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Sample records for a2780-cp70 human ovarian

  1. Theaflavin-3, 3′-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells

    PubMed Central

    TU, YOUYING; KIM, EUNHYE; GAO, YING; RANKIN, GARY O.; LI, BO; CHEN, YI CHARLIE

    2016-01-01

    Ovarian cancer is the most lethal gynecological cancer among women worldwide. Adverse side effects and acquired resistance to conventional platinum based chemotherapy are major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs that target cancer-specific defects. In this study, theaflavin-3, 3′-digallate (TF3), the major theaflavin monomer in black tea, exhibited a potent growth inhibitory effect on the cisplatin-resistant ovarian cancer A2780/CP70 cells (IC50, 23.81 μM), and was less cytotoxic to a normal ovarian IOSE-364 cells (IC50, 59.58 μM) than to the cancer cells. Flow cytometry analysis indicated that TF3 induced preferential apoptosis and G2 cell cycle arrest in A2780/CP70 cells with respect to IOSE-364 cells. TF3 induced apoptosis through both the intrinsic and extrinsic apoptotic pathways, and caused G2 cell cycle arrest via cyclin B1 in A2780/CP70 cells. The p53 protein played an important role in TF3-induced apoptosis and G2 cell cycle arrest. TF3 might upregulate the p53 expression via the Akt/MDM2 pathway. Our findings help elucidate the mechanisms by which TF3 may contribute to the prevention and treatment of platinum-resistant ovarian cancer. PMID:27082635

  2. Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells.

    PubMed

    Luo, Haitao; Rankin, Gary O; Liu, Lingzhi; Daddysman, Matthew K; Jiang, Bing-Hua; Chen, Yi Charlie

    2009-01-01

    Ovarian cancer is 1 of the most significant malignancies in the Western world, and the antiangiogenesis strategy has been postulated for prevention and treatment of ovarian cancers. Kaempferol is a natural flavonoid present in many fruits and vegetables. The antiangiogenesis potential of kaempferol and its underlying mechanisms were investigated in two ovarian cancer cell lines, OVCAR-3 and A2780/CP70. Kaempferol mildly inhibits cell viability but significantly reduces VEGF gene expression at mRNA and protein levels in both ovarian cancer cell lines. In chorioallantoic membranes of chicken embryos, kaempferol significantly inhibits OVCAR-3-induced angiogenesis and tumor growth. HIF-1alpha, a regulator of VEGF, is downregulated by kaempferol treatment in both ovarian cancer cell lines. Kaempferol also represses AKT phosphorylation dose dependently at 5 to 20 muM concentrations. ESRRA is a HIF-independent VEGF regulator, and it is also downregulated by kaempferol in a dose-dependent manner. Overall, this study demonstrated that kaempferol is low in cytotoxicity but inhibits angiogenesis and VEGF expression in human ovarian cancer cells through both HIF-dependent (Akt/HIF) and HIF-independent (ESRRA) pathways and deserves further studies for possible application in angio prevention and treatment of ovarian cancers.

  3. Selecting bioactive phenolic compounds as potential agents to inhibit proliferation and VEGF expression in human ovarian cancer cells

    PubMed Central

    HE, ZHIPING; LI, BO; RANKIN, GARY O.; ROJANASAKUL, YON; CHEN, YI CHARLIE

    2015-01-01

    Ovarian cancer is a disease that continues to cause mortality in female individuals worldwide. Ovarian cancer is challenging to treat due to emerging resistance to chemotherapy, therefore, the identification of effective novel chemotherapeutic agents is important. Polyphenols have demonstrated potential in reducing the risk of developing numerous types of cancer, as well reducing the risk of cancer progression, due to their ability to reduce cell viability and vascular endothelial growth factor (VEGF) expression. In the present study, eight phenolic compounds were screened in two human ovarian cancer cell lines (OVCAR-3 and A2780/CP70) to determine their effect on proliferation suppression and VEGF protein secretion inhibition, in comparison to cisplatin, a conventional chemotherapeutic agent. The current study identified that 40 μM gallic acid (GA) exhibited the greatest inhibitory effect on OVCAR-3 cell viability, compared with all of the phenolic compounds investigated. Similarly to cisplatin, baicalein, GA, nobiletin, tangeretin and baicalin were all identified to exhibit significant VEGF inhibitory effects from ELISA results. Furthermore, western blot analysis indicated that GA effectively decreased the level of the VEGF-binding protein hypoxia-inducible factor-1α in the ovarian cancer cell line. Considering the results of the present study, GA appears to inhibit cell proliferation and, thus, is a potential agent for the treatment of ovarian cancer. PMID:25663929

  4. Sodium Arsenite ± Hyperthermia Sensitizes p53-Expressing Human Ovarian Cancer Cells to Cisplatin by Modulating Platinum-DNA Damage Responses

    PubMed Central

    Muenyi, Clarisse S.; Pinhas, Allan R.; Fan, Teresa W.; Brock, Guy N.; Helm, C. William; States, J. Christopher

    2012-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation. PMID:22331493

  5. CASZ1 is a novel promoter of metastasis in ovarian cancer

    PubMed Central

    Wu, Yi-Ying; Chang, Chia-Lin; Chuang, Yuan-Jhe; Wu, Jia-En; Tung, Chia-Hao; Chen, Yeong-Chang; Chen, Yuh-Ling; Hong, Tse-Ming; Hsu, Keng-Fu

    2016-01-01

    Epithelial ovarian cancer (EOC) carries the highest mortality rate of all gynecologic malignancies. This high mortality rate is attributed to the fact that most cases of ovarian cancer are detected at late stages when metastases are already present. Through microarray analysis, we previously demonstrated that castor zinc finger 1 (CASZ1) is up-regulated in EOC cells. In contrast to its role in EOC, CASZ1 functions a tumor suppressor in neuroblastoma. Human CASZ1 is predominantly expressed in 2 alternatively spliced isoforms: CASZ1a and CASZ1b. In the present study, we investigated the role of CASZ1 in ovarian cancer cell migration and invasion and assessed the value of CASZ1 expression as a prognostic indicator of metastasis in human ovarian cancer. We used a lentivirus expressing CASZ1-shRNA and a plasmid expressing CASZ1 from a CMV promoter to knockdown and overexpress CASZ1, respectively, in the MCAS, RMUG-S, TOV21G, and A2780CP70 ovarian cancer cell lines. mRNA expression levels in tumor tissues and cell lines were measured using quantitative real-time PCR, and CASZ1 protein expression in EOC and paired metastatic tumor tissues was analyzed using immunohistochemistry. We found that CASZ1 was highly expressed in EOC tissues and ovarian cancer cell lines and that CASZ1 knockdown suppressed cell migration and invasion in EOC cells. CASZ1a and CASZ1b exerted similar effects on cell migration and invasion in EOC cells. In addition, CASZ1 promoted the epithelial-mesenchymal transition in EOC cells, and CASZ1 knockdown suppressed cancer metastasis in vivo. Furthermore, CASZ1 protein levels were elevated in human metastatic ovarian tumor tissues. Together, these results indicate that CASZ1 is a novel promoter of EOC metastasis and is highly up-regulated in metastatic EOC tumors. PMID:27429842

  6. Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.

    PubMed

    He, Jun; Yu, Jing-Jie; Xu, Qing; Wang, Lin; Zheng, Jenny Z; Liu, Ling-Zhi; Jiang, Bing-Hua

    2015-01-01

    Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin-resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

  7. Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells

    PubMed Central

    Wu, Yi-Hui; Chiu, Wen-Tai; Young, Ming-Jer; Chang, Tzu-Hao; Huang, Yu-Fang; Chou, Cheng-Yang

    2015-01-01

    Solanum incanum extract (SR-T100), containing the active ingredient solamargine, can induce apoptosis via upregulation of tumor necrosis factor receptor expression and activation of the mitochondrial apoptosis pathway, and has therapeutic effects in patients with actinic keratosis. Here, we evaluate the novel molecular mechanisms underlying SR-T100-regulated stemness and chemoresistance. The concentration of SR-T100 that inhibited 50% cell viability (IC50) was lower in ovarian cancer cells than in nonmalignant cells. Furthermore, the SR-T100 IC50 in chemoresistant cells was similar to the IC50 in chemosensitive cells. Additionally, SR-T100 increased cisplatin and paclitaxel sensitivity in chemoresistant cells. SR-T100 downregulated the expression of stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), Notch1, and FoxM1, and reduced sphere formation in ovarian cancer cells. Using microarray analyses, immunoblotting, luciferase activity, and chromatin immunoprecipitation (ChIP) assays, we showed that SR-T100 suppressed the expression of c/EBPβ and COL11A1, and its promoter activity, in resistant cells, but not sensitive cells. SR-T100, paclitaxel, and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, as compared to the vehicle control, and the combination of cisplatin and SR-T100 was more effective than either treatment alone. SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment. PMID:26366215

  8. Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1α/VEGF signaling pathway in ovarian cancer cells.

    PubMed

    He, Zhiping; Chen, Allen Y; Rojanasakul, Yon; Rankin, Gary O; Chen, Yi Charlie

    2016-01-01

    Gallic acid (GA), a polyphenol, is widely found in numerous fruits and vegetables, particularly in hickory nuts. In the present study, we found that gallic acid, a natural phenolic compound isolated from fruits and vegetables, had a more potent growth inhibitory effect on two ovarian cancer cell lines, OVCAR-3 and A2780/CP70, than the effect on a normal ovarian cell line, IOSE-364. These results demonstrated that GA selectively inhibits the growth of cancer cells. Gene expression was examined by ELISA and western blot analysis, and gene pathways were examined by luciferase assay. It was found that GA inhibited VEGF secretion and suppressed in vitro angiogenesis in a concentration-dependent manner. GA downregulated AKT phosphorylation as well as HIF-1α expression but promoted PTEN expression. The luciferase assay results suggest that the PTEN/AKT/HIF-1α pathway accounts for the inhibitory effect of GA on VEGF expression and in vitro angiogenesis. These findings provide strong support for the high potential of GA in the prevention and therapy of ovarian cancer.

  9. Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1α/VEGF signaling pathway in ovarian cancer cells

    PubMed Central

    HE, ZHIPING; CHEN, ALLEN Y.; ROJANASAKUL, YON; RANKIN, GARY O.; CHEN, YI CHARLIE

    2016-01-01

    Gallic acid (GA), a polyphenol, is widely found in numerous fruits and vegetables, particularly in hickory nuts. In the present study, we found that gallic acid, a natural phenolic compound isolated from fruits and vegetables, had a more potent growth inhibitory effect on two ovarian cancer cell lines, OVCAR-3 and A2780/CP70, than the effect on a normal ovarian cell line, IOSE-364. These results demonstrated that GA selectively inhibits the growth of cancer cells. Gene expression was examined by ELISA and western blot analysis, and gene pathways were examined by luciferase assay. It was found that GA inhibited VEGF secretion and suppressed in vitro angiogenesis in a concentration-dependent manner. GA downregulated AKT phosphorylation as well as HIF-1α expression but promoted PTEN expression. The luciferase assay results suggest that the PTEN/AKT/HIF-1α pathway accounts for the inhibitory effect of GA on VEGF expression and in vitro angiogenesis. These findings provide strong support for the high potential of GA in the prevention and therapy of ovarian cancer. PMID:26530725

  10. NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines

    PubMed Central

    North, William G; Liu, Fuli; Tian, Ruiyang; Abbasi, Hamza; Akerman, Bonnie

    2015-01-01

    We have earlier demonstrated that breast cancer and small-cell lung cancer express functional NMDA receptors that can be targeted to promote cancer cell death. Human ovarian cancer tissues and human ovarian cancer cell lines (SKOV3, A2008, and A2780) have now been shown to also express NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen ovarian cancers in two arrays were screened by immunohistochemistry using polyclonal antibodies that recognize an extracellular moiety on GluN1 and on GluN2B. These specimens comprised malignant tissue with pathology diagnoses of serous papillary cystadenocarcinoma, endometrioid adenocarcinoma, and clear-cell carcinoma. Additionally, archival tissues defined as ovarian adenocarcinoma from ten patients treated at this institute were also evaluated. All of the cancerous tissues demonstrated positive staining patterns with the NMDA-receptor antibodies, while no staining was found for tumor-adjacent normal tissues or sections of normal ovarian tissue. Human ovarian adenocarcinoma cell lines (A2008, A2780, SKOV3) were demonstrated to express GluN1 by Western blotting, but displayed different levels of expression. Through immunocytochemistry utilizing GluN1 antibodies and imaging using a confocal microscope, we were able to demonstrate that GluN1 protein is expressed on the surface of these cells. In addition to these findings, GluN2B protein was demonstrated to be expressed using polyclonal antibodies against this protein. Treatment of all ovarian cell lines with antibodies against GluN1 was found to result in decreased cell viability (P<0.001), with decreases to 10%–25% that of untreated cells. Treatment of control HEK293 cells with various dilutions of GluN1 antibodies had no effect on cell viability. The GluN1 antagonist MK-801 (dizocilpine maleate) and the GluN2B antagonist ifenprodil, like antibodies, dramatically decreased the viability of A2780 ovarian tumor cells (P<0.01). Treatment of A2780 tumor xenografts with

  11. NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines.

    PubMed

    North, William G; Liu, Fuli; Tian, Ruiyang; Abbasi, Hamza; Akerman, Bonnie

    2015-01-01

    We have earlier demonstrated that breast cancer and small-cell lung cancer express functional NMDA receptors that can be targeted to promote cancer cell death. Human ovarian cancer tissues and human ovarian cancer cell lines (SKOV3, A2008, and A2780) have now been shown to also express NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen ovarian cancers in two arrays were screened by immunohistochemistry using polyclonal antibodies that recognize an extracellular moiety on GluN1 and on GluN2B. These specimens comprised malignant tissue with pathology diagnoses of serous papillary cystadenocarcinoma, endometrioid adenocarcinoma, and clear-cell carcinoma. Additionally, archival tissues defined as ovarian adenocarcinoma from ten patients treated at this institute were also evaluated. All of the cancerous tissues demonstrated positive staining patterns with the NMDA-receptor antibodies, while no staining was found for tumor-adjacent normal tissues or sections of normal ovarian tissue. Human ovarian adenocarcinoma cell lines (A2008, A2780, SKOV3) were demonstrated to express GluN1 by Western blotting, but displayed different levels of expression. Through immunocytochemistry utilizing GluN1 antibodies and imaging using a confocal microscope, we were able to demonstrate that GluN1 protein is expressed on the surface of these cells. In addition to these findings, GluN2B protein was demonstrated to be expressed using polyclonal antibodies against this protein. Treatment of all ovarian cell lines with antibodies against GluN1 was found to result in decreased cell viability (P<0.001), with decreases to 10%-25% that of untreated cells. Treatment of control HEK293 cells with various dilutions of GluN1 antibodies had no effect on cell viability. The GluN1 antagonist MK-801 (dizocilpine maleate) and the GluN2B antagonist ifenprodil, like antibodies, dramatically decreased the viability of A2780 ovarian tumor cells (P<0.01). Treatment of A2780 tumor xenografts with

  12. Successful cryopreservation of human ovarian cortex tissues using supercooling.

    PubMed

    Moriguchi, Hisashi; Zhang, Yue; Mihara, Makoto; Sato, Chifumi

    2012-01-01

    The development of new method to cryopreserve human ovarian cortex tissues without damage is needed for the improvement of quality of life (QOL) of female cancer patients. Here we show novel cryopreservation method of human ovarian cortex tissues by using supercooling (S.C.) procedure. Our method will be helpful in order to preserve fertility of female cancer patients.

  13. Second harmonic generation in human ovarian neoplasias

    NASA Astrophysics Data System (ADS)

    Lamonier, L.; Bottcher-Luiz, F.; Pietro, L.; Andrade, L. A. L. A.; de Thomaz, A. A.; Machado, C. L.; Cesar, C. L.

    2010-02-01

    Metastasis is the main cause of death in cancer patients; it requires a complex process of tumor cell dissemination, extra cellular matrix (ECM) remodeling, cell invasion and tumor-host interactions. Collagen is the major component of ECM; its fiber polymerization or degradation evolves in parallel with the evolution of the cancerous lesions. This study aimed to identify the collagen content, spatial distribution and fiber organization in biopsies of benign and malignant human ovarian tissues. Biopsies were prepared in slides without dyes and were exposed to 800nm Ti:Sapphire laser (Spectra Physics, 100 fs pulse duration, 800mW average power, 80MHz repetition rate). The obtained images were recorded at triplets, corresponding to clear field, multiphoton and second harmonic generation (SHG) mycroscopy. Data showed considerable anisotropy in malignant tissues, with regions of dense collagen arranged as individual fibers or in combination with immature segmental filaments. Radial fiber alignment or regions with minimal signal were observed in the high clinical grade tumors, suggesting degradation of original fibers or altered polymerization state of them. These findings allow us to assume that the collagen signature will be a reliable and a promising marker for diagnosis and prognosis in human ovarian cancers.

  14. An Introduction to The Royan Human Ovarian Tissue Bank.

    PubMed

    Abtahi, Naeimeh Sadat; Ebrahimi, Bita; Fathi, Rouhollah; Khodaverdi, Sepideh; Mehdizadeh Kashi, Abolfazl; Valojerdi, Mojtaba Rezazadeh

    2016-01-01

    From December 2000 until 2010, the researchers at Royan Institute conducted a wide range of investigations on ovarian tissue cryopreservation with the intent to provide fertility pres- ervation to cancer patients that were considered to be candidates for these services. In 2010, Royan Institute established the Royan Human Ovarian Tissue Bank as a subgroup of the Embryology Department. Since its inception, approximately 180 patients between the ages of 747 years have undergone consultations. Ovarian samples were cryopreserved from 47 patients (age: 7-35 years) diagnosed with cervical adenocarcinoma (n=9); breast carcinoma (n=7), Ewing's sarcoma (n=7), opposite side ovarian tumor (n=7), endometrial adenocarci- noma (n=4), malignant colon tumors (n=3), as well as Hodgkin's lymphoma, major thalas- semia and acute lymphoblastic leukemia (n=1-2 patients for each disease). Additionally, two patients requested ovarian tissue transplantation after completion of their treatments. PMID:27441061

  15. An Introduction to The Royan Human Ovarian Tissue Bank

    PubMed Central

    Abtahi, Naeimeh Sadat; Ebrahimi, Bita; Fathi, Rouhollah; Khodaverdi, Sepideh; Mehdizadeh Kashi, Abolfazl; Valojerdi, Mojtaba Rezazadeh

    2016-01-01

    From December 2000 until 2010, the researchers at Royan Institute conducted a wide range of investigations on ovarian tissue cryopreservation with the intent to provide fertility pres- ervation to cancer patients that were considered to be candidates for these services. In 2010, Royan Institute established the Royan Human Ovarian Tissue Bank as a subgroup of the Embryology Department. Since its inception, approximately 180 patients between the ages of 747 years have undergone consultations. Ovarian samples were cryopreserved from 47 patients (age: 7-35 years) diagnosed with cervical adenocarcinoma (n=9); breast carcinoma (n=7), Ewing’s sarcoma (n=7), opposite side ovarian tumor (n=7), endometrial adenocarci- noma (n=4), malignant colon tumors (n=3), as well as Hodgkin’s lymphoma, major thalas- semia and acute lymphoblastic leukemia (n=1-2 patients for each disease). Additionally, two patients requested ovarian tissue transplantation after completion of their treatments. PMID:27441061

  16. Overexpression of the β Subunit of Human Chorionic Gonadotropin Promotes the Transformation of Human Ovarian Epithelial Cells and Ovarian Tumorigenesis

    PubMed Central

    Guo, Xiaoqing; Liu, Guangzhi; Schauer, Isaiah G.; Yang, Gong; Mercado-Uribe, Imelda; Yang, Fan; Zhang, Shiwu; He, Yuanli; Liu, Jinsong

    2011-01-01

    Ovarian carcinoma is the most lethal gynecologic malignancy, however underlying molecular events remain elusive. Expression of human chorionic gonadotropin β subunit (β-hCG) is clinically significant for both trophoblastic and nontrophoblastic cancers; however, whether β-hCG facilitates ovarian epithelial cell tumorigenic potential remains uncharacterized. Immortalized nontumorigenic ovarian epithelial T29 and T80 cells stably overexpressing β-hCG were examined for alterations in cell cycle and apoptotic status by flow cytometry, expression of proteins regulating cell cycle and apoptosis by Western blot, proliferation status by MTT assay, anchorage-independent colony formation, and mouse tumor formation. Immunoreactivity for β-hCG was evaluated using mouse xenografts and on human normal ovarian, fallopian tube, endometrium, and ovarian carcinoma tissues. T29 and T80 cells overexpressing β-hCG demonstrated significantly increased proliferation, anchorage-independent colony formation, prosurvival Bcl-XL protein expression, G2-checkpoint progression, elevated cyclins E/D1 and Cdk 2/4/6, and decreased apoptosis. Collectively, these transformational alterations in phenotype facilitated increased xenograft tumorigenesis (P < 0.05). Furthermore, β-hCG immunoreactivity was elevated in malignant ovarian tumors, compared with normal epithelial expression in ovaries, fallopian tube, and endometrium (P < 0.001). Our data indicate that elevated β-hCG transforms ovarian surface epithelial cells, facilitating proliferation, cell cycle progression, and attenuated apoptosis to promote tumorigenesis. Our results further decipher the functional role and molecular mechanism of β-hCG in ovarian carcinoma. β-hCG may contribute to ovarian cancer etiology, which introduces a new therapeutic intervention target for ovarian cancer. PMID:21763678

  17. Human papillomavirus genotyping and integration in ovarian cancer Saudi patients

    PubMed Central

    2013-01-01

    Background Human papillomavirus (HPV) is associated with different malignancies but its role in the pathogenesis of ovarian cancer is controversial. This study investigated the prevalence, genotyping and physical state of HPV in ovarian cancer Saudi patients. Methods Hundred formalin fixed paraffin embedded (FFPE) ovarian carcinoma tissues and their normal adjacent tissues (NAT) were included in the study. HPV was detected by nested polymerase chain reaction (PCR) using degenerated HPVL1 consensus primer pairs MY09/MY11 and GP5+/GP6 + to amplify a broad spectrum of HPV genotypes in a single reaction. The HPV positive samples were further genotyped using DNA sequencing. The physical state of the virus was identified using Amplification of Papillomavirus Oncogene Transcripts (APOT) assay in the samples positive for HPV16 and/or HPV18. Results High percentage of HPV (42%) was observed in ovarian carcinoma compared to 8% in the NAT. The high-risk HPV types 16, 18 and 45 were highly associated with the advanced stages of tumor, while low-risk types 6 and 11 were present in NAT. In malignant tissues, HPV-16 was the most predominant genotype followed by HPV-18 and -45. The percentage of viral integration into the host genome was significantly high (61.1%) compared to 38.9% episomal in HPV positive tumors tissues. In HPV18 genotype the percentage of viral integration was 54.5% compared to 45.5% episomal. Conclusion The high risk HPV genotypes in ovarian cancer may indicate its role in ovarian carcinogenesis. The HPV vaccination is highly recommended to reduce this type of cancer. PMID:24252426

  18. Transformation of the human ovarian surface epithelium with genetically defined elements.

    PubMed

    Shan, Weiwei; Liu, Jinsong

    2013-01-01

    Success in in vitro transformation of primary cells from the human ovarian surface epithelium (OSE) has provided significant insight to the study of human ovarian cancer. Here, we describe the method used to immortalize and transform OSE by serial introduction of viral and nonviral genetic elements as well as to test the tumorigenicity of hence established cell lines in appropriate animal models. Successful transformation of OSE cells in the laboratory is of critical significance to the study of ovarian cancer. It not only allows for testing the roles of numerous potential oncogenes in initiating and promoting human ovarian cancer but provides a convenient tool to comprehensively dissect ovarian tumorigenesis in the laboratory.

  19. Ascitic fluid from human ovarian cancer patients contains growth factors necessary for intraperitoneal growth of human ovarian adenocarcinoma cells.

    PubMed Central

    Mills, G B; May, C; Hill, M; Campbell, S; Shaw, P; Marks, A

    1990-01-01

    Human ovarian cancer, the leading cause of death from gynecologic malignancy, tends to remain localized to the peritoneal cavity until late in the disease. In established disease, ascitic fluid accumulates in the peritoneal cavity. We have previously demonstrated that this ascitic fluid is a potent source of in vitro mitogenic activity including at least one unique growth factor. We now report that the human ovarian adenocarcinoma line, HEY, can be induced to grow intraperitoneally in immunodeficient nude mice in the presence (23/28 mice), but not absence (0/21 mice) of ascitic fluid from ovarian cancer patients. Ascitic fluid from patients with benign disease did not have similar effects on intraperitoneal growth of HEY cells (1/15 mice). Once tumors were established by injections of exogenous ascitic fluid, they could progress in the absence of additional injections of ascitic fluid. The mice eventually developed ascitic fluid which contained potent growth factor activity, suggesting that the tumors eventually produced autologous growth factors. This nude mouse model provides a system to study the action of ovarian cancer growth factors on tumor growth in vivo and to evaluate preclinically, therapeutic approaches designed to counteract the activity of these growth factors. PMID:2394835

  20. Gene expression in human ovarian tissue after xenografting.

    PubMed

    Van Langendonckt, A; Romeu, L; Ambroise, J; Amorim, C; Bearzatto, B; Gala, J L; Donnez, J; Dolmans, M M

    2014-06-01

    Cryobanking and transplantation of ovarian tissue is a promising approach to restore fertility in cancer patients. However, ischemic stress following avascular ovarian cortex grafting is known to induce stromal tissue fibrosis and alterations in follicular development. The aim of the study was to analyze the impact of freeze-thawing and grafting procedures on gene expression in human ovarian tissue. Frozen-thawed ovarian tissue from 14 patients was xenografted for 7 days to nude mice and one ungrafted fragment was used as a control. Immediately after recovery, grafts were processed for RNA extraction and histological analysis. Their expression profile was screened by whole-genome oligonucleotide array (n = 4) and validated by reverse-transcriptase polymerase chain analysis (n = 10). After data filtering, the Limma package was used to build a linear regression model for each gene and to compute its fold change between tissues on Days 0 and 7. After adjusting the P-value by the Sidak method, 84 of the transcripts were significantly altered after 7 days of grafting, including matrix metalloproteinase-9 and -14 and angiogenic factors such as placental growth factor and C-X-C chemokine receptor type 4 (CXCR4). Major biological processes were related to tissue remodeling, including secretory processes, cellular adhesion and response to chemical and hormonal stimuli. Angiopoietin signaling, the interleukin-8 pathway and peroxisome proliferator-activated receptor activation were shown to be differentially regulated. On Day 7, overexpression was confirmed by PCR for interleukin-8, transforming growth factor-beta 1, matrix metalloproteinase-14 and CXCR4, compared with ungrafted controls. In conclusion, new as well as known genes involved in tissue restructuring and angiogenesis were identified and found to play a key role during the first days after human ovarian tissue transplantation. This will facilitate the development of strategies to optimize grafting techniques. PMID

  1. Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination

    PubMed Central

    Ward, Harvey Rodrick Grenville

    2014-01-01

    Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and postlicensure studies. Postmarketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor compare incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence. PMID:26425627

  2. 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.

  3. Functional Expression of TWEAK and the Receptor Fn14 in Human Malignant Ovarian Tumors: Possible Implication for Ovarian Tumor Intervention

    PubMed Central

    Zhu, Jing; Ding, Chuanwei; Xu, Hai-bo; Qiu, Lihua; Di, Wen

    2013-01-01

    The aim of this current study was to investigate the expression of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in human malignant ovarian tumors, and test TWEAK’s potential role on tumor progression in cell models in-vitro. Using immunohistochemistry (IHC), we found that TWEAK and its receptor Fn14 were expressed in human malignant ovarian tumors, but not in normal ovarian tissues or in borderline/benign epithelial ovarian tumors. High levels of TWEAK expression was detected in the majority of malignant tumors (36 out of 41, 87.80%). Similarly, 35 out of 41 (85.37%) malignant ovarian tumors were Fn14 positive. In these malignant ovarian tumors, however, TWEAK/Fn14 expression was not corrected with patients’ clinical subtype/stages or pathological features. In vitro, we demonstrated that TWEAK only inhibited ovarian cancer HO-8910PM cell proliferation in combination with tumor necrosis factor-α (TNF-α), whereas either TWEAK or TNF-α alone didn’t affect HO-8910PM cell growth. TWEAK promoted TNF-α production in cultured THP-1 macrophages. Meanwhile, conditioned media from TWEAK-activated macrophages inhibited cultured HO-8910PM cell proliferation and invasion. Further, TWEAK increased monocyte chemoattractant protein-1 (MCP-1) production in cultured HO-8910PM cells to possibly recruit macrophages. Our results suggest that TWEAK/Fn14, by activating macrophages, could be ovarian tumor suppressors. The unique expression of TWEAK/Fn14 in malignant tumors indicates that it might be detected as a malignant ovarian tumor marker. PMID:23469193

  4. Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/ JNK activation.

    PubMed

    Xu, Limei; Zhang, Xiyu; Li, Yinuo; Lu, Shuhua; Lu, Shan; Li, Jieyin; Wang, Yuqiong; Tian, Xiaoxue; Wei, Jian-Jun; Shao, Changshun; Liu, Zhaojian

    2016-07-01

    Ovarian cancer is the most lethal gynecological malignancy. Patients usually have poor prognosis because of late diagnosis, relapse, and chemoresistance. It is pressing to seek novel agent for the treatment of ovarian cancer. Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus (Nelumbo nucifera). In this study, we investigated the antitumor effect of neferine on ovarian cancer cells. We found that neferine exhibited growth-inhibitory effect on human ovarian cancer cells, whereas showing less cytotoxic to non-malignant fallopian tube epithelial cells. Furthermore, we demonstrated that neferine induced autophagy and inactivated the mTOR pathway. Finally, we found that both p38 MAPK and JNK signaling pathways were activated by neferine treatment and contributed to the induction of autophagy in ovarian cancer cells. In conclusion, our findings showed that neferine induced autophagy of human ovarian cancer cells via p38 MAPK/JNK activation. Neferine may be explored as a promising antitumoral agent in ovarian cancer. PMID:26738868

  5. Pentamethylpyrromethene boron difluoride complexes in human ovarian cancer photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Morgan, Lee R.; Chaudhuri, Aulena; Gillen, Laura E.; Boyer, Joseph H.; Wolford, Lionel T.

    1990-07-01

    Quasiaromatic heterocycles (QAM) such as substituted 1 , 3 , 5 , 7 , 8-pentamethylpyrromethene boron difluorides (PMP-BF2) and - (dimethoxyphosphinylmethyl, methyl) bimane have been evaluated for their abilities to produce cellular toxicities when used in photodynamic therapy (PDT) for ovarian cancer. The most active QAH tested to date has been the disodiuxn salt of PMP-2,6-disulfonate--BF2 (PMPDS-BF2). Human ovarian cancer cells from fifteen different patients have been grown in culture. Cells were obtained from biopsy material and grown in RPMI medium with 10% FBA plus penicillin and streptomycin. Cells were harvested and as single cell suspensions exposed to PMP-BF2 complexes or bimanes in concentrations of 0.004-0.4 ug/106 cells/ml of medium. Initially the cells were exposed to the chemicals for 30 minutes in a 5% CO2 incubator (37°C) with gentle shaking. The cells were washed with plain RPMI medium, then resuspended in the enriched RPMI medium and exposed to a sunlamp for 10-20 minutes. Cells were then allowed to grow in an soft agar culture media at 37°C (5% C02) for 14 days. When compared to controls (only light or only chemicals) there was 100% inhibition of all cellular growth for PMPDSBF2 at the 0.4 ug/mi concentrations. There was variations in concentrations of the chemical needed to produce 100% inhibition when the 15 different ovarian cancer cell specimens were compared at all concentrations. PMP-BF2 complexes are characterized by extremely high extinction coefficients, superior laser activity and little if any triplet-triplet absorption. The biamanes share these properties however are less active in ovarian cancer cell The lasing properties of PMP-BF2, and bimanes will be compared to their PDT effectiveness.

  6. Laparoscopic optical coherence tomography imaging of human ovarian cancer

    PubMed Central

    Hariri, Lida P.; Bonnema, Garret T.; Schmidt, Kathy; Winkler, Amy M.; Korde, Vrushali; Hatch, Kenneth D.; Davis, John R.; Brewer, Molly A.; Barton, Jennifer K.

    2011-01-01

    Objectives Ovarian cancer is the fourth leading cause of cancer-related death among women in the US largely due to late detection secondary to unreliable symptomology and screening tools without adequate resolution. Optical coherence tomography (OCT) is a recently emerging imaging modality with promise in ovarian cancer diagnostics, providing non-destructive subsurface imaging at imaging depths up to 2 mm with near-histological grade resolution (10–20 μm). In this study, we developed the first ever laparoscopic OCT (LOCT) device, evaluated the safety and feasibility of LOCT, and characterized the microstructural features of human ovaries in vivo. Methods A custom LOCT device was fabricated specifically for laparoscopic imaging of the ovaries in patients undergoing oophorectomy. OCT images were compared with histopathology to identify preliminary architectural imaging features of normal and pathologic ovarian tissue. Results Thirty ovaries in 17 primarily peri or post-menopausal women were successfully imaged with LOCT: 16 normal, 5 endometriosis, 3 serous cystadenoma, and 4 adenocarcinoma. Preliminary imaging features developed for each category reveal qualitative differences in the homogeneous character of normal post-menopausal ovary, the ability to image small subsurface inclusion cysts, and distinguishable features for endometriosis, cystadenoma, and adenocarcinoma. Conclusions We present the development and successful implementation of the first laparoscopic OCT probe. Comparison of OCT images and corresponding histopathology allowed for the description of preliminary microstructural features for normal ovary, endometriosis, and benign and malignant surface epithelial neoplasms. These results support the potential of OCT both as a diagnostic tool and imaging modality for further evaluation of ovarian cancer pathogenesis. PMID:19481241

  7. Induction of ovarian function by using short-term human menopausal gonadotrophin in patients with ovarian failure following cytotoxic chemotherapy for haematological malignancy.

    PubMed

    Chatterjee, R; Mills, W; Katz, M; McGarrigle, H H; Goldstone, A H

    1993-07-01

    Currently no treatment has proved successful in inducing ovarian steroidogenic and/or gametogenic recovery in patients with haematological malignancies treated by cytotoxic chemotherapy once biochemical failure becomes manifest i.e., when FSH levels exceed 40 IU/L. This paper reports two such cases with classical biochemical ovarian failure in which ovarian function was induced by brief stimulation with Human Menopausal Gonadotrophin (HMG). PMID:7693105

  8. Primary Human Ovarian Epithelial Cancer Cells Broadly Express HER2 at Immunologically-Detectable Levels

    PubMed Central

    Lanitis, Evripidis; Dangaj, Denarda; Hagemann, Ian S.; Song, De-Gang; Best, Andrew; Sandaltzopoulos, Raphael; Coukos, George; Powell, Daniel J.

    2012-01-01

    The breadth of HER2 expression by primary human ovarian cancers remains controversial, which questions its suitability as a universal antigen in this malignancy. To address these issues, we performed extensive HER2 expression analysis on a wide panel of primary tumors as well as established and short-term human ovarian cancer cell lines. Conventional immunohistochemical (IHC) analysis of multiple tumor sites in 50 cases of high-grade ovarian serous carcinomas revealed HER2 overexpression in 29% of evaluated sites. However, more sensitive detection methods including flow cytometry, western blot analysis and q-PCR revealed HER2 expression in all fresh tumor cells derived from primary ascites or solid tumors as well as all established and short-term cultured cancer cell lines. Cancer cells generally expressed HER2 at higher levels than that found in normal ovarian surface epithelial (OSE) cells. Accordingly, genetically-engineered human T cells expressing an HER2-specific chimeric antigen receptor (CAR) recognized and reacted against all established or primary ovarian cancer cells tested with minimal or no reactivity against normal OSE cells. In conclusion, all human ovarian cancers express immunologically-detectable levels of HER2, indicating that IHC measurement underestimates the true frequency of HER2-expressing ovarian cancers and may limit patient access to otherwise clinically meaningful HER2-targeted therapies. PMID:23189165

  9. Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer.

    PubMed

    Zhou, Bo; Shu, Bin; Xi, Tao; Su, Ning; Liu, Jing

    2015-03-01

    Dub3 is a deubiquitinating enzyme. It is highly expressed in tumor-derived cell lines and has an established role in tumor proliferation. However, the role of Dub3 in human ovarian cancer remains unclear. Expression of Dub3 was evaluated in ovarian cancer tissues and cell lines by immunohistochemistry and Western blot analysis. The relationship between Dub3 expression and clinicopathological characteristics was analyzed. Using RNA interference, the effects of Dub3 on cell proliferation and apoptosis were investigated in ovarian cancer cell line. All normal ovary tissues exhibited very little or no Dub3 immunoreactivity. High levels of Dub3 expression were examined by immunohistochemical analysis in 13.3% of cystadenomas, in 30.0% of borderline tumors, and in 58.9% of ovarian carcinomas, respectively. Dub3 expression was significantly associated with lymph node metastasis and clinical staging (P<0.05). Multivariate survival analysis indicated that Dub3 expression was an independent prognostic indicator of the survival of patients with ovarian cancer. Furthermore, the expression of Cdc25A was closely correlated with that of Dub3 in cancer cells and tissues. Knockdown of Dub3 could inhibit the proliferation of ovarian cancer cells and increase cell apoptosis. These data indicate that the Dub3 might be a valuable biomarker for the prediction of ovarian cancer prognosis and Dub3 inhibition might be a potential strategy for ovarian cancer treatment.

  10. The human ovarian granulosa cell: a stereological approach.

    PubMed Central

    Dhar, A; Dockery, P; O, W S; Turner, K; Lenton, E A; Cooke, I D

    1996-01-01

    The human ovarian granulosa cell is perhaps the most widely studied endocrine cell, but little quantitative structural information exists for this cell. In the present study new and traditional stereological probes have been employed to provide quantitative structural information on these functionally important cells. Granulosa cells were obtained from follicular aspirations from 10 women during in vitro fertilisation procedures. Initially 2 methods were used to estimate the mean nuclear volume of these cells: the mean number weighted nuclear volume was estimated by the Selector and the mean volume weighted nuclear volume by the point sampled intercept method. It was found that the difference between the 2 volume estimates was only 8.5%. The volume weighted mean nuclear volume was used as an estimate of nuclear volume. This was subsequently corrected (taking the percentage difference as the empirical bias) and combined with fractional cell volumes (Vv) to produce estimates of cell, mitochondrial, lipid and nucleolar volume. The proportion of the cell occupied by the nucleus had a remarkably low interindividual variation (CV = 7.6%). The proportion of the nucleus occupied by euchromatin also had a striking low variation (CV < 6%). All other cellular parameters had CVs of less than 35%. The lipid composition of these cells showed the greatest interindividual variability, with a CV of 42% for relative and 54% for absolute volume. The present study outlines a simple protocol for the quantitation of granulosa cell structure using new unbiased stereological probes and providing baseline structural information. Images Figure 2 PMID:8763484

  11. PGPIPN, a Therapeutic Hexapeptide, Suppressed Human Ovarian Cancer Growth by Targeting BCL2

    PubMed Central

    Wei, Cai; Tang, Yigui; Zheng, Xin; Ren, Mingqiang; Qin, Yide

    2013-01-01

    Bioactive peptides, either derived from nature resources or synthesized by rational design, have been demonstrated potential for therapeutic agents against numerous human diseases, including cancer. However, the mechanism of therapeutic peptides against cancer has not been well elucidated. Here we show that PGPIPN, a hexapeptide derived from bovine β-casein, inhibited the proliferation of human ovarian cancer cells line SKOV3 as well as the primary ovarian cancer cells in vitro. Consistently, PGPIPIN also decreased tumor growth rate in xenograft ovarian cancer model mice in a dose-dependent manner. Further study demonstrated that the anti-tumor effect of PGPIPN is partially through promoting cell apoptosis by inhibiting BCL2 pathway. Thus, our study suggests that PGPIPN is a potential therapeutic agent for the treatment of ovarian cancer or other types of cancer. PMID:23593287

  12. Immunobiology of human mucin 1 in a preclinical ovarian tumor model

    PubMed Central

    Budiu, RA; Elishaev, E; Brozick, J; Lee, M; Edwards, RP; Kalinski, P; Vlad, AM

    2014-01-01

    Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express human MUC1+/− as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-rasG12D/+) and the floxed Pten gene (Pten/loxP/loxP). Injection of Cre recombinase-encoding adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1–MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies. PMID:22964632

  13. Simultaneous multiplane imaging of human ovarian cancer by volume holographic imaging.

    PubMed

    Orsinger, Gabriel V; Watson, Jennifer M; Gordon, Michael; Nymeyer, Ariel C; de Leon, Erich E; Brownlee, Johnathan W; Hatch, Kenneth D; Chambers, Setsuko K; Barton, Jennifer K; Kostuk, Raymond K; Romanowski, Marek

    2014-03-01

    Ovarian cancer is the most deadly gynecologic cancer, a fact which is attributable to poor early detection and survival once the disease has reached advanced stages. Intraoperative laparoscopic volume holographic imaging has the potential to provide simultaneous visualization of surface and subsurface structures in ovarian tissues for improved assessment of developing ovarian cancer. In this ex vivo ovarian tissue study, we assembled a benchtop volume holographic imaging system (VHIS) to characterize the microarchitecture of 78 normal and 40 abnormal tissue specimens derived from ovarian, fallopian tube, uterine, and peritoneal tissues, collected from 26 patients aged 22 to 73 undergoing bilateral salpingo-oophorectomy, hysterectomy with bilateral salpingo-oophorectomy, or abdominal cytoreductive surgery. All tissues were successfully imaged with the VHIS in both reflectance- and fluorescence-modes revealing morphological features which can be used to distinguish between normal, benign abnormalities, and cancerous tissues. We present the development and successful application of VHIS for imaging human ovarian tissue. Comparison of VHIS images with corresponding histopathology allowed for qualitatively distinguishing microstructural features unique to the studied tissue type and disease state. These results motivate the development of a laparoscopic VHIS for evaluating the surface and subsurface morphological alterations in ovarian cancer pathogenesis.

  14. Simultaneous multiplane imaging of human ovarian cancer by volume holographic imaging

    PubMed Central

    Orsinger, Gabriel V.; Watson, Jennifer M.; Gordon, Michael; Nymeyer, Ariel C.; de Leon, Erich E.; Brownlee, Johnathan W.; Hatch, Kenneth D.; Chambers, Setsuko K.; Barton, Jennifer K.; Kostuk, Raymond K.; Romanowski, Marek

    2014-01-01

    Abstract. Ovarian cancer is the most deadly gynecologic cancer, a fact which is attributable to poor early detection and survival once the disease has reached advanced stages. Intraoperative laparoscopic volume holographic imaging has the potential to provide simultaneous visualization of surface and subsurface structures in ovarian tissues for improved assessment of developing ovarian cancer. In this ex vivo ovarian tissue study, we assembled a benchtop volume holographic imaging system (VHIS) to characterize the microarchitecture of 78 normal and 40 abnormal tissue specimens derived from ovarian, fallopian tube, uterine, and peritoneal tissues, collected from 26 patients aged 22 to 73 undergoing bilateral salpingo-oophorectomy, hysterectomy with bilateral salpingo-oophorectomy, or abdominal cytoreductive surgery. All tissues were successfully imaged with the VHIS in both reflectance- and fluorescence-modes revealing morphological features which can be used to distinguish between normal, benign abnormalities, and cancerous tissues. We present the development and successful application of VHIS for imaging human ovarian tissue. Comparison of VHIS images with corresponding histopathology allowed for qualitatively distinguishing microstructural features unique to the studied tissue type and disease state. These results motivate the development of a laparoscopic VHIS for evaluating the surface and subsurface morphological alterations in ovarian cancer pathogenesis. PMID:24676382

  15. Pycnogenol reduces talc-induced neoplastic transformation in human ovarian cell cultures.

    PubMed

    Buz'Zard, Amber R; Lau, Benjamin H S

    2007-06-01

    Talc and poor diet have been suggested to increase the risk of developing ovarian cancer; which can be reduced by a diet rich in fruit and vegetables. Talc is ubiquitous despite concern about its safety, role as a possible carcinogen and known ability to cause irritation and inflammation. It was recently shown that Pycnogenol (Pyc; a proprietary mixture of water-soluble bioflavonoids extracted from French maritime pine bark) was selectively toxic to established malignant ovarian germ cells. This study investigated talc-induced carcinogenesis and Pyc-induced chemoprevention. Normal human epithelial and granulosa ovarian cell lines and polymorphonuclear neutrophils (PMN) were treated with talc, or pretreated with Pyc then talc. Cell viability, reactive oxygen species (ROS) generation and neoplastic transformation by soft agar assay were measured. Talc increased proliferation, induced neoplastic transformation and increased ROS generation time-dependently in the ovarian cells and dose-dependently in the PMN. Pretreatment with Pyc inhibited the talc-induced increase in proliferation, decreased the number of transformed colonies and decreased the ROS generation in the ovarian cells. The data suggest that talc may contribute to ovarian neoplastic transformation and Pyc reduced the talc-induced transformation. Taken together, Pyc may prove to be a potent chemopreventative agent against ovarian carcinogenesis.

  16. Human chorionic gonadotropin and its relation to grade, stage and patient survival in ovarian cancer

    PubMed Central

    2012-01-01

    Background An influence of gonadotropins (hCG) on the development of ovarian cancer has been discussed. Therefore, we quantified serum hCG levels in patients with benign and malignant ovarian tumors and the hCG expression in ovarian cancer tissue in order to analyze its relation to grade, stage, gonadotropin receptor (LH-R, FSH-R) expression and survival in ovarian cancer patients. Methods Patients diagnosed and treated for ovarian tumors from 1990 to 2002 were included. Patient characteristics, histology including histological subtype, tumor stage, grading and follow-up data were available. Serum hCG concentration measurement was performed with ELISA technology, hCG tissue expression determined by immunohistochemistry. Results HCG-positive sera were found in 26.7% of patients with benign and 67% of patients with malignant ovarian tumors. In addition, significantly higher hCG serum concentrations were observed in patients with malignant compared to benign ovarian tumors (p = 0.000). Ovarian cancer tissue was positive for hCG expression in 68%. We identified significant differences in hCG tissue expression related to tumor grade (p = 0.022) but no differences with regard to the histological subtype. In addition, mucinous ovarian carcinomas showed a significantly increased hCG expression at FIGO stage III compared to stage I (p = 0.018). We also found a positive correlation of hCG expression to LH-R expression, but not to FSH-R expression. There was no significant correlation between tissue hCG expression and overall ovarian cancer patient survival, but subgroup analysis revealed an increased 5-year survival in LH-R positive/FSH-R negative and hCG positive tumors (hCG positive 75.0% vs. hCG negative 50.5%). Conclusions Serum human gonadotropin levels differ in patients with benign and malignant ovarian tumors. HCG is often expressed in ovarian cancer tissue with a certain variable relation to grade and stage. HCG expression correlates with LH-R expression in ovarian

  17. Effect of Human Ovarian Tissue Vitrification/Warming on the Expression of Genes Related to Folliculogenesis

    PubMed Central

    Shams Mofarahe, Zahra; Ghaffari Novin, Marefat; Jafarabadi, Mina; Salehnia, Mojdeh; Noroozian, Mohsen; Ghorbanmehr, Nassim

    2015-01-01

    Background: Ovarian tissue cryopreservation is an alternative strategy to preserve the fertility of women predicted to undergo premature ovarian failure. This study was designed to evaluate the expression of folliculogenesis-related genes, including factor in the germline alpha (FIGLA), growth differentiation factor-9 (GDF-9), follicle-stimulating hormone receptor (FSHR), and KIT LIGAND after vitrification/warming of human ovarian tissue. Methods: Human ovarian tissue samples were collected from five transsexual women. In the laboratory, the ovarian medullary part was removed by a surgical blade, and the cortical tissue was cut into small pieces. Some pieces were vitrified and warmed and the others were considered as non-vitrified group (control). Follicular normality was assessed with morphological observation by a light microscope, and the expression of FIGLA, KIT LIGAND, GDF-9,, and FSHR genes was examined using real-time RT-PCR in both the vitrified and non-vitrified groups. Results: Overall, 85% of the follicles preserved their normal morphologic feature after warming. The percentage of normal follicles and the expression of FIGLA, KIT LIGAND, GDF-9, and FSHR genes were similar in both vitrified and non-vitrified groups (P > 0.05). Conclusion: Vitrification/warming of human ovarian tissue had no remarkable effect on the expression of folliculogenesis-related genes. PMID:26175108

  18. Age-related decline in ovarian follicle stocks differ between chimpanzees (Pan troglodytes) and humans.

    PubMed

    Cloutier, Christina T; Coxworth, James E; Hawkes, Kristen

    2015-02-01

    Similarity in oldest parturitions in humans and great apes suggests that we maintain ancestral rates of ovarian aging. Consistent with that hypothesis, previous counts of primordial follicles in postmortem ovarian sections from chimpanzees (Pan troglodytes) showed follicle stock decline at the same rate that human stocks decline across the same ages. Here, we correct that finding with a chimpanzee sample more than three times larger than the previous one, which also allows comparison into older ages. Analyses show depletion rates similar until about age 35, but after 35, the human counts continue to fall with age, while the change is much less steep in chimpanzees. This difference implicates likely effects on ovarian dynamics from other physiological systems that are senescing at different rates, and, potentially, different perimenopausal experience for chimpanzees and humans.

  19. Laparoscopic optical coherence tomographic imaging of human ovarian cancer

    NASA Astrophysics Data System (ADS)

    Hariri, Lida P.; Bonnema, Garret T.; Schmidt, Kathy; Hatch, Kenneth; Brewer, Molly; Barton, Jennifer K.

    2008-02-01

    Ovarian cancer is the fourth leading cause of cancer-related death among women in the United States. If diagnosed at an early stage, the 5-year survival rate is 94%, but drops to 68% for regional disease and 29% for distant metastasis; only 19% of all cases are diagnosed at the early, localized stage. Optical coherence tomography is a recently emerging non-destructive imaging technology, achieving high axial resolutions (10-20 microns) at imaging depths up to 2 mm. Previously, we studied OCT imaging in normal and diseased human ovary ex vivo to determine the features OCT is capable of resolving. Changes in collagen were suggested with several of the images that correlated with changes in collagen seen in malignancy. Areas of necrosis and blood vessels were also visualized using OCT, indicative of an underlying tissue abnormality. We recently developed a custom side-firing laparoscopic OCT (LOCT) probe fabricated specifically for in vivo laparoscopic imaging. The LOCT probe consists of a 38 mm diameter handpiece terminated in an 280 mm long, 4.6 mm diameter tip for insertion into the laparoscopic trocar and is capable of obtaining up to 9.5 mm image lengths at 10 micron axial resolution. In this study, we utilize the LOCT probe to image one or both ovaries of 20 patients undergoing laparotomy or transabdominal endoscopy and oophorectomy to determine if OCT is capable of identifying and/or differentiating normal and neoplastic ovary. To date, we have laparoscopically imaged the ovaries of ten patients successfully with no known complications.

  20. Laparoscopic optical coherence tomographic imaging of human ovarian cancer

    NASA Astrophysics Data System (ADS)

    Hariri, Lida P.; Bonnema, Garret T.; Schmidt, Kathy; Korde, Vrushali; Winkler, Amy M.; Hatch, Kenneth; Brewer, Molly; Barton, Jennifer K.

    2009-02-01

    Ovarian cancer is the fourth leading cause of cancer-related death among women. If diagnosed at early stages, 5-year survival rate is 94%, but drops to 68% for regional disease and 29% for distant metastasis; only 19% of cases are diagnosed at early, localized stages. Optical coherence tomography is a recently emerging non-destructive imaging technology, achieving high axial resolutions (10-20 µm) at imaging depths up to 2 mm. Previously, we studied OCT in normal and diseased human ovary ex vivo. Changes in collagen were suggested with several images that correlated with changes in collagen seen in malignancy. Areas of necrosis and blood vessels were also visualized using OCT, indicative of an underlying tissue abnormality. We recently developed a custom side-firing laparoscopic OCT (LOCT) probe fabricated for in vivo imaging. The LOCT probe, consisting of a 38 mm diameter handpiece terminated in a 280 mm long, 4.6 mm diameter tip for insertion into the laparoscopic trocar, is capable of obtaining up to 9.5 mm image lengths at 10 µm axial resolution. In this pilot study, we utilize the LOCT probe to image one or both ovaries of 17 patients undergoing laparotomy or transabdominal endoscopy and oophorectomy to determine if OCT is capable of differentiating normal and neoplastic ovary. We have laparoscopically imaged the ovaries of seventeen patients with no known complications. Initial data evaluation reveals qualitative distinguishability between the features of undiseased post-menopausal ovary and the cystic, non-homogenous appearance of neoplastic ovary such as serous cystadenoma and endometroid adenocarcinoma.

  1. Characteristics of human amniotic fluid mesenchymal stem cells and their tropism to human ovarian cancer.

    PubMed

    Li, Liru; Wang, Dejun; Zhou, Jun; Cheng, Yan; Liang, Tian; Zhang, Guangmei

    2015-01-01

    The mesenchymal stem cells (MSCs) derived from amniotic fluid (AF) have become an attractive stem cells source for cell-based therapy because they can be harvested at low cost and avoid ethical disputes. In human research, stem cells derived from AF gradually became a hot research direction for disease treatment, specifically for their plasticity, their reduced immunogenicity and their tumor tropism regardless of the tumor size, location and source. Our work aimed to obtain and characterize human amniotic fluid mesenchymal stem cells (AFMSCs) and detect their ovarian cancer tropsim in nude mice model. Ten milliliters of twenty independent amniotic fluid samples were collected from 16-20 week pregnant women who underwent amniocentesis for fetal genetic determination in routine prenatal diagnosis in the first affiliated hospital of Harbin medical university. We successfully isolated the AFMSCs from thirteen of twenty amniotic fluid samples. AFMSCs presented a fibroblastic-like morphology during the culture. Flow cytometry analyses showed that the cells were positive for specific stem cell markers CD73,CD90, CD105, CD166 and HLA-ABC (MHC class I), but negative for CD 45,CD40, CD34, CD14 and HLA-DR (MHC class II). RT-PCR results showed that the AFMSCs expressed stem cell marker OCT4. AFMSCs could differentiate into bone cells, fat cells and chondrocytes under certain conditions. AFMSCs had the high motility to migrate to ovarian cancer site but didn't have the tumorigenicity. This study enhances the possibility of AFMSCs as drug carrier in human cell-based therapy. Meanwhile, the research emphasis in the future can also put in targeting therapy of ovarian cancer.

  2. The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer.

    PubMed Central

    Negus, R P; Stamp, G W; Relf, M G; Burke, F; Malik, S T; Bernasconi, S; Allavena, P; Sozzani, S; Mantovani, A; Balkwill, F R

    1995-01-01

    Chemokines may control the macrophage infiltrate found in many solid tumors. In human ovarian cancer, in situ hybridization detected mRNA for the macrophage chemokine monocyte chemoattractant protein-1 (MCP-1) in 16/17 serous carcinomas, 4/4 mucinous carcinomas, 2/2 endometrioid carcinomas, and 1/3 borderline tumors. In serous tumors, mRNA expression mainly localized to the epithelial areas, as did immunoreactive MCP-1 protein. In the other tumors, both stromal and epithelial expression were seen. All tumors contained variable numbers of cells positive for the macrophage marker CD68. MCP-1 mRNA was also detected in the stroma of 5/5 normal ovaries. RT-PCR demonstrated mRNA for MCP-1 in 7/7 serous carcinomas and 6/6 ovarian cancer cell lines. MCP-1 protein was detected by ELISA in ascites from patients with ovarian cancer (mean 4.28 ng/ml) and was produced primarily by the cancer cells. Human MCP-1 protein was also detected in culture supernatants from cell lines and in ascites from human ovarian tumor xenografts which induce a peritoneal monocytosis in nude mice. We conclude that the macrophage chemoattractant MCP-1 is produced by epithelial ovarian cancer and that the tumor cells themselves are probably a major source. MCP-1 may contribute to the accumulation of tumor-associated macrophages, which may subsequently influence tumor behavior. Images PMID:7738202

  3. The marine-derived fungal metabolite, terrein, inhibits cell proliferation and induces cell cycle arrest in human ovarian cancer cells.

    PubMed

    Chen, Yi-Fei; Wang, Shu-Ying; Shen, Hong; Yao, Xiao-Fen; Zhang, Feng-Li; Lai, Dongmei

    2014-12-01

    The difficulties faced in the effective treatment of ovarian cancer are multifactorial, but are mainly associated with relapse and drug resistance. Cancer stem-like cells have been reported to be an important contributor to these hindering factors. In this study, we aimed to investigate the anticancer activities of a bioactive fungal metabolite, namely terrein, against the human epithelial ovarian cancer cell line, SKOV3, primary human ovarian cancer cells and ovarian cancer stem-like cells. Terrein was separated and purified from the fermentation metabolites of the marine sponge-derived fungus, Aspergillus terreus strain PF26. Its anticancer activities against ovarian cancer cells were investigated by cell proliferation assay, cell migration assay, cell apoptosis and cell cycle assays. The ovarian cancer stem-like cells were enriched and cultured in a serum-free in vitro suspension system. Terrein inhibited the proliferation of the ovarian cancer cells by inducing G2/M phase cell cycle arrest. The underlying mechanisms involved the suppression of the expression of LIN28, an important marker gene of stemness in ovarian cancer stem cells. Of note, our study also demonstrated the ability of terrein to inhibit the proliferation of ovarian cancer stem-like cells, in which the expression of LIN28 was also downregulated. Our findings reveal that terrein (produced by fermention) may prove to be a promising drug candidate for the treatment of ovarian cancer by inhibiting the proliferation of cancer stem-like cells.

  4. Epigenetics changes caused by the fusion of human embryonic stem cell and ovarian cancer cells.

    PubMed

    He, Ke; Qu, Hu; Xu, Li-Nan; Gao, Jun; Cheng, Fu-Yi; Xiang, Peng; Zhou, Can-Quan

    2016-10-01

    To observe the effect of gene expression and tumorigenicity in hybrid cells of human embryonic stem cells (hESCs) and ovarian cancer cells in vitro and in vivo using a mouse model, and to determine its feasibility in reprogramming tumour cells growth and apoptosis, for a potential exploration of the role of hESCs and tumour cells fusion in the management of ovarian cancer. Stable transgenic hESCs (H1) and ovarian cancer cell line OVCAR-3 were established before fusion, and cell fusion system was established to analyse the related indicators. PTEN expression in HO-H1 cells was higher than those in the parental stem cells and lower than those in parental tumour cells; the growth of OV-H1 (RFP+GFP) hybrid cells with double fluorescence expressions were obviously slower than that of human embryonic stem cells and OVCAR-3 ovarian cancer cells. The apoptosis signal of the OV-H1 hybrid cells was significantly higher than that of the hESCs and OVCAR-3 ovarian cancer cells. In vivo results showed that compared with 7 days, 28 days and 35 days after inoculation of OV-H1 hybrid cells; also, apoptotic cell detection indicated that much stronger apoptotic signal was found in OV-H1 hybrid cells inoculated mouse. The hESCs can inhibit the growth of OVCAR-3 cells in vitro by suppressing p53 and PTEN expression to suppress the growth of tumour that may be achieved by inducing apoptosis of OVCAR-3 cells. The change of epigenetics after fusion of ovarian cancer cells and hESCs may become a novel direction for treatment of ovarian cancer.

  5. Epigenetics changes caused by the fusion of human embryonic stem cell and ovarian cancer cells.

    PubMed

    He, Ke; Qu, Hu; Xu, Li-Nan; Gao, Jun; Cheng, Fu-Yi; Xiang, Peng; Zhou, Can-Quan

    2016-10-01

    To observe the effect of gene expression and tumorigenicity in hybrid cells of human embryonic stem cells (hESCs) and ovarian cancer cells in vitro and in vivo using a mouse model, and to determine its feasibility in reprogramming tumour cells growth and apoptosis, for a potential exploration of the role of hESCs and tumour cells fusion in the management of ovarian cancer. Stable transgenic hESCs (H1) and ovarian cancer cell line OVCAR-3 were established before fusion, and cell fusion system was established to analyse the related indicators. PTEN expression in HO-H1 cells was higher than those in the parental stem cells and lower than those in parental tumour cells; the growth of OV-H1 (RFP+GFP) hybrid cells with double fluorescence expressions were obviously slower than that of human embryonic stem cells and OVCAR-3 ovarian cancer cells. The apoptosis signal of the OV-H1 hybrid cells was significantly higher than that of the hESCs and OVCAR-3 ovarian cancer cells. In vivo results showed that compared with 7 days, 28 days and 35 days after inoculation of OV-H1 hybrid cells; also, apoptotic cell detection indicated that much stronger apoptotic signal was found in OV-H1 hybrid cells inoculated mouse. The hESCs can inhibit the growth of OVCAR-3 cells in vitro by suppressing p53 and PTEN expression to suppress the growth of tumour that may be achieved by inducing apoptosis of OVCAR-3 cells. The change of epigenetics after fusion of ovarian cancer cells and hESCs may become a novel direction for treatment of ovarian cancer. PMID:27377320

  6. Epigenetics changes caused by the fusion of human embryonic stem cell and ovarian cancer cells

    PubMed Central

    He, Ke; Qu, Hu; Xu, Li-Nan; Gao, Jun; Cheng, Fu-Yi; Xiang, Peng; Zhou, Can-Quan

    2016-01-01

    To observe the effect of gene expression and tumorigenicity in hybrid cells of human embryonic stem cells (hESCs) and ovarian cancer cells in vitro and in vivo using a mouse model, and to determine its feasibility in reprogramming tumour cells growth and apoptosis, for a potential exploration of the role of hESCs and tumour cells fusion in the management of ovarian cancer. Stable transgenic hESCs (H1) and ovarian cancer cell line OVCAR-3 were established before fusion, and cell fusion system was established to analyse the related indicators. PTEN expression in HO-H1 cells was higher than those in the parental stem cells and lower than those in parental tumour cells; the growth of OV-H1 (RFP+GFP) hybrid cells with double fluorescence expressions were obviously slower than that of human embryonic stem cells and OVCAR-3 ovarian cancer cells. The apoptosis signal of the OV-H1 hybrid cells was significantly higher than that of the hESCs and OVCAR-3 ovarian cancer cells. In vivo results showed that compared with 7 days, 28 days and 35 days after inoculation of OV-H1 hybrid cells; also, apoptotic cell detection indicated that much stronger apoptotic signal was found in OV-H1 hybrid cells inoculated mouse. The hESCs can inhibit the growth of OVCAR-3 cells in vitro by suppressing p53 and PTEN expression to suppress the growth of tumour that may be achieved by inducing apoptosis of OVCAR-3 cells. The change of epigenetics after fusion of ovarian cancer cells and hESCs may become a novel direction for treatment of ovarian cancer. PMID:27377320

  7. An endogenous aryl hydrocarbon receptor ligand inhibits proliferation and migration of human ovarian cancer cells.

    PubMed

    Wang, Kai; Li, Yan; Jiang, Yi-Zhou; Dai, Cai-Feng; Patankar, Manish S; Song, Jia-Sheng; Zheng, Jing

    2013-10-28

    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor mediates many biological processes. Herein, we investigated if 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, an endogenous AhR ligand) regulated proliferation and migration of human ovarian cancer cells via AhR. We found that AhR was widely present in many histotypes of ovarian cancer tissues. ITE suppressed OVCAR-3 cell proliferation and SKOV-3 cell migration in vitro, which were blocked by AhR knockdown. ITE also suppressed OVCAR-3 cell growth in mice. These data suggest that the ITE might potentially be used for therapeutic intervention for at least a subset of human ovarian cancer.

  8. Noxa enhances the cytotoxic effect of gemcitabine in human ovarian cancer cells.

    PubMed

    Cao, Kang; Yang, Jing; Lin, Chao; Wang, Bao-ning; Yang, Yuan; Zhang, Jing; Dai, Jun; Li, Lei; Nie, Chun-lai; Yuan, Zhu; Li, Ming-yuan

    2012-05-01

    Noxa is an important proapoptotic protein in the intrinsic pathway of cell apoptosis. Experiments were carried out to investigate whether Noxa could, therefore, enhance the cytotoxic effect of gemcitabine in human ovarian cancer cell lines (A2780 and COC1). In this study, the combined treatment of Noxa and gemcitabine, in vitro, significantly inhibited the proliferation of A2780 and COC1 cells, as verified by MTT assay, Hoechst staining, and flow cytometric analysis. Moreover, the combination of Noxa and gemcitabine inhibited tumor growth and prolonged the survival of nude mice in vivo. The combined treatment also inhibited the growth of tumor xenografts through the inhibition of proliferation and the induction of apoptosis, as observed in immunohistochemical anti-PCNA staining and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay. Our data suggest that Noxa exhibited potent proapoptotic activity against human ovarian cancer cells, and the combination of Noxa and gemcitabine showed a more significant cytotoxic effect against ovarian cancer cells in comparison with either of these agents alone. To our knowledge, we have provided the first evidence that Noxa can enhance therapeutic responses of ovarian cancer cells to gemcitabine, and that it could be potentially useful as a chemosensitizer in ovarian cancer therapy.

  9. The effect of Setarud (IMODTM) on angiogenesis in transplanted human ovarian tissue to nude mice

    PubMed Central

    Hormozi, Maryam; Talebi, Saeed; Khorram Khorshid, Hamid Reza; Zarnani, Amir-Hassan; Kamali, Koorosh; Jeddi-Tehrani, Mahmood; Soltangoraee, Haleh; Akhondi, Mohammad Mehdi

    2015-01-01

    Background: One of the promising methods in fertility preservation among women with cancer is cryopreservation of ovarian cortex but there are many drawbacks such as apoptosis and considerable reduction of follicular density in the transplanted ovary. One solution to reduce ischemic damage is enhancing angiogenesis after transplantation of ovarian cortex tissue. Objective: The aim of this study was to investigate the effect of Setarud, on angiogenesis in transplanted human ovarian tissue. Materials and Methods: In this case control study, twenty four nude mice were implanted subcutaneously, with human ovarian tissues, from four women. The mice were randomly divided into two groups (n=12): the experimental group was treated with Setarud, while control group received only vehicle. Each group was divided into three subgroups (n=4) based on the graft recovery days post transplantation (PT). The transplanted fragments were removed on days 2, 7, and 30 PT and the expression of Angiopoietin-1, Angiopoietin-2, and Vascular endothelial growth factor at both gene and protein levels and vascular density were studied in the grafted ovarian tissues. Results: On the 2nd and 7th day PT, the level of Angiopoietin-1 gene expression in case group was significantly lower than that in control group, while the opposite results were obtained for Angiopoietin-2 and Vascular endothelial growth factor. These results were also confirmed at the protein level. The density of vessels in Setarud group elevated significantly on day 7 PT compared to pre-treatment state. Conclusion: Our results showed that administration of Setarud may stimulates angiogenesis in transplanted human ovarian tissues, although further researches are needed before a clear judgment is made. PMID:26644788

  10. Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.

    PubMed

    Wen, Wei; Liang, Wei; Wu, Jun; Kowolik, Claudia M; Buettner, Ralf; Scuto, Anna; Hsieh, Meng-Yin; Hong, Hao; Brown, Christine E; Forman, Stephen J; Horne, David; Morgan, Robert; Wakabayashi, Mark; Dellinger, Thanh H; Han, Ernest S; Yim, John H; Jove, Richard

    2014-12-01

    JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small-molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.

  11. Human chorionic gonadotropin β subunit affects the expression of apoptosis-regulating factors in ovarian cancer.

    PubMed

    Szczerba, Anna; Śliwa, Aleksandra; Kubiczak, Marta; Nowak-Markwitz, Ewa; Jankowska, Anna

    2016-01-01

    Expression of human chorionic gonadotropin, especially its free β subunit (hCGβ) were shown to play an important role in cancer growth, invasion and metastasis. It is postulated that hCGβ is one of the factors determining cancer cell survival. To test this hypothesis, we applied two models: an in vitro model of ovarian cancer using OVCAR-3 and SKOV-3 cell lines transfected with the CGB5 gene and an in vivo model of ovarian cancer tissues. The material was tested against changes in expression level of genes encoding factors involved in apoptosis: BCL2, BAX and BIRC5. Overexpression of hCGβ was found to cause a decrease in expression of the analyzed genes in the transfected cells compared with the control cells. In ovarian cancer tissues, high expression of CGB was related to significantly lower BCL2 but higher BAX and BIRC5 transcript levels. Moreover, a low BCL2/BAX ratio, characteristic of advanced stages of ovarian cancer, was revealed. Since tumors were discriminated by a significantly lower LHCGR level than the level noted in healthy fallopian tubes and ovaries, it may be stated that the effect of hCGβ on changes in the expression of apoptosis-regulating agents observed in ovarian cancer is LHCGR-independent. The results of the study suggest that the biological effects evoked by hCGβ are related to apoptosis suppression.

  12. Human umbilical cord blood-mesenchymal stem cells transplantation renovates the ovarian surface epithelium in a rat model of premature ovarian failure: Possible direct and indirect effects.

    PubMed

    Elfayomy, Amr K; Almasry, Shaima M; El-Tarhouny, Shereen A; Eldomiaty, Magda A

    2016-08-01

    This study aimed to isolate mesenchymal stem cells (MSC) from human umbilical cord blood (HCB) and to explore their influence on the ovarian epithelium after paclitaxel-induced ovarian failure. Ninety-five rats were divided into 6 groups: control, paclitaxel, paclitaxel and saline, HCB-MSC-treated for 2 weeks, HCB-MSC-treated for 4 weeks, and HCB-MSC-treated for 6 weeks. HCB cells were studied for CD34, CD44, and Oct ¾ using flow cytometry. Serum levels of FSH and E2 were measured using ELISA, RT-PCR analysis for human gene; beta-actin (ACTB), immunohistochemical analysis for CK 8/18, TGF-ß, PCNA and CASP-3 were performed. We found that ACTB gene was expressed in all rats' ovaries received HCB-MSC. After 4 weeks of transplantation, there was significant reduction in FSH, elevation in E2 levels, stabilization of the surface epithelium morphostasis, an increase in the antral follicle count and increase in integrated densities (ID) of CK 8/18, TGF-ß, and PCNA expressions and decrease in ID of CASP-3 expression. We concluded that HCB-MSC can restore the ovarian function after paclitaxel injection through a direct triggering effect on the ovarian epithelium and/or indirect enrichment of ovarian niche through regulating tissue expression of CK 8/18, TGF-ß and PCNA. These molecules are crucial in regulating folliculogenesis and suppressing CASP-3-induced apoptosis.

  13. Overexpression of Notch3 and pS6 Is Associated with Poor Prognosis in Human Ovarian Epithelial Cancer

    PubMed Central

    Yun, Rongna; Yu, Xiaolin; Huang, Genhua; Tan, Buzhen

    2016-01-01

    Notch3 and pS6 play important roles in tumor angiogenesis. To assess the expression of Notch3 and pS6 in Chinese ovarian epithelial cancer patients, a ten-year follow-up study was performed in ovarian epithelial cancer tissues from 120 specimens of human ovarian epithelial cancer, 30 specimens from benign ovarian tumors, and 30 samples from healthy ovaries by immunohistochemistry. The results indicate that the expression of Notch3 and pS6 was higher in ovarian epithelial cancer than in normal ovary tissues and in benign ovarian tumor tissues (p < 0.01). In tumor tissues, Notch3 expression and pS6 expression were negatively associated with age (p > 0.05) but positively associated with clinical stage, pathological grading, histologic type, lymph node metastasis, and ascites (p < 0.05 or p < 0.01). A follow-up survey of 64 patients with ovarian epithelial cancer showed that patients with high Notch3 and pS6 expression had a shorter survival time (p < 0.01), in which the clinical stage (p < 0.05) and Notch3 expression (p < 0.01) played important roles. In conclusion, Notch3 and pS6 are significantly related to ovarian epithelial cancer development and prognosis, and their combination represents a potential biomarker and therapeutic target in ovarian tumor angiogenesis. PMID:27445438

  14. Isolation of alpha 1-protease inhibitor from human normal and malignant ovarian tissue.

    PubMed Central

    Bagdasarian, A; Wheeler, J; Stewart, G J; Ahmed, S S; Colman, R W

    1981-01-01

    Proteolytic enzymes are associated with normal and neoplastic tissues. Therefore protease inhibitors might also be involved in the control of cell function. alpha 1-protease antigen and antitryptic activity have been found in normal and neoplastic human ovarian homogenate. The inhibitor has been localized to ovarian stromal cells or tumor cells by immunoperoxidase staining. The protein was purified to apparent homogeneity as judged by alkaline gel and sodium dodecyl sulfate (SDS) gel electrophoresis. Immunochemical studies revealed antigenic similarity of plasma alpha 1-protease inhibitor by double immunodiffusion and similar mobility on immunoelectrophoresis and two-dimensional electroimmunodiffusion. The molecular weight was similar to that described for plasma alpha 1-protease inhibitor: 60,000 by gel filtration and 53,500 by SDS electrophoresis. Furthermore, the phenotypic pattern as determined by acid starch gel electrophoresis and immunoprecipitation was PiMM, which is the predominant genetic variant in normal plasma alpha 1-protease inhibitor. An inhibitor ws isolated and purified from an ovarian carcinoma that exhibited functional, immunochemical, and physical similarity to the normal ovarian alpha 1-protease inhibitor. alpha 1-protease inhibitor from normal and malignant ovaries competitively inhibited bovine pancreatic trypsin at incubation times of 5 min at 30 degrees C. Inhibition constant (Ki) values were calculated at 0.67 and 0.51 inhibitory units, respectively. The alpha 1-protease inhibitor in malignant cells may be a factor in the control of proliferation in this tissue. Since ovulation is in part a proteolytic event, the alpha 1-protease inhibitor in ovarian cells may play a role in the control of this specialized tissue. Persistance of this protein in malignant ovarian tissue may be a vestige of its differentiated origin. Images PMID:6161137

  15. Correlating optical coherence elastography based strain measurements with collagen content of the human ovarian tissue.

    PubMed

    Nandy, Sreyankar; Salehi, Hassan S; Wang, Tianheng; Wang, Xiaohong; Sanders, Melinda; Kueck, Angela; Brewer, Molly; Zhu, Quing

    2015-10-01

    In this manuscript, the initial feasibility of a catheter based phase stabilized swept source optical coherence tomography (OCT) system was studied for characterization of the strain inside different human ovarian tissue groups. The ovarian tissue samples were periodically compressed with 500 Hz square wave signal along the axial direction between the surface of an unfocused transducer and a glass cover slide. The displacement and corresponding strain were calculated during loading from different locations for each tissue sample. A total of 27 ex vivo ovaries from 16 patients were investigated. Statistically significant difference (p < 0.001) was observed between the average displacement and strain of the normal and malignant tissue groups. A sensitivity of 93.2% and a specificity of 83% were achieved using 25 microstrain (με) as the threshold. The collagen content of the tissues was quantified from the Sirius Red stained histological sections. The average collagen area fraction (CAF) obtained from the tissue groups were found to have a strong negative correlation (R = -0.75, p < 0.0001) with the amount of strain inside the tissue. This indicates much softer and degenerated tissue structure for the malignant ovaries as compared to the dense, collagen rich structure of the normal ovarian tissue. The initial results indicate that the swept source OCT system can be useful for estimating the elasticity of the human ovarian tissue. PMID:26504631

  16. YAP induces cisplatin resistance through activation of autophagy in human ovarian carcinoma cells

    PubMed Central

    Xiao, Lan; Shi, Xiao-Yan; Zhang, Ying; Zhu, Ying; Zhu, Lin; Tian, Wang; Zhu, Bing-Kun; Wei, Zhao-Lian

    2016-01-01

    Objective To identify the role of YAP in cisplatin resistance in human ovarian cancer cells and in the regulation of autophagy in these cancer cells. Materials and methods The cisplatin-sensitive OV2008 parental cell line and its cisplatin-resistant variant C13K were cultured. RNA interference was used to knock down the YAP gene. Accumulation of GFP-LC3 puncta was performed by fluorescence microscopy. The formation of autophagosomes was observed by transmission electron microscopy. Drug sensitivity was examined using CCK-8 assay, while apoptosis, the level of intracellular rhodamine 123 and lysosomal acidification were analyzed by fluorescence-activated cell sorting. Acid phosphatase activity was measured using an acid phosphatase-assay kit. Real-time polymerase chain reaction, Western blotting, and immunofluorescence detection were used to detect the protein and messenger RNA expression of YAP, YAP target genes, CCND1, cleaved PARP, and caspase 3, Atg-3 and -5, and the LC3B protein. Results YAP signaling may regulate cisplatin resistance in ovarian cancer cells by augmenting cellular autophagic flux. After knockdown of YAP-sensitized C13K cells to cisplatin by inducing a decrease in autophagy, YAP led to an increase in autophagy via enhancement of autolysosome degradation. Conclusion YAP-mediated autophagy may play a protective role in cisplatin-resistant human ovarian cancer cells. Therefore, YAP-mediated autophagy should be explored as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies. PMID:27073322

  17. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    SciTech Connect

    Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

    2013-08-02

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

  18. Transplantation of ovarian granulosa-like cells derived from human induced pluripotent stem cells for the treatment of murine premature ovarian failure

    PubMed Central

    LIU, TE; LI, QIONG; WANG, SUWEI; CHEN, CHUAN; ZHENG, JIN

    2016-01-01

    Premature ovarian failure (POF) is a common cause of female infertility, for which there are currently no ideal treatments or medications. Furthermore, apoptosis of ovarian granulosa cells (OGCs) is an important mechanism underlying the decline in ovarian reserve and function. In the present study, several cellular growth factors and hormones were used to induce the differentiation of human induced pluripotent stem cells (iPSCs) into ovarian granulosa-like cells (OGLCs) in vitro. Immunohistochemical staining demonstrated that OGLCs derived from iPSCs strongly expressed granulosa cell markers, including anti-Müllerian hormone, inhibin α, inhibin β and follicle-stimulating hormone receptor, but did not express stem cell markers, including octamer-binding transcription factor 4, SRY (sex determining region Y)-box 2, Nanog and stage-specific embryonic antigen-4 12 days post-induction. In addition, a mouse model of POF was generated by cyclophosphamide treatment. Subsequently, iPSC-derived OGLCs were transplanted into the POF mice (OGLCs-iPSCs-POF group) in vivo. Results indicated that, compared with the control group (POF mice treated with phosphate-buffered saline), the growth state of OGLCs was markedly improved, and mature follicles could be detected in the ovarian tissue of the OGLCs-iPSCs-POF group. Immunohistochemical staining demonstrated that iPSC-derived OGLCs transplanted into POF mice not only exhibited substantial growth in murine ovarian tissues, but also strongly expressed OGC markers. Furthermore, enzyme-linked immunosorbent assays indicated that the levels of the hormone estradiol in peripheral blood samples were significantly enhanced following transplantation of iPSC-derived OGLCs into POF mice. Furthermore, ovarian tissue weight was significantly higher in the OGLCs-iPSCs-POF group compared with in the control group, and the number of atretic follicles in OGLCs-iPSCs-POF mice was significantly reduced, as compared with in the control mice. These

  19. Milder is better? advantages and disadvantages of "mild" ovarian stimulation for human in vitro fertilization

    PubMed Central

    2011-01-01

    In the last decades, several steps have been made aiming at rendering human IVF more successful on one side, more tolerable on the other side. The "mild" ovarian stimulation approach, in which a lower-than-average dose of exogenous gonadotropins is given and gonadotropin treatment is started from day 2 to 7 of the cycle, represents a significant step toward a more patient's friendly IVF. However, a clear view of its virtues and defects is still lacking, because only a few prospective randomized trials comparing "mild" vs. conventional stimulation exist, and they do not consider some important aspects, such as, e.g., thawing cycles. This review gives a complete panorama of the "mild" stimulation philosophy, showing its advantages vs. conventional ovarian stimulation, but also discussing its disadvantages. Both patients with a normal ovarian responsiveness to exogenous gonadotropins and women with a poor ovarian reserve are considered. Overall, we conclude that the level of evidence supporting the use of "mild" stimulation protocols is still rather poor, and further, properly powered prospective studies about "mild" treatment regimens are required. PMID:21324155

  20. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition.

    PubMed

    Zhang, Jie; Wang, Wenjing; Qian, Lin; Zhang, Qiuwan; Lai, Dongmei; Qi, Cong

    2015-11-01

    Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent. PMID:26323892

  1. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition.

    PubMed

    Zhang, Jie; Wang, Wenjing; Qian, Lin; Zhang, Qiuwan; Lai, Dongmei; Qi, Cong

    2015-11-01

    Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent.

  2. Luteinizing hormone receptors in human ovarian follicles and corpora lutea during the menstrual cycle

    SciTech Connect

    Yamoto, M.; Nakano, R.; Iwasaki, M.; Ikoma, H.; Furukawa, K.

    1986-08-01

    The binding of /sup 125/I-labeled human luteinizing hormone (hLH) to the 2000-g fraction of human ovarian follicles and corpora lutea during the entire menstrual cycle was examined. Specific high affinity, low capacity receptors for hLH were demonstrated in the 2000-g fraction of both follicles and corpora lutea. Specific binding of /sup 125/I-labeled hLH to follicular tissue increased from the early follicular phase to the ovulatory phase. Specific binding of /sup 125/I-labeled hLH to luteal tissue increased from the early luteal phase to the midluteal phase and decreased towards the late luteal phase. The results of the present study indicate that the increase and decrease in receptors for hLH during the menstrual cycle might play an important role in the regulation of the ovarian cycle.

  3. In vitro grown human ovarian follicles from cancer patients support oocyte growth

    PubMed Central

    Xu, Min; Barrett, Susan L.; West-Farrell, Erin; Kondapalli, Laxmi A.; Kiesewetter, Sarah E.; Shea, Lonnie D.; Woodruff, Teresa K.

    2009-01-01

    BACKGROUND Young female adult and adolescent cancer patients facing life-preserving but fertility-threatening chemo- or radiation-therapy are increasingly seeking options to protect their reproductive potential. Ovarian tissue cryopreservation with transplantation is a promising technique to safeguard fertility in cancer patients. However, this method may risk re-introduction of the original cancer to the survivor of the disease. Thus, developing a method for in vitro growth of immature follicles may provide a method for fertility restoration in the future. METHODS Human secondary follicles were isolated from ovarian tissues obtained from cancer patients and grown in vitro within a bio-engineered culture system for 30 days. RESULTS Human ovarian follicles became steroidogenically active, and developed from the early secondary to antral stage in vitro. The follicles contained healthy, growing oocytes that were connected by transzonal projections between the somatic cells and oocyte. CONCLUSIONS Our data support the notion that human follicle development can be achieved in vitro in a bio-engineered culture system. More studies are required to investigate whether the fully sized oocytes obtained from in vitro grown follicle are competent to resume meiosis and be fertilized. PMID:19597190

  4. Analytical Validation of AmpliChip p53 Research Test for Archival Human Ovarian FFPE Sections.

    PubMed

    Marton, Matthew J; McNamara, Andrew R; Nikoloff, D Michele; Nakao, Aki; Cheng, Jonathan

    2015-01-01

    The p53 tumor suppressor gene (TP53) is reported to be mutated in nearly half of all tumors and plays a central role in genome integrity. Detection of mutations in p53 can be accomplished by many assays, including the AmpliChip p53 Research Test. The AmpliChip p53 Research Test has been successfully used to determine p53 status in hematologic malignancies and fresh frozen solid tissues but there are few reports of using the assay with formalin fixed, paraffin-embedded (FFPE) tissue. The objective of this study was to describe analytical performance characterization of the AmpliChip p53 Research Test to detect p53 mutations in genomic DNA isolated from archival FFPE human ovarian tumor tissues. Method correlation with sequencing showed 96% mutation-wise agreement and 99% chip-wise agreement. We furthermore observed 100% agreement (113/113) of the most prevalent TP53 mutations. Workflow reproducibility was 96.8% across 8 samples, with 2 operators, 2 reagent lots and 2 instruments. Section-to-section reproducibility was 100% for each sample across a 60 μm region of the FFPE block from ovarian tumors. These data indicate that the AmpliChip p53 Research Test is an accurate and reproducible method for detecting mutations in TP53 from archival FFPE human ovarian specimens.

  5. Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise.

    PubMed

    Soleimani, Reza; Heytens, Elke; Darzynkiewicz, Zbigniew; Oktay, Kutluk

    2011-08-01

    The mechanism of chemotherapy-induced acceleration of ovarian aging is not fully understood. We used doxorubicin, a widely used cancer chemotherapeutic, in a variety of in vivo xenograft, and in vitro models to investigate the impact of chemotherapy-induced aging on the human ovary. Doxorubicin caused massive double-strand-DNA-breaks in primordial follicles, oocytes, and granulosa cells in a dose dependent fashion as revealed by accumulating γH2AX foci. This damage was associated with apoptotic oocyte death and resulted in the activation of ATM. It appeared that the repair response enabled a minor proportion of oocytes (34.7%) and granulosa cells (12.1%) to survive while the majority succumbed to apoptotic death. Paradoxically, inhibition of ATM by KU-55933 resulted in improved survival, probably via prevention of downstream activation of TAp63α. Furthermore, doxorubicin caused vascular and stromal damage in the human ovary, which might impair ovarian function both pre- and post-menopausally. Chemotherapy-induced premature ovarian aging appears to result from a complex process involving both the germ- and non-germ cell components of the ovary. These effects may have clinical implications in aging both for premenopausal and postmenopausal cancer survivors. PMID:21869459

  6. Recognition of serous ovarian tumors in human samples by multimodal nonlinear optical microscopy

    NASA Astrophysics Data System (ADS)

    Adur, Javier; Pelegati, Vitor B.; Costa, Leverson F. L.; Pietro, Luciana; de Thomaz, Andre A.; Almeida, Diogo B.; Bottcher-Luiz, Fatima; Andrade, Liliana A. L. A.; Cesar, Carlos L.

    2011-09-01

    We used a multimodal nonlinear optics microscopy, specifically two-photon excited fluorescence (TPEF), second and third harmonic generation (SHG/THG) microscopies, to observe pathological conditions of ovarian tissues obtained from human samples. We show that strong TPEF + SHG + THG signals can be obtained in fixed samples stained with hematoxylin and eosin (H&E) stored for a very long time, and that H&E staining enhanced the THG signal. We then used the multimodal TPEF-SHG-THG microscopies in a stored file of H&E stained samples of human ovarian cancer to obtain complementary information about the epithelium/stromal interface, such as the transformation of epithelium surface (THG) and the overall fibrillary tissue architecture (SHG). This multicontrast nonlinear optics microscopy is able to not only differentiate between cancerous and healthy tissue, but can also distinguish between normal, benign, borderline, and malignant specimens according to their collagen disposition and compression levels within the extracellular matrix. The dimensions of the layers of epithelia can also be measured precisely and automatically. Our data demonstrate that optical techniques can detect pathological changes associated with ovarian cancer.

  7. Analytical Validation of AmpliChip p53 Research Test for Archival Human Ovarian FFPE Sections.

    PubMed

    Marton, Matthew J; McNamara, Andrew R; Nikoloff, D Michele; Nakao, Aki; Cheng, Jonathan

    2015-01-01

    The p53 tumor suppressor gene (TP53) is reported to be mutated in nearly half of all tumors and plays a central role in genome integrity. Detection of mutations in p53 can be accomplished by many assays, including the AmpliChip p53 Research Test. The AmpliChip p53 Research Test has been successfully used to determine p53 status in hematologic malignancies and fresh frozen solid tissues but there are few reports of using the assay with formalin fixed, paraffin-embedded (FFPE) tissue. The objective of this study was to describe analytical performance characterization of the AmpliChip p53 Research Test to detect p53 mutations in genomic DNA isolated from archival FFPE human ovarian tumor tissues. Method correlation with sequencing showed 96% mutation-wise agreement and 99% chip-wise agreement. We furthermore observed 100% agreement (113/113) of the most prevalent TP53 mutations. Workflow reproducibility was 96.8% across 8 samples, with 2 operators, 2 reagent lots and 2 instruments. Section-to-section reproducibility was 100% for each sample across a 60 μm region of the FFPE block from ovarian tumors. These data indicate that the AmpliChip p53 Research Test is an accurate and reproducible method for detecting mutations in TP53 from archival FFPE human ovarian specimens. PMID:26125596

  8. Granulosa Cell Apoptosis Induced by a Novel FSH Binding Inhibitory Peptide From Human Ovarian Follicular Fluid

    PubMed Central

    Chitnis, Swati S.; Navlakhe, Rajshri M.; Shinde, Gayatri C.; Barve, Sharmila J.; D'Souza, Serena; Mahale, Smita D.; Nandedkar, Tarala D.

    2008-01-01

    Pituitary gonadotropins, follicle-stimulating hormone and luteinizing hormone, are the key regulators of ovarian folliculogenesis; these are known to be directly or indirectly modulated by many intraovarian factors. Our group has identified and studied one such novel peptide from human ovarian follicular fluid. Its partial N-terminal eight amino acid sequence has been deduced, referred to as octapeptide (OP). OP induces follicular atresia in mice and interferes with normal ovarian function in non-human primates, this action being similar to the native peptide. Thus, in this study, an attempt has been made to elucidate the mechanism of action of the synthetic OP by studying the pathway of follicular atresia in mouse ovary. Changes in granulosa cells were studied using various apoptotic markers by flow cytometry and immunohistochemistry. An increase in apoptotic cell population in atretic- and peptide-treated groups was observed compared with normal controls. Interestingly, both these groups exhibited differences in the apoptotic pathway. Results showed that the mitochondrial pathway was predominant in the atretic group, whereas the Fas-FasL pathway was predominant in the peptide-treated groups. The ultrastructural study also showed apoptotic changes in the OP-treated and atretic groups; the pattern of apoptosis differed at the subcellular level. (J Histochem Cytochem 56:961–968, 2008) PMID:18645207

  9. Amplification and overexpression of aurora kinase A (AURKA) in immortalized human ovarian epithelial (HOSE) cells.

    PubMed

    Chung, C M; Man, C; Jin, Y; Jin, C; Guan, X Y; Wang, Q; Wan, T S K; Cheung, A L M; Tsao, S W

    2005-07-01

    Immortalization is an early and essential step of human carcinogenesis. Amplification of chromosome 20q has been shown to be a common event in immortalized cells and cancers. We have previously reported that gain and amplification of chromosome 20q is a non-random and common event in immortalized human ovarian surface epithelial (HOSE) cells. The chromosome 20q harbors genes including TGIF2 (20q11.2-q12), AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and AURKA (20q13.2-q13.3), which were previously reported to be amplified and overexpressed in ovarian cancers. Some of these genes may be involved in immortalization of HOSE cells and represent crucial premalignant changes in ovarian surface epithelium. Investigation of the involvement of these genes was examined in four pairs of pre-crisis (preimmortalized) and post-crisis (immortalized) HOSE cells. Overexpression of AURKA (Aurora kinase A), also known as BTAK and STK15, by both real time-quantitative polymerase chain reaction (RT-QPCR) and Western blotting was detected in all the four immortalized HOSE cells examined while overexpression of AIB1 and ZNF217 was observed in two of four immortalized HOSE cells examined. Overexpression of TGIF2 and PTPN1 was not significant in our immortalized HOSE cell systems. The degree of overexpression of AURKA was shown to be closely associated with the amplification of chromosome 20q in immortalized HOSE cells. Fluorescence in situ hybridization (FISH) with labeled P1 artificial clone (PAC) confirmed the amplification of the chromosomal region (20q13.2-13.3) where AURKA resides. DNA amplification of AURKA was also confirmed using semi-quantitative PCR. Our study showed that amplification and overexpression of AURKA is a common and significant event during immortