliplatin had similar values for CBRs (44.4% and 44.1%) and PFS (2.5 and 3.4 months), respectively. Docetaxel (weekly) exhibited a notably low AER of 2.7%, and topotecan was associated with a relatively long PFS (7.7 months). For cis/carboplatin-pretreated patients, the existing active agents, such as oxaliplatin, gemcitabine, topotecan, and especially bevacizumab, are promising. Docetaxel (weekly) is well tolerated and might offer a particularly viable option for heavily pretreated patients. However, additional research to identify for a continued search for the optimal combination of chemotherapeutics or novel agents is still warranted. PMID:26166110

  18. Uterine metastases in ovarian carcinoma: frequency and survival in women who underwent hysterectomy

    PubMed Central

    Chetrit, Angela; Sadetzki, Siegal

    2010-01-01

    Objective Possible reasons for hysterectomy in the initial surgical management of advanced invasive epithelial ovarian carcinoma (EOC) might be a high frequency of uterine involvement and its impact on survival. The aim of the present study was to describe the frequency of uterine involvement and its association with survival in an unselected population of EOC patients who underwent hysterectomy. Methods All incident cases of EOC diagnosed in Israeli Jewish women between March 1994 to June 1999, were identified within the framework of a nationwide case-control epidemiological study. The target population of the present report includes all stage II-IV EOC patients who had a uterus at the time of diagnosis. Of the 822 such patients, 695 fulfilled the inclusion criterion. Excluded were 141 patients for various reasons. The present analysis is based on the remaining 554 patients. Results Uterine involvement was present in 291 (52.5%) of the patients and it was macroscopic in only 78 (14.1%). The serosa was the most common site of isolated metastases. Multivariate analysis showed that advanced stage significantly increased the risk for uterine involvement. The overall median survival with any uterine involvement was significantly lower compared to those with no involvement (38.9 months vs. 58.0 months; p<0.001). Conclusion There is an association between uterine involvement, whether macro- or microscopic, and lower survival even after hysterectomy although residual tumor could not be included in the analysis. Further studies are required to establish whether uterine involvement itself is an unfavorable risk factor or merely a marker of other unfavorable prognostic factors. PMID:20922143

  19. miR-30a inhibits endothelin A receptor and chemoresistance in ovarian carcinoma

    PubMed Central

    Rosanò, Laura; Tocci, Piera; Semprucci, Elisa; Di Castro, Valeriana; Caprara, Valentina; Ferrandina, Gabriella; Sacconi, Andrea; Blandino, Giovanni; Bagnato, Anna

    2016-01-01

    Drug resistance remains the major clinical barrier to successful treatment in epithelial ovarian carcinoma (EOC) patients, and the evidence of microRNA involvement in drug resistance has been recently emerging. Endothelin-1 (ET-1)/ETA receptor (ETAR) axis is aberrantly activated in chemoresistant EOC cells and elicits pleiotropic effects promoting epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance. However, the relationship between ETAR and miRNA is still unknown. Hence, in this study we evaluated whether dysregulation of miRNA might enhance ETAR expression in sensitive and resistant EOC cells. Based on bioinformatic tools, we selected putative miRNA able to recognize the 3′UTR of ETAR. An inverse correlation was observed between the expression levels of miR-30a and ETAR in both EOC cell lines and tumor samples. miR-30a was found to specifically bind to the 3′UTR of ETAR mRNA, indicating that ETAR is a direct target of miR-30a. Overexpression of miR-30a decreased Akt and mitogen activated protein kinase signaling pathway activation, cell proliferation, invasion, plasticity, EMT marker levels, and vascular endothelial growth factor release. Interestingly, ectopic expression of miR-30a re-sensitized platinum-resistant EOC cells to cisplatinum-induced apoptosis. Consistently, resistant EOC xenografts overexpressing miR-30a resulted in significantly less tumor growth than controls. Together our study provides a new perspective on the regulatory mechanism of ETAR gene. Interestingly, our findings highlight that blockade of ETAR regulatory axis is the mechanism underlying the tumor suppressor function of miR-30a in chemoresistant EOC cells. PMID:26675258

  20. p16/MTS1 inactivation in ovarian carcinomas: high frequency of reduced protein expression associated with hyper-methylation or mutation in endometrioid and mucinous tumors.

    PubMed

    Milde-Langosch, K; Ocon, E; Becker, G; Löning, T

    1998-02-20

    Inactivation of the tumor-suppressor gene p16 (MTS1/ CDKN2/INK4a) has been described in various human malignancies. Although p16 deletion has been found in various ovarian tumor cell lines, p16 inactivation by homozygous deletion or mutation has been reported only sporadically in primary ovarian carcinomas. In a comprehensive study, we analyzed p16 protein expression by immuno-histochemistry (IHC) on paraffin sections of 94 primary ovarian carcinomas of different histological subtype. Loss of expression was detected in 19 primary tumors (20%), mainly mucinous and endometrioid carcinomas. To reveal the cause of suppressed expression, we performed (i) analysis of homozygous deletions by comparative PCR after micro-dissection, (ii) mutation analysis by single-strand conformation polymorphism analysis and subsequent direct sequencing and (iii) methylation-specific PCR to determine the methylation status of 5'-CpG islands. Loss of or weak p16 expression was caused by hyper-methylation (12/19 IHC-negative cases), somatic mutation (10 tumors) or homozygous deletion (1 case). Aberrant p 16 results by one of these methods were detected in 71-79% of endometrioid and mucinous, but in only 10% of serous-papillary, carcinomas. Our data suggest that p16 inactivation is a typical feature of certain subtypes of ovarian carcinoma.

  1. Deregulation of let-7e in epithelial ovarian cancer promotes the development of resistance to cisplatin

    PubMed Central

    Cai, J; Yang, C; Yang, Q; Ding, H; Jia, J; Guo, J; Wang, J; Wang, Z

    2013-01-01

    Drug resistance remains a major clinical obstacle to successful treatment in ovarian cancer patients, and the evidence of microRNAs involvement in drug resistance has been emerging recently. In this report, we investigated the role of let-7e in the development of cisplatin-resistant ovarian cancer. On the cellular level, let-7e expression was significantly reduced in cisplatin-resistant human epithelial ovarian cancer (EOC) cell line A2780/CP compared with parental A2780 cell and decreased in a concentration-dependent manner in A2780, SKOV3 and ES2 cells treated with cisplatin. Overexpression of let-7e by transfection of agomir could resensitize A2780/CP and reduce the expression of cisplatin-resistant-related proteins enhancer of zeste 2 (EZH2) and cyclin D1 (CCND1), whereas let-7e inhibitors increased resistance to cisplatin in parental A2780 cells. Quantitative methylation-specific PCR analysis showed hypermethylation of the CpG island adjacent to let-7e in A2780/CP cells, and demethylation treatment with 5-aza-CdR or transfection of pYr-let-7e-shRNA plasmid containing unmethylated let-7e DNA sequence could restore let-7e expression and partly reduce the chemoresistance. In addition, cisplatin combined with let-7e agomirs inhibited the growth of A2780/CP xenograft more effectively than cisplatin alone. Diminished expression of EZH2 and CCND1 and higher cisplatin concentrations in tumor tissue of mice subjected to administration of let-7e agomirs in addition to cisplatin were revealed by immunohistochemistry and atomic absorption spectroscopy, respectively. Taken together, our findings suggest that let-7e may act as a promising therapeutic target for improvement of the sensibility to cisplatin in EOC. PMID:24100610

  2. Belinostat in Treating Patients With Advanced Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer or Ovarian Low Malignant Potential Tumors

    ClinicalTrials.gov

    2016-10-20

    Fallopian Tube Carcinoma; Primary Peritoneal Carcinoma; Recurrent Borderline Ovarian Surface Epithelial-Stromal Tumor; Recurrent Ovarian Carcinoma; Stage III Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage III Ovarian Cancer; Stage IV Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage IV Ovarian Cancer

  3. Oral squamous cell carcinoma in a patient treated with long-term pegylated liposomal doxorubicin for recurrent ovarian cancer

    PubMed Central

    Pezzoli, Matteo; Bona Galvagno, Maurizio; Bongioannini, Guido

    2015-01-01

    We present a case of a woman who developed an oral squamous cell carcinoma (SCC) after being treated for a recurrent ovarian carcinoma with subtotal gastric resection and adjuvant pegylated liposomal doxorubicin (PLD). She received six cycles of PLD induction and maintenance therapy, which was continued for 5 years. She was free from disease at the following visits but 3 years later she developed SCC of her left inferior edentulous gums. The patient was negative for human papillomavirus and had never smoked in her life or had a history of alcohol use or any other environmental risk factors. PLD is known to accumulate in eccrine glands of the hands and the feet and in the oral mucosa, therefore causing skin toxicity and mucositis. It is conceivable that this specific biodistribution to the oral mucosa may be responsible for the onset of SCC. PMID:25589526

  4. Expression of MAGE-C1/CT7 and selected cancer/testis antigens in ovarian borderline tumours and primary and recurrent ovarian carcinomas.

    PubMed

    Zimmermann, Anne-Katrin; Imig, Jochen; Klar, Agnes; Renner, Christoph; Korol, Dimitri; Fink, Daniel; Stadlmann, Sylvia; Singer, Gad; Knuth, Alexander; Moch, Holger; Caduff, Rosmarie

    2013-05-01

    MAGE-C1/CT7, NY-ESO-1, GAGE and MAGE-A4 are members of the cancer/testis (CT) antigen family, which have been proposed as potential targets for cancer immunotherapy. To determine the prevalence and biologic relevance of the novel CT antigen MAGE-C1/CT7 and other antigens, 36 ovarian borderline tumours (BTs), 230 primary ovarian carcinomas (OCs) and 80 recurrent OCs were immunohistochemically analysed using the monoclonal antibodies CT7-33 (MAGE-C1/CT7), E978 (NY-ESO-1), clone 26 (GAGE) and 57B (MAGE-A4). Positivity of at least one CT antigen was present in 39.5 % (81/205) of primary OC and in 50 % (26/52) of all recurrences. Expression of the novel CT antigen MAGE-C1/CT7 was most commonly seen with positivity in 24.5 % of primary and 35.1 % of recurrent OC. MAGE-A4, GAGE and NY-ESO-1 expressions were seen in 22.7, 13.9 and 7.1 % of primary and 22.6, 17.5 and 8.9 % of recurrent OC, respectively. Analysis of histological subtypes (serous, endometrioid, clear cell, mucinous and transitional) exhibited variable expression with negativity in all mucinous OC. High-grade serous OC revealed CT antigen expression in 5.6 to 28 % with MAGE-C1/CT7 being the most frequent, but without correlation with stage or overall survival. MAGE-C1/CT7 expression and coexpression of CT antigens were significantly correlated with grade of endometrioid OC. None of the BT showed CT antigen expression. No significant correlation was seen with stage, overall survival or response to chemotherapy. In summary, CT antigens are expressed in a certain subset of OC with no expression in BT or OC of mucinous histology. These findings may have implications for the design of polyvalent vaccination strategies for ovarian carcinomas.

  5. Carboplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-01-31

    High Grade Ovarian Serous Adenocarcinoma; Ovarian Endometrioid Tumor; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  6. Toll-like receptor 8: augmentation of innate immunity in platinum resistant ovarian carcinoma

    PubMed Central

    Brueseke, Taylor J; Tewari, Krishnansu S

    2013-01-01

    Ovarian cancer is the most deadly gynecologic cancer, with 15,000 anticipated deaths within the United States alone in 2012, and new treatment strategies are needed. Ovarian cancer tumors are known to host an immunosuppressive microenvironment. This suppression may be reversible via activation of the innate immune response. Toll-like receptor 8 activates innate immunity while simultaneously inhibiting the effects of regulatory T cells within the ovarian cancer tumors. VTX-2337 is a novel small molecule ligand of Toll-like receptor 8 and is currently the subject of a Phase II randomized, double-blind, placebo-controlled trial Gynecologic Oncology Group (GOG)-3003 for patients with recurrent platinum-resistant ovarian cancer. We look forward to the results of this trial as support for the paradigm of process therapy in the treatment of ovarian cancer. PMID:23723721

  7. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas

    PubMed Central

    Yu, Yinhua; Xu, Fengji; Peng, Hongqi; Fang, Xianjun; Zhao, Shulei; Li, Yang; Cuevas, Bruce; Kuo, Wen-Lin; Gray, Joe W.; Siciliano, Michael; Mills, Gordon B.; Bast, Robert C.

    1999-01-01

    Using differential display PCR, we have identified a gene [NOEY2, ARHI (designation by the Human Gene Nomenclature Committee)] with high homology to ras and rap that is expressed consistently in normal ovarian and breast epithelial cells but not in ovarian and breast cancers. Reexpression of NOEY2 through transfection suppresses clonogenic growth of breast and ovarian cancer cells. Growth suppression was associated with down-regulation of the cyclin D1 promoter activity and induction of p21WAF1/CIP1. In an effort to identify mechanisms leading to NOEY2 silencing in cancer, we found that the gene is expressed monoallelically and is imprinted maternally. Loss of heterozygosity of the gene was detected in 41% of ovarian and breast cancers. In most of cancer samples with loss of heterozygosity, the nonimprinted functional allele was deleted. Thus, NOEY2 appears to be a putative imprinted tumor suppressor gene whose function is abrogated in ovarian and breast cancers. PMID:9874798

  8. Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

    SciTech Connect

    Ferramosca, Alessandra; Conte, Annalea; Guerra, Flora; Felline, Serena; Rimoli, Maria Grazia; Mollo, Ernesto; Zara, Vincenzo; Terlizzi, Antonio

    2016-05-13

    The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

  9. Modulation of c-fms proto-oncogene in an ovarian carcinoma cell line by a hammerhead ribozyme.

    PubMed Central

    Yokoyama, Y.; Morishita, S.; Takahashi, Y.; Hashimoto, M.; Tamaya, T.

    1997-01-01

    Co-expression of macrophage colony-stimulating factor (M-CSF) and its receptor (c-fms) is often found in ovarian epithelial carcinoma, suggesting the existence of autocrine regulation of cell growth by M-CSF. To block this autocrine loop, we have developed hammerhead ribozymes against c-fms mRNA. As target sites of the ribozyme, we chose the GUC sequence in codon 18 and codon 27 of c-fms mRNA. Two kinds of ribozymes were able to cleave an artificial c-fms RNA substrate in a cell-free system, although the ribozyme against codon 18 was much more efficient than that against codon 27. We next constructed an expression vector carrying a ribozyme sequence that targeted the GUC sequence in codon 18 of c-fms mRNA. It was introduced into TYK-nu cells that expressed M-CSF and its receptor. Its transfectant showed a reduced growth potential. The expression levels of c-fms protein and mRNA in the transfectant were clearly decreased with the expression of ribozyme RNA compared with that of an untransfected control or a transfectant with the vector without the ribozyme sequence. These results suggest that the ribozyme against GUC in codon 18 of c-fms mRNA is a promising tool for blocking the autocrine loop of M-CSF in ovarian epithelial carcinoma. Images Figure 2 Figure 3 Figure 5 Figure 6 PMID:9376277

  10. [Serous and non-serous ovarian carcinoma: histological tumor type as related to the grade of differentiation and disease prognosis].

    PubMed

    Ferreira, Patrícia Andréia Rodrigues; Sallum, Luis Felipe Trincas Assad; Sarian, Luis Otávio; Andrade, Liliana A Lucci De Angelo; Derchain, Sophie

    2012-05-01

    To compare the clinical-pathological features of women with serous and non-serous ovarian tumors and to identify the factors associated with survival. In this reconstructed cohort study, 152 women with ovarian carcinoma, who attended medical consultations between 1993 and 2008 and who were followed-up until 2010 were included. The histological type was clearly established for all women: 81 serous carcinomas and 71 non-serous tumors (17 endometrioid, 44 mucinous and 10 clear cell carcinomas). The crude and adjusted odds ratios (OR), with the respective 95% confidence intervals (95%CI), were calculated for the clinical and pathological features, comparing serous and non-serous histological types. The Hazard Ratios (HR) with 95%CI was calculated for overall survival, considering the clinical and pathological features. Comparison of serous to non-serous tumor types by univariate analysis revealed that serous tumors were more frequently found in postmenopausal women, and were predominantly high histological grade (G2 and G3), advanced stage, with CA125>250 U/mL, and with positive peritoneal cytology. After multivariate regression, the only association remaining was that of high histological grade with serous tumors (adjusted OR 15.1; 95%CI 2.9-77.9). We observed 58 deaths from the disease. There was no difference in overall survival between women with serous carcinoma and women with non-serous carcinoma (HR 0.4; 95%CI 0.1 - 1.1). It was observed that women aged 50 years or less (HR 0.4; 95%CI 0.1-0.9) and those who were in menacne (HR 0.3; 95%CI 0.1-0.9) had a longer survival compared respectively to those above 50 years of age and menopaused. High histological grade (G2 and G3) (p<0.01), stages II-IV (p<0.008) and positive cytology (p<0.001) were significantly associated with worse prognosis. CA125 and the presence of ascites did not correlate with survival. Survival was poor when the disease was diagnosed in stages II to IV and compared to stage I (log-rank p<0

  11. Differential effects of rapalogues, dual kinase inhibitors on human ovarian carcinoma cells in vitro.

    PubMed

    Rogers-Broadway, Karly-Rai; Chudasama, Dimple; Pados, George; Tsolakidis, Dimitris; Goumenou, Anastasia; Hall, Marcia; Karteris, Emmanouil

    2016-07-01

    Ovarian cancer is the second most common gynaecological malignancy and was diagnosed in over 7,000 women in 2011 in the UK. There are currently no reliable biomarkers available for use in a regular screening assay for ovarian cancer and due to characteristic late presentation (78% in stages III and IV) ovarian cancer has a low survival rate (35% after 10 years). The mTOR pathway is a central regulator of growth, proliferation, apoptosis and angiogenesis; providing balance between available resources such as amino acids and growth factors, and stresses such as hypoxia, to control cellular behaviour accordingly. Emerging data links mTOR with the aetiopathogenesis of ovarian cancer. We hypothesised that mTOR inhibitors could play a therapeutic role in ovarian cancer treatment. In this study we began by validating the expression of four main mTOR pathway components, mTOR, DEPTOR, rictor and raptor, at gene and protein level in in vitro models of endometrioid (MDAH‑2774) and clear cell (SKOV3) ovarian cancer using qPCR and ImageStream technology. Using a wound healing assay we show that inhibition of the mTOR pathway using rapamycin, rapalogues, resveratrol and NVP BEZ-235 induces a cytostatic and not cytotoxic response up to 18 h in these cell lines. We extended these findings up to 72 h with a proliferation assay and show that the effects of inhibition of the mTOR pathway are primarily mediated by the dephosphorylation of p70S6 kinase. We show that mTOR inhibition does not involve alteration of mTOR pathway components or induce caspase 9 cleavage. Preclinical studies including ovarian tissue of ovarian cancer patients, unaffected controls and patients with unrelated gynaecological conditions show that DEPTOR is reliably upregulated in ovarian cancer.

  12. Loss of ALDH1A1 expression is an early event in the pathogenesis of ovarian high-grade serous carcinoma.

    PubMed

    Chui, M Herman; Wang, Yihong; Wu, Ren-Chin; Seidman, Jeffrey; Kurman, Robert J; Wang, Tian-Li; Shih, Ie-Ming

    2015-03-01

    Tumor-initiating cells are thought to share features with normal somatic stem cells. In mice, stem cells at the ovarian hilum have been shown to express the stem cell marker, aldehyde dehydrogenase isoform 1A1 (ALDH1A1), and are prone to malignant transformation. The potential relevance of this finding to humans has not been established. In this study, we used immunohistochemistry to assess the distribution of ALDH1A1 staining in the epithelium of human fallopian tubes, with particular reference to the transition of tubal epithelium to mesothelium (ie, tubal-mesothelial junction), ovarian surface epithelium, as well as putative precursors of ovarian high-grade serous carcinoma, namely, serous tubal intraepithelial carcinoma and 'p53 signatures,' and overt serous carcinoma. Expression of ALDH1A1 was detected in both secretory and ciliated tubal epithelial cells, tubal-mesothelial junctions and ovarian surface epithelium, but was absent in serous tubal intraepithelial carcinoma and p53 signatures. Positive staining in high-grade serous carcinoma, when present, was typically limited to rare tumor cells. In silico analyses of the mRNA expression data set from The Cancer Genome Atlas revealed downregulation of ALDH1A1 transcripts in high-grade serous carcinoma relative to normal tubal epithelium, and no association between ALDH1A1 expression levels and overall survival. Our results do not support ALDH1A1 as a specific marker of stem cells in human fallopian tube and demonstrate that its loss of expression is an early event in the development of high-grade serous carcinoma.

  13. Characterization of mitochondria in cisplatin-resistant human ovarian carcinoma cells.

    PubMed

    Hirama, Masanori; Isonishi, Seiji; Yasuda, Makoto; Ishikawa, Hiroshi

    2006-11-01

    One of the mechanisms of cisplatin cell cytotoxicity is the mitochondria-associated induction of apoptosis. The morphological or functional change of mitochondria in cisplatin-resistant cells has already been reported. Herein we present additional data describing the mitochondrial genomic and functional changes in cisplatin- resistant cells. Cisplatin increased the level of apoptotic cells in cisplatin-sensitive human ovarian carcinoma OV 2008 and C13 cells by 3.90+/-1.01 (SD; N=3) (p<0.01)-fold and 2.03+/-0.20 (SD; N=3) (p<0.01)-fold compared to the basal apoptotic level. This indicates a lower level induction of apoptosis by 50% in cisplatin-resistant OV 2008/C13 *5.25 variant (C13) cells. In both cell types, cisplatin cytotoxicity is mostly inhibited by the caspase-9 inhibitor as well as the caspase-3 inhibitor, Ac-DEVD-CHO, suggesting that the mitochondrial downstream event was functioning well in both the C13 cells and in OV 2008 cells. Mitochondrial transmembrane potential (DeltaPsim) determined by flow cytometry using DiOC6-stained cells revealed a significant depolarization of C13 cells as compared to OV 2008 cells. Treatment of these cells with cisplatin or hydrogen peroxide induces complete mitochondrial DNA damage in OV 2008 cells, while only partial DNA-destruction is observed in C13 cells, strongly suggesting that mitochondria are resistant to cisplatin and oxidative stress response. Continuous oxygen consumption of these cells monitored by a multi-channel dissolved oxygen meter is 1.70-fold higher in OV 2008 cells than C13 cells and the oxygen consumption was decreased by 30% in C13 cells, suggesting mitochondrial respiratory malfunction in these cells. The hypothesis generated here is that mitochondrial DNA resistance to cisplatin and oxidative stress response might be one of the main characteristics concerning the lower level of apoptosis induced by cisplatin. However, the mechanism by which the mitochondrial DNA encoded molecule is involved in

  14. The variant hepatocyte nuclear factor 1 activates the P1 promoter of the human alpha-folate receptor gene in ovarian carcinoma.

    PubMed

    Tomassetti, Antonella; Mangiarotti, Fabio; Mazzi, Mimma; Sforzini, Sabrina; Miotti, Silvia; Galmozzi, Enrico; Elwood, Patrick C; Canevari, Silvana

    2003-02-01

    The alpha folate receptor (alpha FR) is a membrane glycoprotein that binds folates, and mediates their uptake and that of antifolate drugs. alpha FR is absent on ovarian surface epithelium (OSE) but is detectable during early transforming events in this epithelium, with increasing expression levels in association with tumor progression. Analysis of transcriptional regulation of the alpha FR gene have revealed two promoter regions, P1 and P4, flanking exons 1 and 4, respectively, and a requirement for three SP1 sites and an INR element for optimal P4 activity. Here, we focused on the P1 transcription regulation in ovarian carcinoma cells. RNase protection assay indicated that the 5'-untranslated region is heterogeneous because of different start sites and alternative splicing of exon 3. A core region of the P1 promoter was sufficient for maximal promoter activity in ovarian carcinoma cell lines but not in OSE cells or in alpha FR-nonexpressing cell lines. Deletion and mutation analysis of this core promoter identified a cis-regulatory element at position +27 to +33 of the untranslated exon 1, which is responsible for maximum P1 activity. This element formed an abundant DNA-protein complex with nuclear proteins from ovarian cancer cells but not from other cell lines or OSE cells. Competition experiments and supershift assays demonstrated binding of the P1 cis-regulatory element by a transcription factor involved in embryonic development, the variant hepatocyte nuclear factor-1 (vHNF1). Analysis of RNA from various cell lines and surgical specimens confirmed that vHNF1 is expressed in ovarian carcinomas. Thus, vHNF1 regulates tissue-specific transcription in ovarian carcinoma.

  15. DMU-212 inhibits tumor growth in xenograft model of human ovarian cancer.

    PubMed

    Piotrowska, Hanna; Myszkowski, Krzysztof; Abraszek, Joanna; Kwiatkowska-Borowczyk, Eliza; Amarowicz, Ryszard; Murias, Marek; Wierzchowski, Marcin; Jodynis-Liebert, Jadwiga

    2014-05-01

    DMU-212 has been shown to evoke a mitochondrial apoptotic pathway in transformed fibroblasts and breast cancer. However, recently published data indicated the ability of DMU-212 to evoke apoptosis in both mitochondria- and receptor-mediated manner in two ovarian cancer cell lines, namely A-2780 and SKOV-3, which showed varied sensitivity to the compound tested. The pronounced cytotoxic effects of DMU-212 observed in A-2780 cells were related to the execution of extracellular apoptosis pathway and cell cycle arrest in G2/M phase. In view of the great anticancer potential of DMU-212 against A-2780 cell line, the aim of the current study was to assess antiproliferative activity of DMU-212 in xenograft model of ovarian cancer. To evaluate in vitro metabolic properties of cells that were to be injected into SCID mice, uptake and decline of DMU-212 in A-2780 ovarian cancer cell line was investigated. It was found that the concentration of the test compound in A-2780 cells was growing within first eight hours, and then the gradual decline was observed. A-2780 cells stably transfected with pcDNA3.1/Zeo(-)-Luc vector were subcutaneously inoculated into the right flanks of SCID mice. After seven days of the treatment with DMU-212 (50mg/kg b.w), tumor growth appeared to be suppressed in the animals treated with the compound tested. At day 14 of the experiment, tumor burden in mice treated with DMU-212 was significantly lower, as compared to untreated controls. Our findings suggest that DMU-212 might be considered as a potential anticancer agent used in ovarian cancer therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  16. [Gastric metastasis from ovarian carcinoma revealed by a gastro-splenic perforation].

    PubMed

    Dupuychaffray, Jean-Pierre; Auger, Christine; Funes De La Vega, Mathilde; Riche, Agnès; Boulanger, Vincent; Blanchot, Philippe

    2004-05-01

    Metastatic disease involving the stomach is unusual. We report the case of a gastric metastasis from ovarian cancer revealed by gastro-splenic perforation. The gastric metastasis was diagnosed 17 years after the diagnosis of primary cancer.

  17. EGEN-001 and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2014-08-11

    Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer

  18. Cutaneous metastasis of ovarian carcinoma with shadow cells mimicking a primary pilomatrical neoplasm.

    PubMed

    Lalich, Daniel; Tawfik, Ossama; Chapman, Julia; Fraga, Garth

    2010-07-01

    Shadow cells are characteristic of pilomatricoma, although they have been described in other cutaneous and visceral neoplasms, particularly endometrioid adenocarcinomas of the female genital tract. We describe a metastasis of an ovarian endometrioid adenocarcinoma with shadow cells to the skin that was initially misinterpreted as a pilomatricoma. We compare the histology of the ovarian neoplasm to 21 pilomatricomas. This is the first reported case of a cutaneous metastasis of a visceral neoplasm mimicking a primary pilomatrical neoplasm.

  19. Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion

    PubMed Central

    2010-01-01

    Background Elevated Plexin-B1 expression has been found in diverse human cancers and in non-neoplastic tissues, and it mediates diverse biological and pathological activities. However, whether or not Plexin-B1 expression is involved in human ovarian tumors remains unclear. In the present study, Plexin-B1 expression was explored in benign and malignant human ovarian tumor tissues. In addition, the impact of Plexin-B1 expression on ovarian cancer cell proliferation, migration and invasion were investigated in vitro. Methods Plexin-B1 expression was analyzed in normal and benign ovarian tissues and serous ovarian tumors (both borderline and malignant) by immunohistochemical staining, as well as in four human ovarian cancer cell lines (A2780, C13*, SKOV3, and OV2008) by RT-PCR and western blot analyses. Furthermore, endogenous Plexin-B1 expression was suppressed by Plexin-B1 siRNA in SKOV3 cells, which overexpress Plexin-B1. Protein levels of Plexin-B1, AKT and AKTSer473 were examined by western blot analysis. Cell proliferation, migration and invasion were measured with MTT, wound healing and boyden chamber assays, respectively, and the cytoskeleton was monitored via F-actin staining. Results Expression levels of Plexin-B1 protein were significantly higher in serous ovarian carcinomas than in normal ovaries or benign ovarian neoplasms, and in the former, Plexin-B1 expression was positively correlated with lymphatic metastasis, and the membrane and cytoplasm of cancer cells stained positively. SKOV3 cells displayed the highest Plexin-B1 expression at both the mRNA and protein levels among the four tested human ovarian cancer cell lines and was selected as a cell model for further in vitro experiments. Plexin-B1 siRNA significantly suppressed phosphorylation of AKT at Ser473 in SKOV3 cells, but it did not alter total AKT expression. In addition, silencing of Plexin-B1 in SKOV3 cells inhibited cell migration and invasion and reorganized the cytoskeleton, whereas cell

  20. Improved clinical outcomes of patients with ovarian carcinoma arising in endometriosis

    PubMed Central

    Zhou, Jiayi; Lu, Yingying; Wang, Zehua; Liu, Haiou; Xu, Congjian

    2017-01-01

    Background Despite enormous efforts to dissect the role of endometriosis in ovarian cancer development, the difference in prognosis between ovarian cancer patients with or without endometriosis remains elusive. The purpose of this study is to assess the association between endometriosis and the prognosis in patients with ovarian cancer. Results Ovarian cancer arising in endometriosis tended to be presented as clear cell histology, early stage, less intraperitoneal metastasis and ascites, and lower CA125 level compared with those without endometriosis. Multivariate Cox regression analysis identified endometriosis as an independent prognostic factor for progression free survival (P = 0.002) and overall survival (P = 0.009) in all patients and especially for early stage. A nomogram integrating endometriosis, FIGO stage and CA125 was established to predict progression free survival and overall survival. Materials and methods This study retrospectively enrolled 196 ovarian cancers arising or not in endometriosis judged by adjunctive use of CD10 immunohistochemistry in conjunction with H&E staining specimens. Clinicopathologic variables, progression-free survival (PFS) and overall survival (OS) were recorded. Kaplan-Meier analysis was performed to compare survival curves. Cox regression models were used to analyze the effect of endometriosis on PFS and OS. A prognostic nomogram was constructed based on the independent prognostic factors identified by multivariate analysis. Conclusions Endometriosis is an independent predictor of prognosis in ovarian cancer patients. PMID:27992377

  1. Ovarian pathology in risk-reducing salpingo-oophorectomies from women with BRCA mutations, emphasizing the differential diagnosis of occult primary and metastatic carcinoma.

    PubMed

    Rabban, Joseph T; Barnes, Michael; Chen, Lee-May; Powell, Catherine B; Crawford, Beth; Zaloudek, Charles J

    2009-08-01

    Risk-reducing salpingo-oophorectomy (RRSO) is an effective prophylactic procedure for women with mutations in BRCA1 or BRCA2 genes, both of which confer an increased lifetime risk for ovarian, tubal, peritoneal, and breast cancer. In addition to lowering this risk, RRSO also offers the opportunity to detect occult early-stage fallopian tube or ovarian carcinoma. The differential diagnosis of occult tubal/ovarian cancer includes a spectrum of benign tubal and ovarian alterations and also occult metastatic breast cancer, although only rare cases of the latter have been reported in RRSO. Neoadjuvant breast cancer chemotherapy may contribute to diagnostic difficulty due to treatment-induced cytologic alterations. With the aim of elucidating features which may help with differential diagnosis, this study reports the incidence and pathologic features of benign ovarian alterations, benign ovarian tumors, and occult primary and metastatic malignancies in prophylactic oophorectomies from 108 women with a BRCA mutation and from 35 women with other strong risk factors for hereditary breast/ovarian carcinoma. We direct particular emphasis on morphologic features of primary ovarian lesions that may mimic occult metastatic breast cancer. We also evaluate histologic alterations due to neoadjuvant breast cancer chemotherapy in the ovary and fallopian tube of patients who received such treatment immediately preceding RRSO. Comparison is made to ovarian metastases of breast cancer in our hospital-based population of breast cancer patients, none of whom underwent RRSO. Overall, 69% of RRSO patients had a personal history of breast cancer. Neoadjuvant breast cancer chemotherapy was administered in 15%. Occult primary carcinoma occurred in 7 (6.5%) BRCA patients (5 in fallopian tube, 1 in fallopian tube and ovary, 1 in ovary). Ovarian metastasis of breast cancer occurred in 1 (1%) BRCA patient undergoing RRSO and in up to a similar proportion (0.8%) of the hospital-based population of

  2. Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma.

    PubMed

    Ramakrishnan, Mallika; Mathur, Sandeep R; Mukhopadhyay, Asok

    2013-09-01

    For a long time, the external milieu of cancer cells was considered to be of secondary importance when compared with its intrinsic properties. That has changed now as the microenvironment is considered to be a major contributing factor toward the progression of tumor. In this study, we show that in human and mouse epithelial ovarian carcinoma and mouse lung carcinoma, the interaction between tumor-infiltrating hematopoietic cells and epithelial cancer cells results in their fusion. Intriguingly, even after the fusion event, cancer cells retain the expression of the pan-hematopoietic marker (CD45) and various markers of hematopoietic lineage, including those of hematopoietic stem cells, indicating that the hematopoietic genome is not completely reprogrammed. This observation may have implications on the bone marrow contribution to the cancer stem cell population. Interestingly, it was seen that in both cancer models, the expression of chemokine receptor CXCR4 was largely contributed to by the fused compartment of cancer cells. We hypothesize that the superior migratory potential gained by the cancer cells due to the fusion helps in its dissemination to various secondary organs upon activation of the CXCR4/CXCL12 axis. We are the first to report the presence of a hemato-epithelial cancer compartment, which contributes to stem cell markers and CXCR4 in epithelial carcinoma. This finding has repercussions on CXCR4-based therapeutics and opens new avenues in discovering novel molecular targets against fusion and metastasis.

  3. Serous tubal intraepithelial carcinoma localizes to the tubal-peritoneal junction: a pivotal clue to the site of origin of extrauterine high-grade serous carcinoma (ovarian cancer).

    PubMed

    Seidman, Jeffrey D

    2015-03-01

    absent (P<0.0001). Myosalpingeal invasion was present in 40% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P not significant). It is concluded that serous tubal intraepithelial carcinoma occurs at and in the immediate vicinity of the TPJ. In combination with the findings that STICs are present in a majority of cases when the TPJ is present, that flat STICs are smaller than papillary STICs, and that lamina propria invasion is more frequent in the presence of STIC, these data support STIC as the precursor of extrauterine high-grade serous carcinoma, they provide important clues to the site of origin of high-grade serous carcinoma (ovarian cancer), and can guide further research.

  4. Vaccine Therapy in Treating Patients With Stage IIIC-IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Cancer Following Surgery and Chemotherapy

    ClinicalTrials.gov

    2016-12-28

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Tumor; Fallopian Tube Mucinous Neoplasm; Fallopian Tube Serous Neoplasm; Fallopian Tube Transitional Cell Carcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  5. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations.

    PubMed

    Yamamoto, Sohei; Tsuda, Hitoshi; Takano, Masashi; Tamai, Seiichi; Matsubara, Osamu

    2012-04-01

    ARID1A is a recently identified tumor suppressor gene that is mutated in ∼50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations. A total of 42 clear-cell carcinoma cases with adjacent putative precursor lesions (endometriosis-associated carcinoma cases (n=28) and (clear-cell) adenofibroma-associated carcinoma cases (n=14)) were selected and subjected to immunohistochemical analysis for ARID1A protein expression and direct genomic DNA sequencing of exons 9 and 20 of the PIK3CA gene. ARID1A immunoreactivity was deficient in 17 (61%) of the 28 endometriosis-associated carcinomas and 6 (43%) of the 14 adenofibroma-associated carcinomas. Among the precursor lesions adjacent to the 23 ARID1A-deficient carcinomas, 86% of the non-atypical endometriosis (12 of 14) and 100% of the atypical endometriosis (14 of 14), benign (3 of 3), and borderline (6 of 6) clear-cell adenofibroma components were found to be ARID1A deficient. In contrast, in the 19 patients with ARID1A-intact carcinomas, all of the adjacent precursor lesions retained ARID1A expression regardless of their types and cytological atypia. Analysis of 22 solitary endometrioses and 10 endometrioses distant from ARID1A-deficient carcinomas showed that all of these lesions were diffusely immunoreactive for ARID1A. Among the 42 clear-cell carcinomas, somatic mutations of PIK3CA were detected in 17 (40%) tumors and majority (71%) of these were ARID1A-deficient carcinomas. These results suggest that loss of ARID1A protein expression occurs as a very early event in ovarian clear-cell carcinoma development, similar to the pattern of PIK3CA mutation recently reported by our group, and frequently coexists (not mutually

  6. Allelic loss at 7q31.1 in human primary ovarian carcinomas suggests the existence of a tumor suppressor gene.

    PubMed

    Zenklusen, J C; Weitzel, J N; Ball, H G; Conti, C J

    1995-07-20

    We studied loss of heterozygosity (LOH) in chromosome 7q in order to determine the location of a putative tumor suppressor gene (TSG) in human epithelial ovarian carcinomas. Samples were obtained from 26 primary ovarian carcinomas at the time of staging laparotomy. Paired normal and tumoral DNAs were used as templates for polymerase chain reaction amplification of a set of 14 (C-A)n microsatellite repeats on 7q21-qter. All the cases studied presented LOH at one or more loci on 7q. Seventy-three percent LOH (in 14 of 19 informative cases) were detected in D7S522 at 7q31.1. The percentages of LOH were normally distributed around microsatellite D7S522 determining a smallest common deleted region of 1 cM. The high incidence of LOH in primary ovarian carcinomas suggests that a TSG relevant to the development of ovarian cancers is present at 7q31.1, confirming our previous functional evidence for a TSG in this region.

  7. Transitional cell carcinoma of the endometrium associated with benign ovarian brenner tumor: a case report with immunohistochemistry molecular analysis and a review of the literature.

    PubMed

    Giordano, Giovanna; D'Adda, Tiziana; Gnetti, Letizia; Merisio, Carla; Raboni, Stefano

    2007-07-01

    Transitional cell carcinoma of the endometrium (TCCE) is a subtype of endometrial carcinoma, characterized by a prominent papillary pattern, resembling the papillary carcinoma of the urothelium. This neoplasm is very rare, with only 13 cases reported in the international literature. In this paper, a new case of TCCE associated with benign ovarian Brenner tumor is described. This association is extremely rare, with only 1 other case reported. A review of the literature is performed to delineate the clinico pathologic features of this malignancy. Moreover, immunohistochemical and molecular studies are carried out in the effort to establish the phenotype and etiology of this rare neoplasm. The molecular study, by polymerase chain reaction (PCR) failing to reveal the presence of HPV DNA, demonstrates that neither the TCCE nor the ovarian Brenner tumor is caused by an HPV infection. The association of TCCE with benign ovarian Brenner tumor could be a coincidental event. Conversely, this finding could be the manifestation of a multicentric metaplastic process (neometaplasia), involving both the coelomic epithelium of the ovary and the Mullerian epithelium of the uterus, or the evidence of "field effect" that manifests differently at different anatomical sites. In our view, other cases of TCCE associated with ovarian Brenner tumor should be reported to confirm the last 2 hypotheses.

  8. Decreased expression of CYP27B1 correlates with the increased aggressiveness of ovarian carcinomas

    PubMed Central

    BROŻYNA, ANNA A.; JÓŹWICKI, WOJCIECH; JOCHYMSKI, CEZARY; SLOMINSKI, ANDRZEJ T.

    2015-01-01

    CYP27B1 hydroxylates 25-hydroxyvitamin D3 in position C1α into biologically active 1,25-dihydroxyvitamin D3, calcitriol. CYP27B1 is expressed in normal tissues and tumors. Since calcitriol indicates anticancer activities and CYP27B1 expression can be deregulated during malignant progression, we analyzed its expression in ovarian cancers in relation to pathomorphological features of tumors and overall survival (OS). Expression of CYP27B1 was evaluated in 61 ovarian tumors, 18 metastases and 10 normal ovaries. Normal ovarian epithelium showed the highest levels CYP27B1 with a significant decrease in its expression in ovarian cancers. Both poorly differentiated primary tumors and metastases showed the lowest level of CYP27B1 expression, while non-metastasizing tumors showed a higher CYP27B1 level than tumors that developed metastases. The expression of CYP27B1 was positively correlated with a lower proliferation rate, lower dynamism of tumor growth and tumor infiltrating lymphocyte response. Furthermore, CYP27B1 expression was negatively correlated with tumor cell modeling of their microenvironment. CYP27B1 expression was also associated with longer OS time. In summary, our results suggest that local expression of CYP27B1 in ovarian tumor cells can modify their behavior and promote a less aggressive phenotype by affecting local concentrations of active of vitamin D levels within the tumor microenvironment. PMID:25501638

  9. Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line

    SciTech Connect

    Vaskivuo, Liisa; Rysae, Jaana; Koivuperae, Johanna; Myllynen, Paeivi; Vaskivuo, Tommi; Chvalova, Katerina; Serpi, Raisa; Savolainen, Eeva-Riitta; Puistola, Ulla; Vaehaekangas, Kirsi . E-mail: kirsi.vahakangas@uku.fi

    2006-10-01

    p14{sup ARF} tumor suppressor protein regulates p53 by interfering with mdm2-p53 interaction. p14{sup ARF} is activated in response to oncogenic stimuli but little is known of the responses of endogenous p14{sup ARF} to different types of cellular stress or DNA damage. Azidothymidine (AZT) is being tested in several clinical trials as an enhancer of anticancer chemotherapy. However, the knowledge of the relationship between AZT and cellular pathways, e.g. p53 pathway, is very limited. In this study, we show that AZT, cisplatin (CDDP) and docetaxel (DTX) all induce unique molecular responses in OVCAR-3 ovarian carcinoma cells carrying a mutated p53, while in A2780, ovarian carcinoma and MCF-7 breast carcinoma cells with wild type p53, all of these drugs cause similar p53 responses. We found that endogenous p14{sup ARF} protein in OVCAR-3 cells is down-regulated by DTX but induced by AZT and a short CDDP pulse treatment. In HT-29 colon carcinoma cells with a mutated p53, all treatments down-regulated p14{sup ARF} protein. Both CDDP and AZT increased the expression of p14ARF mRNA in OVCAR-3 cells. Differences in cell death induced by these drugs did not explain the differences in protein and mRNA expressions. No increase in the level of either c-Myc or H-ras oncoproteins was seen in OVCAR-3 cells after AZT or CDDP-treatment. These results suggest that p14{sup ARF} can respond to DNA damage without oncogene activation in cell lines without functional p53.

  10. Syndrome of inappropriate antidiuretic hormone secretion following irinotecan-cisplatin administration as a treatment for recurrent ovarian clear cell carcinoma

    PubMed Central

    Kwon, Do Youn; Han, Gwan Hee; Ulak, Roshani; Lee, Jong Min; Lee, Seon Kyung

    2017-01-01

    Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has various causes including central nervous system disorders, pulmonary and endocrine diseases, paraneoplastic syndromes, and use of certain drugs. SIADH induced by chemotherapy with irinotecan-cisplatin is not a common complication. Here, we review a case of SIADH after treatment with irinotecan-cisplatin. A 45-year-old woman received adjuvant chemotherapy (paclitaxel-carboplatin) for ovarian clear cell carcinoma, but the cancer recurred within 9 months of chemotherapy. Subsequently, a second line of combination chemotherapy containing irinotecan-cisplatin was initiated. However, 5 days after chemotherapy administration, her general condition began to deteriorate; her hematological tests revealed hyponatremia. Therefore, it is imperative to consider the possibility of SIADH in patients being treated with irinotecan-cisplatin–based chemotherapy. Proper monitoring of serum sodium levels and assessment of clinical symptoms should be performed in such patients for early diagnosis and prompt management. PMID:28217682

  11. Syndrome of inappropriate antidiuretic hormone secretion following irinotecan-cisplatin administration as a treatment for recurrent ovarian clear cell carcinoma.

    PubMed

    Kwon, Do Youn; Han, Gwan Hee; Ulak, Roshani; Ki, Kyung Do; Lee, Jong Min; Lee, Seon Kyung

    2017-01-01

    Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has various causes including central nervous system disorders, pulmonary and endocrine diseases, paraneoplastic syndromes, and use of certain drugs. SIADH induced by chemotherapy with irinotecan-cisplatin is not a common complication. Here, we review a case of SIADH after treatment with irinotecan-cisplatin. A 45-year-old woman received adjuvant chemotherapy (paclitaxel-carboplatin) for ovarian clear cell carcinoma, but the cancer recurred within 9 months of chemotherapy. Subsequently, a second line of combination chemotherapy containing irinotecan-cisplatin was initiated. However, 5 days after chemotherapy administration, her general condition began to deteriorate; her hematological tests revealed hyponatremia. Therefore, it is imperative to consider the possibility of SIADH in patients being treated with irinotecan-cisplatin-based chemotherapy. Proper monitoring of serum sodium levels and assessment of clinical symptoms should be performed in such patients for early diagnosis and prompt management.

  12. Incidence of serous tubal intraepithelial carcinoma (STIC) by algorithm classification in serous ovarian tumor associated with PAX8 expression in tubal epithelia: a study of single institution in Japan.

    PubMed

    Munakata, Satoru; Yamamoto, Toshiya

    2015-01-01

    Serous ovarian carcinoma is now hypothesized to originate from fallopian tube epithelium (FTE). We investigated the FTE abnormalities in the patients with epithelial ovarian tumors. Our study included 55 cases of serous tumors (24 carcinomas, 8 borderline tumors, and 23 adenomas), 14 mucinous carcinomas, 22 endometrioid carcinomas, 5 clear cell carcinomas, and 2 malignant Brenner tumors. FTE was diagnosed by the diagnostic algorithm, which combines the data of morphology, and p53, Ki-67 immunostaining, as serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive. Serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive were observed in 5, 3, 0, and 16 cases in serous carcinoma; 0, 3, 0, and 5 cases in serous borderline tumor; 0, 1, 1, and 21 cases in serous adenoma; 0, 0, 1, and 13 cases in mucinous carcinoma; 0, 0, 3, and 19 cases in endometrioid carcinoma; 0, 0, 0, and 5 cases in clear cell carcinoma; and 0, 1, 0, and 1 case in malignant Brenner tumor. Among tumors of serous histology and between carcinomas, FTE abnormalities differed significantly (P<0.05). Serous tubal intraepithelial carcinomas were only found in serous carcinoma. The incidence of secretory cell proliferation (SCP) was examined by PAX8 expression. The rate of SCP was extremely high in serous carcinoma (96%). Among tumors of serous histology and between carcinomas, an incidence of SCP differed significantly (P<0.05). Patients with SCP were significantly older (P<0.0001). Our observations were concordant with the hypothesis of serous ovarian carcinogenesis. The SCP has a meaningful association with serous ovarian cancer.

  13. HERV-K hypomethylation in ovarian clear cell carcinoma is associated with a poor prognosis and platinum resistance.

    PubMed

    Iramaneerat, Kanokwan; Rattanatunyong, Prakasit; Khemapech, Nipon; Triratanachat, Surang; Mutirangura, Apiwat

    2011-01-01

    In general, ovarian clear cell carcinoma (OCCC) has a history of poor response to standard platinum-based chemotherapy regimens, and advanced cases have short survival periods. Therefore, the discovery of a biomarker for the pretreatment prediction of OCCC is crucial. Loss of methylation of a retrotransposable sequence, such as long interspersed repetitive sequence 1 (LINE-1), frequently occurs in cancers, including ovarian cancer, and it has been proven to be associated with poor survival. The expressions of human endogenous retrovirus (HERV) K and E were found to be increased in tissues from patients with OCCC. Here, we propose that methylation levels of HERV are associated with treatment response and prognosis of OCCC. Twenty-nine patients with OCCC were enrolled. Methylation levels of HERV-K, HERV-E, and LINE-1 were measured from microdissected cancer and normal ovarian tissues. The methylation levels were correlated with stage, treatment response, and prognosis. Methylation levels of HERV-K, HERV-E, and LINE-1 were decreased in tissues from patients with advanced stage cancer (P = 0.0179, P = 0.0021, and P = 0.0307, respectively). Human endogenous retrovirus K demonstrated significantly lower methylation levels in the platinum-resistant group (P = 0.0004). Patients with lower levels of methylated (hypomethylated) HERV-K had a shorter mean overall survival (P = 0.006). In advanced OCCC cases, patients with hypomethylated HERV-K had shorter mean progression-free survival (P = 0.018) and mean overall survival (P = 0.018) than did patients with higher methylation levels of HERV-K. Methylation levels of HERV-K, HERV-E, and LINE-1 are decreased during OCCC multistep carcinogenesis. Moreover, HERV-K hypomethylation is a promising biomarker for predicting OCCC treatment response and prognosis.

  14. Genomic Instability and Copy-Number Heterogeneity of Chromosome 19q, Including the Kallikrein Locus, in Ovarian Carcinomas

    PubMed Central

    Bayani, Jane; Marrano, Paula; Graham, Cassandra; Zheng, Yingye; Li, Lin; Katsaros, Dionyssios; Lassus, Heini; Butzow, Ralf; Squire, Jeremy A.; Diamandis, Eleftherios P.

    2011-01-01

    Many tissue kallikrein (KLK) genes and proteins are candidate diagnostic, prognostic and predictive biomarkers for ovarian cancer (OCa). We previously demonstrated that the KLK locus (19q13.3/4) is subject to copy-number gains and structural rearrangements in a pilot study of cell lines and ovarian cancer primary tissues, shown to overexpress KLK gene family members. To determine the overall frequency of genomic instability and copy-number changes, a retrospective study was conducted using formalin-fixed paraffin embedded (FFPE) tissues. Eighty-one chemotherapy naïve serous OCas were examined using 3-colour fluorescence in situ hybridization (FISH) to identify structural and numerical changes on 19q, including the KLK locus; in addition to immunohistochemistry (IHC) for KLK6, which has been shown to be overexpressed in OCa. The KLK locus was subject to copy-number changes in ~83% of cases: net gain in 51%, net loss in 30% and amplified in 2%; and found to be chromosomally unstable (p<0.001). All cases showed a wide range of immuoreactivity for KLK6 by IHC. Although no strong correlation could be found with copy number, the latter was contributing factor to the observed KLK6 protein overexpression. Moreover, univariate and multivariate analyses showed an association between the net loss of the KLK locus with longer disease-free survival. Interestingly, FISH analyses indicated that chromosome 19q was subject to structural rearrangement in 62% of cases and was significantly correlated to tumor grade (p<0.001). We conclude that numerical and structural aberrations of chromosome 19q, affect genes including the KLK gene members, may contributing to ovarian carcinoma progression and aggressiveness. PMID:20800559

  15. (18)F-FDG PET/CT as predictor of tumour biology and prognosis in epithelial ovarian carcinoma.

    PubMed

    González García, B; García Vicente, A M; Jiménez Londoño, G A; Pena Pardo, F J; Bellón Guardia, M E; Talavera Rubio, M P; Palomar Muñoz, A; Gómez Herrero, P; Soriano Castrejón, Á M

    To investigate the relationship between maximum standardised uptake value (SUVmax) of ovarian lesions and histopathology subtypes, and their involvement in the response and prognosis of patients with epithelial ovarian carcinoma (EOC). A retrospective analysis of 31 patients with EOC and (18)F-FDG-PET/CT before treatment, including an assessment of the SUVmax of ovarian lesion. Histopathological diagnosis and follow-up was performed. A study was made on the relationship between the SUVmax and histological type (type I and II) and tumour stage, as well as the role of various parameters (SUVmax, histology, stage) on the patient outcomes (complete response [CR], overall survival [OS], disease-free survival [DFS], and disease-free [DF] status, at 12 and 24 months). The medium SUVmax in type I lesions was lower than in type II (6.3 and 9.3, respectively; P=.03). A 7.1 cut-off was set for SUVmax in order to identify type II EOC (sensitivity: 77.8%, specificity: 69.2%; AUC=0.748; P=.02). No significant relationship was found between tumour stage and SUVmax. CR was more common in early stages; relative risk (RR) of 1.64; P=.003, as well as in type I tumours and a lower SUVmax. Tumour stage was decisive in DFS (P=.04), LE24m (0.07) and OS (P=.08). Longer DFS and a higher percentage of DF 24m were observed in type I tumours (RR: 1.32; P=.26). SUVmax was related to EOC histology, so could predict the response and prognosis of these patients. No association was found between glycolytic activity of the primary tumor with the response and prognosis. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  16. Preliminary studies on LED-activated pyropheophorbide-α methyl ester killing cisplatin-resistant ovarian carcinoma cells

    NASA Astrophysics Data System (ADS)

    Tan, Yong; Xu, Chuan Shan; Xia, Xin Shu; Yu, He Ping; Bai, Ding Qun; He, Yong; Xu, Jing; Wang, Ping; Wang, Xin Na; Leung, Albert Wing Nang

    2009-05-01

    In the present study, a novel LED source was applied for activating pyropheophorbids-a methyl ester (MPPa) in cisplatin-resistant ovarian cell line COC1/DDP cells. MPPa concentration was 2 μM and light energy from 0.125-8 J/cm2. Cytotoxicity was investigated 24 h using MTT reduction assay and light microscopy after treatment. Cellular ultrastructure was observed using transmission electron microscopy (TEM) and nuclear chromatin by fluorescent microscope with Hoechst33258 staining. MTT reduction assay showed that the cytotoxicity of LED-activated MPPa in the COC1/DDP cells increased along with the light dose of LED source and LED-activated MPPa resulted in light-dependent cytotoxicity. The observations from light microscopy reinforced the above results. TEM showed that necrotic cells with the disruption of karyotheca, karyorrhexis, and karyolysis of nucleus and apoptotic cells, especially the apoptotic body, can be seen post LED-activated MPPa. Hoechst33258 staining showed that condensation of chromatin and nuclear fragmentations could be found in many treated cells and some of them formed the structure of apoptotic bodies when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm2 irradiation of LED source. The findings demonstrated that the novel LED source could efficiently activated MPPa and LED-activated MPPa could significantly kill cisplatin-resistant ovarian cell line COC1/DDP cells through two major pathways including necrosis and apoptosis, suggesting that LED is a novel and efficient light source and LED-activated MPPa might be potential therapeutic modality for treating cisplatin-resistant ovarian carcinoma.

  17. ADAM12 is a prognostic factor associated with an aggressive molecular subtype of high-grade serous ovarian carcinoma.

    PubMed

    Cheon, Dong-Joo; Li, Andrew J; Beach, Jessica A; Walts, Ann E; Tran, Hang; Lester, Jenny; Karlan, Beth Y; Orsulic, Sandra

    2015-07-01

    ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high-grade serous ovarian carcinoma (HGSOC). Here, we sought to determine if high levels of the ADAM12 protein and/or messenger RNA (mRNA) are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were transforming growth factor (TGF)β signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFβ signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective.

  18. [Histological subtypes of ovarian carcinoma and their importance for clinical prognosis].

    PubMed

    Zlatkov, V

    2015-01-01

    Ovarian cancer is one of the most common and most lethal cancers. For Bulgaria (2012) it occupies third place in the structure of gynecological malignancies with a share of 22.6 percent, while regarding mortality is at first place with 35.7 percent. New cases are 838 with crude incidence 22.3 x 10(5), and the deaths are 463 with crude mortality 12.3 x 10(5). Ovarian tumors, even when they are of the same histological type clearly differ in their cellular differentiation, molecular characteristiques and subsequently in their biological behavior. In this review, we discuss the frequency origin, morphology and molecular characteristiques of the five major subtypes of ovarian cancer--serous low and high grade, mucinous, endometroid and and clear cell. The role of different risk and prognostic factors for the efficiency of the treatment and control of disease been discussed.

  19. Transcriptomic analysis of an in vitro murine model of ovarian carcinoma: functional similarity to the human disease and identification of prospective tumoral markers and targets.

    PubMed

    Urzúa, Ulises; Roby, Katherine F; Gangi, Lisa M; Cherry, James M; Powell, John I; Munroe, David J

    2006-03-01

    Ovarian cancer is an aggressive disease of poor prognostic when detected at advanced stage. It is widely accepted that the ovarian surface epithelium plays a central role in disease etiology, but little is known about disease progression at the molecular level. To identify genes involved in ovarian tumorigenesis, we carried out a genome-wide transcriptomic analysis of six spontaneously transformed mouse ovarian surface epithelial (MOSE) cell lines, an in vitro model for human ovarian carcinoma. Loess normalization followed by statistical analysis with control of multiple testing resulted in 509 differentially expressed genes using an adjusted P-value < or = 0.05 as cut-off. The top 20 differentially expressed genes included 10 genes (Spp1, Cyp1b1, Btg1, Cfh, Mt1, Mt2, Igfbp5, Gstm1, Gstm2, and Esr1) implicated in various aspects of ovarian carcinomas, and other 3 genes (Gsto1, Lcn7, and Alcam) associated to breast cancer. Upon functional analysis, the majority of alterations affected genes involved in glutathione metabolism and MAPK signaling pathways. Interestingly, over 20% of the aberrantly expressed genes were related to extracellular components, suggestive of potential markers of disease progression. In addition, we identified the genes Pura, Cnn3, Arpc1b, Map4k4, Tgfb1i4, and Crsp2 correlated to in vivo tumorigenic parameters previously reported for these cells. Taken together, our findings support the utility of MOSE cells in studying ovarian cancer biology and as a source of novel diagnostic and therapeutic targets. Copyright 2005 Wiley-Liss, Inc.

  20. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis.

    PubMed

    Yemelyanova, Anna; Vang, Russell; Kshirsagar, Malti; Lu, Dan; Marks, Morgan A; Shih, Ie Ming; Kurman, Robert J

    2011-09-01

    Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. The immunoprofile that correlates with wild-type TP53, however, is not as clear. In particular, the significance of completely negative immunostaining is controversial. The aim of this study was to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. A total of 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, 2 malignant mesodermal mixed tumors (carcinosarcomas), 2 low-grade serous carcinomas, 4 clear cell carcinomas, 1 well-differentiated endometrioid carcinoma, and 5 carcinomas with mixed epithelial differentiation) were analyzed for TP53 mutations by nucleotide sequencing (exons 4-9), and subjected to immunohistochemical analysis of p53 expression. Thirty six tumors contained functional mutations and 13 had wild type TP53. Five tumors were found to harbor known TP53 polymorphism and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a wide range of immunolabeling patterns, with the most common pattern showing ≤10% of positive cells in 6 cases (46%). Mutant TP53 was associated with 60-100% positive cells in 23 cases (64% of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (0% cells staining) had a mutation of TP53 in 65% of cases and wild-type TP53 in 11%. Combining two immunohistochemical labeling patterns associated with TP53 mutations (0% and 60-100% positive cells), correctly identified a mutation in 94% of cases (P<0.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a

  1. Regulation of Murine Ovarian Epithelial Carcinoma by Vaccination against the Cytoplasmic Domain of Anti-Müllerian Hormone Receptor II

    PubMed Central

    Sakalar, Cagri; Mazumder, Suparna; Johnson, Justin M.; Altuntas, Cengiz Z.; Jaini, Ritika; Aguilar, Robert; Prasad, Sathyamangla V. Naga; Connolly, Denise C.; Tuohy, Vincent K.

    2015-01-01

    Anti-Müllerian hormone receptor, type II (AMHR2), is a differentiation protein expressed in 90% of primary epithelial ovarian carcinomas (EOCs), the most deadly gynecologic malignancy. We propose that AMHR2 may serve as a useful target for vaccination against EOC. To this end, we generated the recombinant 399-amino acid cytoplasmic domain of mouse AMHR2 (AMHR2-CD) and tested its efficacy as a vaccine target in inhibiting growth of the ID8 transplantable EOC cell line in C57BL/6 mice and in preventing growth of autochthonous EOCs that occur spontaneously in transgenic mice. We found that AMHR2-CD immunization of C57BL/6 females induced a prominent antigen-specific proinflammatory CD4+ T cell response that resulted in a mild transient autoimmune oophoritis that resolved rapidly with no detectable lingering adverse effects on ovarian function. AMHR2-CD vaccination significantly inhibited ID8 tumor growth when administered either prophylactically or therapeutically, and protection against EOC growth was passively transferred into naive recipients with AMHR2-CD-primed CD4+ T cells but not with primed B cells. In addition, prophylactic AMHR2-CD vaccination of TgMISIIR-TAg transgenic mice significantly inhibited growth of autochthonous EOCs and provided a 41.7% increase in mean overall survival. We conclude that AMHR2-CD vaccination provides effective immunotherapy of EOC with relatively benign autoimmune complications. PMID:26618181

  2. Establishment and characterization of a platinum- and paclitaxel-resistant high grade serous ovarian carcinoma cell line.

    PubMed

    Teng, Pang-Ning; Bateman, Nicholas W; Wang, Guisong; Litzi, Tracy; Blanton, Brian E; Hood, Brian L; Conrads, Kelly A; Ao, Wei; Oliver, Kate E; Darcy, Kathleen M; McGuire, William P; Paz, Keren; Sidransky, David; Hamilton, Chad A; Maxwell, G Larry; Conrads, Thomas P

    2017-07-01

    High grade serous ovarian cancer (HGSOC) patients have a high recurrence rate after surgery and adjuvant chemotherapy due to inherent or acquired drug resistance. Cell lines derived from HGSOC tumors that are resistant to chemotherapeutic agents represent useful pre-clinical models for drug discovery. Here, we describe establishment of a human ovarian carcinoma cell line, which we term WHIRC01, from a patient-derived mouse xenograft established from a chemorefractory HGSOC patient who did not respond to carboplatin and paclitaxel therapy. This newly derived cell line is platinum- and paclitaxel-resistant with cisplatin, carboplatin, and paclitaxel half-maximal lethal doses of 15, 130, and 20 µM, respectively. Molecular characterization of this cell line was performed using targeted DNA exome sequencing, transcriptomics (RNA-seq), and mass spectrometry-based proteomic analyses. Results from exomic sequencing revealed mutations in TP53 consistent with HGSOC. Transcriptomic and proteomic analyses of WHIRC01 showed high level of alpha-enolase and vimentin, which are associated with cell migration and epithelial-mesenchymal transition. WHIRC01 represents a chemorefractory human HGSOC cell line model with a comprehensive molecular profile to aid future investigations of drug resistance mechanisms and screening of chemotherapeutic agents.

  3. Risk factors of epithelial ovarian carcinomas among women with endometriosis: a systematic review.

    PubMed

    Thomsen, Line H; Schnack, Tine H; Buchardi, Kristina; Hummelshoj, Lone; Missmer, Stacey A; Forman, Axel; Blaakaer, Jan

    2017-06-01

    The objective of this review was to evaluate the published literature on epidemiologic risk factors for epithelial ovarian cancer among women with a diagnosis of endometriosis. A systematic literature search was conducted in PubMed and Scopus. Studies comparing epidemiologic risk factors of epithelial ovarian cancer among women with endometriosis were included. A quality assessment was conducted using the Newcastle-Ottawa Scale. Eight of 794 articles met the inclusion criteria. A lower risk of epithelial ovarian cancer was observed in women with documented complete surgical excision of endometriotic tissue and suggested among women with unilateral oophorectomy. The use of oral contraceptives (≥10 years) may be associated with a lower risk of epithelial ovarian cancer among women with endometriosis, whereas older age at endometriosis diagnosis (≥45 years, pre- or postmenopausal), nulliparity, hyperestrogenism (endogenous or exogenous), premenopausal status at endometriosis diagnosis, solid compartments as well as larger size of endometrioma (≥9 cm in diameter at endometriosis diagnosis) were all associated with an increased risk of ovarian cancer. A subgroup of women with endometriosis characterized by endometriosis observed through surgery or imaging after the age of 45 years, nulliparity, postmenopausal status at endometriosis diagnosis, larger size of endometrioma (>9 cm) at endometriosis diagnosis, hyperestrogenism (endogenous or exogenous) and/or cysts with solid compartments may have an elevated risk of epithelial ovarian cancer. However, due to the limited number and size of studies in this area we cannot draw definitive conclusions. Further research into a risk factor profile among women with endometriosis is needed before clear recommendations can be made. © 2016 Nordic Federation of Societies of Obstetrics and Gynecology.

  4. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells.

    PubMed

    Safaei, Roohangiz; Larson, Barrett J; Cheng, Timothy C; Gibson, Michael A; Otani, Shinji; Naerdemann, Wiltrud; Howell, Stephen B

    2005-10-01

    Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma cells was compared with that in CDDP-resistant 2008/C13*5.25 subline using deconvoluting imaging and specific dyes and antibodies. The lysosomal compartment in CDDP-resistant cells was reduced to just 40% of that in the parental CDDP-sensitive cells (P<0.002). This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined by both microscopy and Western blot analysis. The CDDP-resistant cells released more protein as exosomes and Western blot analysis revealed that these exosomes contained substantially more LAMP1 than those released by the CDDP-sensitive cells. Following loading of the whole cell with CDDP, the exosomes released from 2008/C13*5.25 cells contained 2.6-fold more platinum than those released from sensitive cells. Enhanced exosomal export was accompanied by higher exosomal levels of the putative CDDP export transporters MRP2, ATP7A, and ATP7B. Expression profiling identified significant increases in the expression of several genes whose products function in membrane fusion and vesicle trafficking. This study shows that the lysosomal compartment of human ovarian carcinoma cells selected for stable resistance to CDDP is markedly reduced in size, and that these cells abnormally sort some lysosomal proteins and the putative CDDP transporters into an exosomal pathway that also exports CDDP.

  5. Chicken Pleiotrophin: Regulation of Tissue Specific Expression by Estrogen in the Oviduct and Distinct Expression Pattern in the Ovarian Carcinomas

    PubMed Central

    Lim, Whasun; Kim, Jinyoung; Bazer, Fuller W.; Han, Jae Yong; Song, Gwonhwa

    2012-01-01

    Pleiotrophin (PTN) is a developmentally-regulated growth factor which is widely distributed in various tissues and also detected in many kinds of carcinomas. However, little is known about the PTN gene in chickens. In the present study, we found chicken PTN to be highly conserved with respect to mammalian PTN genes (91–92.6%) and its mRNA was most abundant in brain, heart and oviduct. This study focused on the PTN gene in the oviduct where it was detected in the glandular (GE) and luminal (LE) epithelial cells. Treatment of young chicks with diethylstilbesterol induced PTN mRNA and protein in GE and LE, but not in other cell types of the oviduct. Further, several microRNAs, specifically miR-499 and miR-1709 were discovered to influence PTN expression via its 3′-UTR which suggests that post-transcriptional regulation influences PTN expression in chickens. We also compared expression patterns and CpG methylation status of the PTN gene in normal and cancerous ovaries from chickens. Our results indicated that PTN is most abundant in the GE of adenocarcinoma of cancerous, but not normal ovaries of hens. Bisulfite sequencing revealed that 30- and 40% of −1311 and −1339 CpG sites are demethylated in ovarian cancer cells, respectively. Collectively, these results indicate that chicken PTN is a novel estrogen-induced gene expressed mainly in the oviductal epithelia implicating PTN regulation of oviduct development and egg formation, and also suggest that PTN is a biomarker for epithelial ovarian carcinoma that could be used for diagnosis and monitoring effects of therapies for the disease. PMID:22496782

  6. Cross-reactivity between Candida albicans and human ovarian carcinoma as revealed by monoclonal antibodies PA10F and C6.

    PubMed Central

    Schneider, J.; Moragues, D.; Martínez, N.; Romero, H.; Jimenez, E.; Pontón, J.

    1998-01-01

    Summary Antibodies against Candida albicans antigenic determinants have been reported to cross-react with human tumour cells. We have found that two monoclonal antibodies, C6 and PA1OF, developed at our laboratory against C. albicans antigenic determinants, cross-react with human ovarian cancer on Western blots and immunohistochemistry. We have subsequently used one of them, PA10OF, to test by means of immunohistochemistry a series of 37 human ovarian carcinomas. Out of 37 tumours, 25 (67.6%) expressed the antigen recognized by PA1OF. The reactivity, however, was concentrated on the subgroup of particularly aggressive, invasive carcinomas in advanced stages of the disease (19 out of 24 positive), whereas the antigen was expressed significantly less (P=0.0007) in the subgroup of much less aggressive stage I tumours of low malignant potential, also called borderline carcinomas (2 out of 13 positive). This cross-reactivity between C. albicans and ovarian carcinoma seems to be attributable to a common antigenic determinant related to tumour aggressiveness. Images Figure 1 Figure 2 Figure 3 PMID:9528850

  7. Cross-reactivity between Candida albicans and human ovarian carcinoma as revealed by monoclonal antibodies PA10F and C6.

    PubMed

    Schneider, J; Moragues, D; Martínez, N; Romero, H; Jimenez, E; Pontón, J

    1998-03-01

    Summary Antibodies against Candida albicans antigenic determinants have been reported to cross-react with human tumour cells. We have found that two monoclonal antibodies, C6 and PA1OF, developed at our laboratory against C. albicans antigenic determinants, cross-react with human ovarian cancer on Western blots and immunohistochemistry. We have subsequently used one of them, PA10OF, to test by means of immunohistochemistry a series of 37 human ovarian carcinomas. Out of 37 tumours, 25 (67.6%) expressed the antigen recognized by PA1OF. The reactivity, however, was concentrated on the subgroup of particularly aggressive, invasive carcinomas in advanced stages of the disease (19 out of 24 positive), whereas the antigen was expressed significantly less (P=0.0007) in the subgroup of much less aggressive stage I tumours of low malignant potential, also called borderline carcinomas (2 out of 13 positive). This cross-reactivity between C. albicans and ovarian carcinoma seems to be attributable to a common antigenic determinant related to tumour aggressiveness.

  8. High expression of HO-1 predicts poor prognosis of ovarian cancer patients and promotes proliferation and aggressiveness of ovarian cancer cells.

    PubMed

    Zhao, Z; Xu, Y; Lu, J; Xue, J; Liu, P

    2017-08-14

    HO-1 has been proved to be associated with tumor aggressivity and poor prognosis in various cancers. Our study provides the first study to demonstrate the relationship of HO-1 expression and clinical characteristics in ovarian cancer patients. Immunohistochemistry and western blotting were used to examine the expression of HO-1 in tissue species and fresh tissues. CCK-8 was used to investigate cell viability. Transwell chamber was performed to estimate migration and invasion capacities in A2780 and Skov-3 cells. Immunohistochemistry and western blotting showed that the expression of HO-1 was higher in ovarian cancer tissues than normal ovarian tissues. High expression of HO-1 was significantly associated with serous ovarian cancer, high FIGO stage, lymph node metastasis, and non-optimal debulking. Patients with high expression of HO-1 exhibited an unfavorable prognosis. In vitro inducing the expression of HO-1 promoted the proliferation and metastasis of A2780 and Skov-3 cells, with the increased expressions of mesenchymal marker (Vimentin), epithelial-mesenchymal transition-associated transcript factor (Zeb-1), anti-apoptotic protein (Bcl-2), and the decreased expressions of epithelial marker (Keratin) and pro-apoptotic protein (Bax). Meanwhile, after incubating A2780 and Skov-3 together with HO-1 inhibitor, above results could be reversed. HO-1 might be a potential marker for prediction of ovarian cancer prognosis and a target for ovarian cancer treatment.

  9. Multidrug resistance-associated biomarkers PGP, GST-pi, Topo-II and LRP as prognostic factors in primary ovarian carcinoma.

    PubMed

    Lu, D; Shi, H-C; Wang, Z-X; Gu, X-W; Zeng, Y J

    2011-01-01

    This study aims to investigate the expression of P-glycoprotein (PGP), glutathione S-transferase pi (GST-pi), DNA topoisomerase II (Topo-II) and lung resistance-related protein (LRP) in ovarian carcinoma, thus providing better chemotherapy choice and post-operative prognosis for ovarian carcinoma patients. A total of 80 primary ovarian carcinoma, 16 benign ovarian epithelial neoplasm, and 12 normal ovarian tissue samples were collected. Immunohistochemistry was used to detect the expression of PGP, GST-pi, Topo-II and LRP, and the results were analysed by correlation with clinicopathological parameters. Positive expression rates of PGP, GST-pi, Topo-II and LRP in patients with ovarian carcinoma (57.5%, 58.8%, 76.3% and 73.8%, respectively) were all higher than those found in normal and benign tissue (P<0.05). In clinical stages I/II vs. III/IV, the expression rates of PGP, GST-pi, Topo-II and LRP were 40.7% vs. 66% (P<0.05), 40.7% vs. 67.9% (P<0.05), 66.7% vs. 81.1% (P>0.05) and 55.6% vs. 83.0% (P<0.05), respectively. Carcinoma differentiation ranged from well to poor, and expression levels of each marker were as follows: PGP, 57.9%, 62.1% and 53.1% (P>0.05); GST-pi, 36.8%, 55.2% and 75.0% (P<0.05); Topo-II, 52.6%, 79.3% and 87.5% (P<0.05); and LRP, 84.2%, 69.0% and 71.9% (P>0.05). Ovarian carcinoma patients with PGP-, GST-pi-, Topo-II- and LRP-positive expression had a shorter median survival time than those who were negative for these markers (PGP: 36 months vs. 48 months [P=0.0017]; GST-pi: 36 months vs. 41 months [P=0.0103]; Topo-II: 37 months vs. 39 months [P=0.3811]; LRP: 37 months vs. 55 months [P=0.002]). COX regression analysis demonstrated that the clinical stage of the tumour, and the expression of PGP, GST-pi or LRP, may influence patient survival time after surgery. The relative death risk for patients with clinical stage III/IV tumours increased 9.46-fold compared to those with stage I/II tumours. The relative death risk in the PGP-, GST-pi- and LRP

  10. Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas.

    PubMed

    Anglesio, Michael S; Kommoss, Stefan; Tolcher, Mary C; Clarke, Blaise; Galletta, Laura; Porter, Henry; Damaraju, Sambasivarao; Fereday, Sian; Winterhoff, Boris J; Kalloger, Steve E; Senz, Janine; Yang, Winnie; Steed, Helen; Allo, Ghassan; Ferguson, Sarah; Shaw, Patricia; Teoman, Attila; Garcia, Joaquin J; Schoolmeester, John K; Bakkum-Gamez, Jamie; Tinker, Anna V; Bowtell, David D; Huntsman, David G; Gilks, C Blake; McAlpine, Jessica N

    2013-01-01

    Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases

  11. ESRRA-C11orf20 Is a Recurrent Gene Fusion in Serous Ovarian Carcinoma

    PubMed Central

    Green, Ann E.; Nielsen, Julie S.; Nelson, Brad H.; Drescher, Charles W.; Brown, Patrick O.

    2011-01-01

    Every year, ovarian cancer kills approximately 14,000 women in the United States and more than 140,000 women worldwide. Most of these deaths are caused by tumors of the serous histological type, which is rarely diagnosed before it has disseminated. By deep paired-end sequencing of mRNA from serous ovarian cancers, followed by deep sequencing of the corresponding genomic region, we identified a recurrent fusion transcript. The fusion transcript joins the 5′ exons of ESRRA, encoding a ligand-independent member of the nuclear-hormone receptor superfamily, to the 3′ exons of C11orf20, a conserved but uncharacterized gene located immediately upstream of ESRRA in the reference genome. To estimate the prevalence of the fusion, we tested 67 cases of serous ovarian cancer by RT-PCR and sequencing and confirmed its presence in 10 of these. Targeted resequencing of the corresponding genomic region from two fusion-positive tumor samples identified a nearly clonal chromosomal rearrangement positioning ESRRA upstream of C11orf20 in one tumor, and evidence of local copy number variation in the ESRRA locus in the second tumor. We hypothesize that the recurrent novel fusion transcript may play a role in pathogenesis of a substantial fraction of serous ovarian cancers and could provide a molecular marker for detection of the cancer. Gene fusions involving adjacent or nearby genes can readily escape detection but may play important roles in the development and progression of cancer. PMID:21949640

  12. First In-Mouse Development and Application of a Surgically Relevant Xenograft Model of Ovarian Carcinoma

    PubMed Central

    Helland, Øystein; Popa, Mihaela; Vintermyr, Olav K.; Molven, Anders; Gjertsen, Bjørn Tore; Bjørge, Line; McCormack, Emmet

    2014-01-01

    Purpose Preclinical models of epithelial ovarian cancer have not been exploited to evaluate the clinical standard combination therapy of surgical debulking with follow-up chemotherapy. As surgery is critical to patient survival, here we establish a combined surgical/chemotherapy xenograft model of epithelial ovarian cancer and demonstrate its translational relevance. Experimental Design SKOV-3luc+ ovary cancer cells were injected topically into the ovaries of immunodeficient mice. Disease development and effect of clinical standard treatment including hysterectomy, bilateral salpingoophorectomy and removal of metastasis with follow up chemotherapy (carboplatin 12 mg/kg + paclitaxel 15 mg/kg) was evaluated by clinical parameters. Tumor burden was quantified by bioluminescence imaging (BLI). Results The xenograft ovarian tumors developed were poorly differentiated and multicystic and the disease disseminated into the peritoneal cavity. When compared to the controls with a mean survival time of 4.9 weeks, mice treated with surgery and chemotherapy, surgery or chemotherapy demonstrated significantly improved mean survival of 16.1 weeks (p = 0.0008), 12.7 weeks (p = 0.0008), or 10.4 weeks (p = 0.008), respectively. Conclusion Combined surgical intervention and adjuvant chemotherapy was demonstrated for the first time in an orthotopic xenograft model of ovarian cancer. Similar to observation in human studies the combined approach resulted in the longest medial survival time, advocating application of this strategy in future preclinical therapeutic development for this disease. PMID:24594904

  13. Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer

    NASA Astrophysics Data System (ADS)

    Gao, Xiang; Wang, Bilan; Wei, Xiawei; Men, Ke; Zheng, Fengjin; Zhou, Yingfeng; Zheng, Yu; Gou, Maling; Huang, Meijuan; Guo, Gang; Huang, Ning; Qian, Zhiyong; Wei, Yuquan

    2012-10-01

    Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy.

  14. HER2 Status in Ovarian Carcinomas: A Multicenter GINECO Study of 320 Patients

    PubMed Central

    Tuefferd, Marianne; Couturier, Jérôme; Penault-Llorca, Frédérique; Vincent-Salomon, Anne; Broët, Philippe; Guastalla, Jean-Paul; Allouache, Djelila; Combe, Martin; Weber, Béatrice; Pujade-Lauraine, Eric; Camilleri-Broët, Sophie

    2007-01-01

    Background Despite a typically good response to first-line combination chemotherapy, the prognosis for patients with advanced ovarian cancer remains poor because of acquired chemoresistance. The use of targeted therapies such as trastuzumab may potentially improve outcomes for patients with ovarian cancer. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature. In this study, HER2 gene status was evaluated in a large, multicentric series of 320 patients with advanced ovarian cancer, including 243 patients enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin-based chemotherapy. Methodology/Principal Findings The HER2 status of primary tumors and metastases was evaluated by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis of paraffin-embedded tissue on conventional slides. The prognostic impact of HER2 expression was analyzed. HER2 gene was overexpressed and amplified in 6.6% of analyzed tumors. Despite frequent intratumoral heterogeneity, no statistically significant difference was detected between primary tumors and corresponding metastases. Conclusions/Significance Our results show that the decision algorithm usually used in breast cancer (IHC as a screening test, with equivocal results confirmed by FISH) is appropriate in ovarian cancer. In contrast to previous series, HER2-positive status did not influence outcome in the present study, possibly due to the fact that patients in our study received paclitaxel/carboplatin-based chemotherapy. This raises the question of whether HER2 status and paclitaxel sensitively are linked. PMID:17987122

  15. Platelet adhesion and degranulation induce pro-survival and pro-angiogenic signalling in ovarian cancer cells.

    PubMed

    Egan, Karl; Crowley, Darragh; Smyth, Paul; O'Toole, Sharon; Spillane, Cathy; Martin, Cara; Gallagher, Michael; Canney, Aoife; Norris, Lucy; Conlon, Niamh; McEvoy, Lynda; Ffrench, Brendan; Stordal, Britta; Keegan, Helen; Finn, Stephen; McEneaney, Victoria; Laios, Alex; Ducrée, Jens; Dunne, Eimear; Smith, Leila; Berndt, Michael; Sheils, Orla; Kenny, Dermot; O'Leary, John

    2011-01-01

    Thrombosis is common in ovarian cancer. However, the interaction of platelets with ovarian cancer cells has not been critically examined. To address this, we investigated platelet interactions in a range of ovarian cancer cell lines with different metastatic potentials [HIO-80, 59M, SK-OV-3, A2780, A2780cis]. Platelets adhered to ovarian cancer cells with the most significant adhesion to the 59M cell line. Ovarian cancer cells induced platelet activation [P-selectin expression] in a dose dependent manner, with the most significant activation seen in response to the 59M cell line. The platelet antagonists [cangrelor, MRS2179, and apyrase] inhibited 59M cell induced activation suggesting a P2Y12 and P2Y1 receptor mediated mechanism of platelet activation dependent on the release of ADP by 59M cells. A2780 and 59M cells potentiated PAR-1, PAR-4, and TxA2 receptor mediated platelet activation, but had no effect on ADP, epinephrine, or collagen induced activation. Analysis of gene expression changes in ovarian cancer cells following treatment with washed platelets or platelet releasate showed a subtle but valid upregulation of anti-apoptotic, anti-autophagy pro-angiogenic, pro-cell cycle and metabolic genes. Thus, ovarian cancer cells with different metastatic potential adhere and activate platelets differentially while both platelets and platelet releasate mediate pro-survival and pro-angiogenic signals in ovarian cancer cells.

  16. Paclitaxel, Polyglutamate Paclitaxel, or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Peritoneal Cancer, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-05-03

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  17. Mitochondrial comparative proteomics of human ovarian cancer cells and their platinum-resistant sublines.

    PubMed

    Dai, Zhiqin; Yin, Jie; He, Haojie; Li, Wenrui; Hou, Chunmei; Qian, Xiaohong; Mao, Ning; Pan, Lingya

    2010-11-01

    Resistance to platinum-based chemotherapy is the major obstacle to successful treatment of ovarian cancer. It is evident that mitochondrial defects and the dysfunctions of oxidative phosphorylation and energy production in ovarian cancer cells were directly related to their resistance to platinum drugs. Using 2-D DIGE, we compared mitochondrial proteins from two platinum-sensitive human ovarian cancer cell lines (SKOV3 and A2780) with that of four platinum-resistant sublines (SKOV3/CDDP, SKOV3/CBP, A2780/CDDP, and A2780/CBP). Among the 236 differentially expressed spots, five mitochondrial proteins (ATP-α, PRDX3, PHB, ETF, and ALDH) that participate in the electron transport respiratory chain were identified through mass spectrometry. All of them are downregulated in one or two of the platinum-resistant cell lines. Three proteins (ATP-α, PRDX3, and PHB) were validated by using western blot and immunohistochemistry. There is a significant decrease of PHB in tumor tissues from ovarian cancer patients who were resistant to platinum-based chemotherapies. This is the first direct mitochondrial proteomic comparison between platinum-sensitive and resistant ovarian cancer cells. These studies demonstrated that 2-D DIGE-based proteomic analysis could be a powerful tool to investigate limited mitochondrial proteins, and the association of PHB expression with platinum resistance indicates that mitochondria defects may contribute to platinum resistance in ovarian cancer cells.

  18. Preclinical evaluation on the tumor suppression efficiency and combination drug effects of fermented wheat germ extract in human ovarian carcinoma cells.

    PubMed

    Wang, Chia-Woei; Wang, Chien-Kai; Chang, Yu-Jia; Choong, Chen-Yen; Lin, Chi-Shian; Tai, Cheng-Jeng; Tai, Chen-Jei

    2015-01-01

    Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 μg/mL and 246.11 μg/mL after 48 h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate-ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES-2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients.

  19. Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

    DTIC Science & Technology

    2005-08-01

    membralin molecules were confined to high-grade serous carcinomas. This project, designed to test our proposed model of diverse pathways in the pathogenesis...carcinoma are characterized by distinctive molecular genetic alterations and specific gene expression. This project, designed to test our proposed...Z, Chan DW, Kurman RJ, Shih IM. Assessment of plasma DNA levels, allelic imbalance and CA 125 as diagnostic tests for cancer. J Natl Can Inst, 94

  20. Use of clozapine alongside chemotherapy in a treatment-resistant bipolar disorder patient with ovarian carcinoma: A case report and brief review

    PubMed Central

    Pakhre, Ashish; Krishnan, Aarya; Pattanayak, Raman Deep; Khandelwal, Sudhir K.

    2016-01-01

    Regular monitoring of blood counts ensures the safety of clozapine use; however, certain clinical situations may pose a dilemma for management such as use of clozapine in the presence of myelosuppressive chemotherapy. Further, there is very limited literature to guide such decisions. We report a case of a clozapine-stabilized, treatment-resistant bipolar disorder patient with ovarian carcinoma requiring chemotherapy. The clinical challenges are discussed in light of a brief review of the available reports. PMID:28197007

  1. The Primary Effect on the Proteome of ARID1A-mutated Ovarian Clear Cell Carcinoma is Downregulation of the Mevalonate Pathway at the Post-transcriptional Level*

    PubMed Central

    Goldman, Aaron R.; Bitler, Benjamin G.; Schug, Zachary; Conejo-Garcia, Jose R.; Zhang, Rugang; Speicher, David W.

    2016-01-01

    Inactivating mutations in ARID1A, which encodes a subunit of the SWI/SNF chromatin-remodeling complex, are found in over half of ovarian clear cell carcinoma cases and more broadly across most types of cancers. To identify ARID1A-dependent changes in intracellular signaling pathways, we performed proteome analyses of isogenic ovarian clear cell carcinoma cell lines with or without ARID1A expression. Knockout of ARID1A in an ovarian clear cell carcinoma cell line with wild-type ARID1A, OVCA429, primarily resulted in downregulation of the mevalonate pathway, an important metabolic pathway involved in isoprenoid synthesis, cholesterol synthesis, and other downstream pathways. In a complementary experiment, expression of wild-type ARID1A in an ovarian clear cell carcinoma cell line containing mutated ARID1A, OVISE, affected the mevalonate pathway in a reciprocal manner. A striking aspect of these analyses was that, although only 5% of the detected proteome showed significant abundance changes, most proteins in the mevalonate pathway were coordinately affected by ARID1A status. There were generally corresponding changes when comparing the proteomics data to our previously published microarray data for ectopic expression of ARID1A in the OVISE cell line. However, ARID1A-dependent changes were not detected for genes within the mevalonate pathway. This discrepancy suggests that the mevalonate pathway is not regulated directly by ARID1A-mediated transcription and may be regulated post-transcriptionally. We conclude that ARID1A status indirectly influences the mevalonate pathway and probably influences other processes including glycogen metabolism and 14-3-3-mediated signaling. Further, our findings demonstrate that changes in mRNA levels are sometimes poor indicators of signaling pathways affected by gene manipulations in cancer cells. PMID:27654507

  2. The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma.

    PubMed

    Chang, Kuang-Leei; Lee, Ming-Yung; Chao, Wan-Ru; Han, Chih-Ping

    2016-12-28

    Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutant-enriched PCR Kits (FemtoPath®), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I).

  3. Synthetic paclitaxel-octreotide conjugate reversing the resistance of A2780/Taxol to paclitaxel in xenografted tumor in nude mice

    PubMed Central

    Chen, Xi; Zhang, Xiao-Yu; Shen, Yang; Fan, Li-Li; Ren, Mu-Lan; Wu, Yong-Ping

    2016-01-01

    Peptide hormone-based targeted therapy to tumors has been studied extensively. Our previous study shows that somatostatin receptor expresses high level on drug-resistant human ovarian cancer. The paclitaxel-octreotide conjugate (POC) exhibits enhanced growth inhibition, as well as reduced toxicity, in paclitaxel-resistant human ovarian cancer cells. The aim of this study was to investigate the effect of targeted cytotoxicity and potential reversal mechanism of resistance in paclitaxel-resistant human ovarian cancer cells xenografted into nude mice. The SSTR2 shows higher expression levels in tumor tissue. Moreover, fluorescein-labeled POC displays favorable targeting in tumor cells. POC presents the perfect efficacy in inhibiting tumor growth and exerts lower or no toxic effects on normal tissues. Real-time PCR and Western Blotting has demonstrated that the mRNA and protein expressions of SSTR2 in POC group were significantly higher, while MDR1, α-tubulin, βIII-tubulin, VEGF and MMP-9 were significantly lower than in the other treatment groups and controls. Combined with the previous study in vitro, this study evaluates an effective approach on the treatment of paclitaxel-resistant ovarian cancer which expresses somatostatin receptor SSTR. Our investigation has also revealed the possible molecular mechanism of POC in treating the ovarian cancer, and therefore, provided a theoretical basis for the clinical application of this newly-invented compound. PMID:27825139

  4. Synthetic paclitaxel-octreotide conjugate reversing the resistance of A2780/Taxol to paclitaxel in xenografted tumor in nude mice.

    PubMed

    Chen, Xi; Zhang, Xiao-Yu; Shen, Yang; Fan, Li-Li; Ren, Mu-Lan; Wu, Yong-Ping

    2016-12-13

    Peptide hormone-based targeted therapy to tumors has been studied extensively. Our previous study shows that somatostatin receptor expresses high level on drug-resistant human ovarian cancer. The paclitaxel-octreotide conjugate (POC) exhibits enhanced growth inhibition, as well as reduced toxicity, in paclitaxel-resistant human ovarian cancer cells. The aim of this study was to investigate the effect of targeted cytotoxicity and potential reversal mechanism of resistance in paclitaxel-resistant human ovarian cancer cells xenografted into nude mice. The SSTR2 shows higher expression levels in tumor tissue. Moreover, fluorescein-labeled POC displays favorable targeting in tumor cells. POC presents the perfect efficacy in inhibiting tumor growth and exerts lower or no toxic effects on normal tissues. Real-time PCR and Western Blotting has demonstrated that the mRNA and protein expressions of SSTR2 in POC group were significantly higher, while MDR1, α-tubulin, βIII-tubulin, VEGF and MMP-9 were significantly lower than in the other treatment groups and controls. Combined with the previous study in vitro, this study evaluates an effective approach on the treatment of paclitaxel-resistant ovarian cancer which expresses somatostatin receptor SSTR. Our investigation has also revealed the possible molecular mechanism of POC in treating the ovarian cancer, and therefore, provided a theoretical basis for the clinical application of this newly-invented compound.

  5. Prevention of Ovarian High-Grade Serous Carcinoma by Elucidating Its Early Changes

    DTIC Science & Technology

    2014-10-01

    regulations are in place, coordinate intellectual and material property, organize regular meetings of the investigators including the Annual Ovarian...were propagated on collagen IV coated plates in MCDB105/M199 media supplemented with BPE, EGF, insulin and hydrocortisone. Cells were immortalized...undergoing surgery for HGSC. FTE Cells were propagated on collagen IV coated plates in MCDB105/M199 media supplemented with BPE, EGF, insulin and

  6. Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

    DTIC Science & Technology

    2006-08-01

    has used virus extracts to increase whole-cell vaccine immuno- genicity, based on the observation that viruses can be highly inflammatory. This led to...molecular targets for future development of cancer targeted therapy . 3 lesions and normal tissues that could serve as an important research tool for...potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations. Cancer Res 65:1994-2000, 2005. K concepts and conundrums

  7. Prevention of Ovarian High Grade Serous Carcinoma by Elucidating Its Early Changes

    DTIC Science & Technology

    2015-10-01

    associated precursor lesions are modifiable by oral contraceptives (OCPs) or anti- inflammatory agents as OCPs in particular are known to prevent ovarian...DNA damage levels after exposure at different time points. Task 3. Determine whether oral contraceptives (OCPs) and NSAIDs reduce the...cancer. In addition, Project 5 will determine if these biomarkers and associated precursor lesions are modifiable by oral contraceptives (OCPs) or anti

  8. Amplification of the bromodomain-containing protein 4 gene in ovarian high-grade serous carcinoma is associated with worse prognosis and survival

    PubMed Central

    UCAR, DUYGU; LIN, DOUGLAS I.

    2015-01-01

    High-grade serous carcinoma (HGSC) of the ovary is an aggressive and devastating neoplasm and the identification of novel therapeutic targets may result in a significant decrease in patient morbidity and mortality. Over the last few years, chromatin regulators have become attractive targets for cancer therapy. More specifically, bromodomain-containing protein 4 (BRD4), a protein that is associated with acetylated chromatin and transcriptional activation, has been shown to selectively regulate the transcription of key oncogenic drivers, such as CMYC, in several tumor types. The Cancer Genome Atlas (TCGA) Project has molecularly characterized the genome of ovarian serous carcinomas, which enabled us to study the association of genomic alterations of BRD4 with patient survival and clinicopathological characteristics. Our analysis using clinical and genomic data from the TCGA ovarian carcinoma samples revealed that somatic amplification of BRD4 (observed in 12% of the cases) was correlated with increased BRD4 mRNA levels and is significantly associated with worse overall and progression-free survival compared to wild-type cases. These findings support the hypothesis that future studies and trials investigating newly developed BRD4 inhibitors are required in a subset of patients with ovarian HGSC. PMID:26807235

  9. An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

    PubMed Central

    Baratta, Maria Giuseppina; Schinzel, Anna C.; Zwang, Yaara; Bandopadhayay, Pratiti; Bowman-Colin, Christian; Kutt, Jennifer; Curtis, Jennifer; Piao, Huiying; Wong, Laura C.; Kung, Andrew L.; Beroukhim, Rameen; Bradner, James E.; Drapkin, Ronny; Hahn, William C.; Liu, Joyce F.; Livingston, David M.

    2015-01-01

    High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs. PMID:25535366

  10. An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma.

    PubMed

    Baratta, Maria Giuseppina; Schinzel, Anna C; Zwang, Yaara; Bandopadhayay, Pratiti; Bowman-Colin, Christian; Kutt, Jennifer; Curtis, Jennifer; Piao, Huiying; Wong, Laura C; Kung, Andrew L; Beroukhim, Rameen; Bradner, James E; Drapkin, Ronny; Hahn, William C; Liu, Joyce F; Livingston, David M

    2015-01-06

    High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs.

  11. Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells.

    PubMed

    Do, Thuy-Vy; Hirst, Jeff; Hyter, Stephen; Roby, Katherine F; Godwin, Andrew K

    2017-08-01

    Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells. We discovered that AURKA modulated the expression and activity of PARP, a crucial mediator of DNA repair that is a target of therapeutic interest for the treatment of ovarian and other cancers. Further, specific inhibition of AURKA activity with the small molecule inhibitor, alisertib, stimulated the non-homologous end-joining (NHEJ) repair pathway by elevating DNA-PKcs activity, a catalytic subunit required for double-strand break (DSB) repair, as well as decreased the expression of PARP and BRCA1/2, which are required for high-fidelity homologous recombination-based DNA repair. Further, AURKA inhibition stimulates error-prone NHEJ repair of DNA double-strand breaks with incompatible ends. Consistent with in vitro findings, alisertib treatment increased phosphorylated DNA-PKcs(pDNA-PKcs(T2609)) and decreased PARP levels in vivo. Collectively, these results reveal new non-mitotic functions for AURKA in the regulation of DNA repair, which may inform of new therapeutic targets and strategies for treating ovarian cancer.

  12. Epithelial-mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: prognostic value and prospective role in ovarian cancer therapeutics.

    PubMed

    Koutsaki, Maria; Spandidos, Demetrios A; Zaravinos, Apostolos

    2014-09-01

    MicroRNAs (miRNAs) are a family of short ribonucleic acids found to play a pivotal role in cancer pathogenesis. MiRNAs are crucial in cellular differentiation, growth, stress response, cell death and other fundamental cellular processes, and their involvement in ovarian cancer has been recently shown. They can repress the expression of important cancer-related genes and they can also function both as oncogenes and tumour suppressor genes. During epithelial-mesenchymal transition (EMT), epithelial cells lose their cell polarity and cell-cell adhesion and gain migratory and invasive properties. In the ovarian surface epithelium, EMT is considered the key regulator of the post-ovulatory repair process and it can be triggered by a range of environmental stimuli. The aberrant expression of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) in ovarian carcinoma and its involvement in ovarian cancer initiation and progression has been well-demonstrated. The miR-200 family members seem to be strongly associated with a pathologic EMT and to have a metastasis suppressive role. MiRNA signatures can accurately distinguish ovarian cancer from the normal ovary and can be used as diagnostic tools to predict the clinical response to chemotherapy. Recent evidence suggests a growing list of new miRNAs (miR-187, miR-34a, miR-506, miRNA-138, miR-30c, miR-30d, miR-30e-3p, miR-370 and miR-106a, among others) that are also implicated in ovarian carcinoma-associated EMT, either enhancing or suppressing it. MiRNA-based gene therapy provides a prospective anti-tumour approach for integrated cancer therapy. The aim of nanotechnology-based delivery approach for miRNA therapy is to overcome challenges in miRNA delivery and to effectively encourage the reprogramming of miRNA networks in cancer cells, which may lead to a clinically translatable miRNA-based therapy to benefit ovarian cancer patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Changes in Brain Function in Patients With Stage I, Stage II, Stage III, or Stage IV Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Who Are Receiving Chemotherapy

    ClinicalTrials.gov

    2016-10-26

    Cognitive Side Effects of Cancer Therapy; Malignant Ovarian Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Choriocarcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Dysgerminoma; Ovarian Embryonal Carcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Germ Cell Tumor; Ovarian Mucinous Cystadenocarcinoma; Ovarian Polyembryoma; Ovarian Sarcoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Teratoma; Ovarian Yolk Sac Tumor; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IA Ovarian Germ Cell Tumor; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IB Ovarian Germ Cell Tumor; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IC Ovarian Germ Cell Tumor; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIC Ovarian Germ Cell Tumor; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  14. Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients.

    PubMed

    Mignogna, Chiara; Staropoli, Nicoletta; Botta, Cirino; De Marco, Carmela; Rizzuto, Antonia; Morelli, Michele; Di Cello, Annalisa; Franco, Renato; Camastra, Caterina; Presta, Ivan; Malara, Natalia; Salvino, Angela; Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Barni, Tullio; Donato, Giuseppe; Di Vito, Anna

    2016-05-21

    High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10-0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months). On these bases, a careful selection of patients who could benefit from chemotherapy is recommended to avoid unnecessary side effects and for a better disease outcome. In this retrospective study, an immunohistochemical evaluation of Aurora Kinase A (AURKA) was performed on 41 cases of HGSOC according to platinum-status. Taking into account the number and intensity of AURKA positive cells we built a predictive score able to discriminate with high accuracy platinum-sensitive patients from platinum-resistant patients (p < 0.001). Furthermore, we observed that AURKA overexpression correlates to worse overall survival (p = 0.001; HR 0.14). We here suggest AURKA as new effective tool to predict the biological behavior of HGSOC. Particularly, our results indicate that AURKA has a role both as predictor of platinum-resistance and as prognostic factor, that deserves further investigation in prospective clinical trials. Indeed, in the era of personalized medicine, AURKA could assist the clinicians in selecting the best treatment and represent, at the same time, a promising new therapeutic target in EOC treatment.

  15. The effect of NFATc1 on vascular generation and the possible underlying mechanism in epithelial ovarian carcinoma.

    PubMed

    Li, Long; Yu, Jihui; Duan, Zhaoning; Dang, Hong-Xing

    2016-04-01

    We investigated the effect of nuclear factor of activated T cells c1 (NFATc1) on the growth and vascular generation of human ovarian carcinoma SKOV3 cell-transplanted tumors in nude mice and explored the possible underlying mechanism. NFATc1 siRNA was transfected into the SKOV3 cells, which were then subjected to immunofluorescence tests and real-time reverse transcription polymerase chain reaction (RT-PCR) to determine the transfection-induced inhibition rate. The tumor volumes in the nude mice in all groups were measured to determine the in vivo antitumor effect of NFATc1 siRNA. Immunohistochemical (IHC) methods were employed to detect NFATc1 expression in tumor tissue, combined with cytokeratin (CK) staining to label the epithelial origin of the tumor tissue. CD34 and podoplanin were used as markers for labeling microvessels and microlymphatic vessels, respectively. The densities of microvessels and microlymphatic vessels in each group were calculated and statistically analyzed. RT-PCR and western blotting were performed to detect the protein and mRNA expression levels of NFATc1, the ELR+ CXC chemokine interleukin (IL)-8, fibroblast growth factor-2 (FGF-2), and platelet-derived growth factor BB (PDGF BB) in xenografted tumor tissue in all groups. NFATc1 was highly expressed in tumor tissue in the control groups. The intervention group exhibited a tumor growth inhibition rate of 57.08% and presented a lower tumor weight and volume compared with the two control groups. In the control groups, the microvessel densities were 12.00 ± 1.65 and 11.47 ± 0.32, respectively, and the microlymphatic vessel densities were 10.03 ± 0.96 and 9.95 ± 1.12; these values were significantly higher than in the intervention group. RT-PCR and western blot shows that NFATc1 siRNA could markedly suppress the expression of IL-8, FGF-2 and PDGF BB at the mRNA and the protein level. In conclusion, it was shown that NFATc1 siRNA significantly suppresses the growth and vascular generation

  16. Usefulness of human epididymis protein 4 in predicting cytoreductive surgical outcomes for advanced ovarian tubal and peritoneal carcinoma

    PubMed Central

    Tang, Zhijian; Chang, Xiaohong; Ye, Xue; Li, Yi; Cheng, Hongyan

    2015-01-01

    Objective Human epididymis protein 4 (HE4) is a promising biomarker of epithelial ovarian cancer (EOC). But its role in assessing the primary optimal debulking (OD) of EOC remains unknown. The purpose of this study is to elucidate the ability of preoperative HE4 in predicting the primary cytoreductive outcomes in advanced EOC, tubal or peritoneal carcinoma. Methods We reviewed the records of 90 patients with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at the Department of Obstetrics and Gynecology of Peking University People’s Hospital between November 2005 and October 2010. Preoperative serum HE4 and CA125 levels were detected with EIA kit. A receiver operating characteristic (ROC) curve was used to determine the most useful HE4 cut-off value. Logistic regression analysis was performed to identify significant preoperative clinical characteristics to predict optimal primary cytoreduction. Results OD was achieved in 47.7% (43/48) of patients. The median preoperative HE4 level for patients with OD vs. suboptimal debulking was 423 and 820 pmol/L, respectively (P<0.001). The areas under the ROC curve for HE4 and CA125 were 0.716 and 0.599, respectively (P=0.080). The most useful HE4 cut-off value was 473 pmol/L. Suboptimal cytoreduction was obtained in 66.7% (38/57) of cases with HE4 ≥473 pmol/L compared with only 27.3% (9/33) of cases with HE4 <473 pmol/L. At this threshold, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for diagnosing suboptimal debulking were 81%, 56%, 67%, and 73%, respectively. Logistic regression analysis showed that the patients with HE4 ≥473 pmol/L were less likely to achieve OD (odds ratio =5.044, P=0.002). Conclusions Preoperative serum HE4 may be helpful to predict whether optimal cytoreductive surgery could be obtained or whether extended cytoreduction would be needed by an interdisciplinary team. PMID:26157328

  17. Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

    PubMed

    Stiff, P J; McKenzie, R S; Alberts, D S; Sosman, J A; Dolan, J R; Rad, N; McCloskey, T

    1994-01-01

    To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone. A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro. We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma. This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

  18. Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma

    PubMed Central

    Prentice, Leah M; Klausen, Christian; Kalloger, Steve; Köbel, Martin; McKinney, Steven; Santos, Jennifer L; Kenney, Challayne; Mehl, Erika; Gilks, C Blake; Leung, Peter; Swenerton, Ken; Huntsman, David G; Aparicio, Samuel AJ

    2007-01-01

    Background Kisspeptins and their G-protein coupled receptor, GPR54 are required for GnRH release and have been associated with anti-metastatic tumour cell behaviour in model systems. The latter might suggest that their overexpression would be associated with a better prognosis in cancer. However, kisspeptin/GPR54 interactions (autocrine, paracrine, and/or endocrine) could also impact tumour behaviour in a negative manner. Here, for the first time, we associate the immunoreactivity of the kisspeptin/GPR54 ligand-receptor pair with favourable prognosis in a large cohort of ovarian carcinomas. Methods Immunohistochemical analysis for kisspeptin and GPR54 was performed on a tissue microarray (TMA) consisting of 518 early stage ovarian carcinomas, all with linked clinical outcome data. The TMA was scored using a staining intensity scale of 0 (negative), +1 (mild-moderate), and +2 (strong). Strong staining cases were considered either kisspeptin or GPR54 positive and designated as 1, while all other cases were considered negative and designated 0. All statistical analysis was conducted using two-sided tests and a p value equal to or less than 0.05 was considered significant. Results Kisspeptin and GPR54 immunoreactive cases show a favourable prognosis in univariable disease specific survival (p = 0.0023, p = 0.0092), as well as in overall survival (p = 0.0006, p = 0.0002). Furthermore, kisspeptin is an independent marker for favourable prognosis as determined by multivariable disease specific (p = 0.0046) and overall survival analysis (p = 0.0170), while GPR54 is an independent marker for overall survival only (p = 0.0303). Both kisspeptin positive and GPR54 positive cases are strongly associated with the ovarian carcinoma clear cell subtype (p < 0.0001, p < 0.0001), and GPR54 is significantly associated with favourable prognosis in overall survival within the clear cell subtype (p = 0.0102). Conclusion Kisspeptin and GPR54 immunoreactivity are significantly associated

  19. Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

    PubMed Central

    Alonezi, Sanad; Tusiimire, Jonans; Wallace, Jennifer; Dufton, Mark J.; Parkinson, John A.; Young, Louise C.; Clements, Carol J.; Park, Jin-Kyu; Jeon, Jong-Woon; Ferro, Valerie A.; Watson, David G.

    2017-01-01

    Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg/mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed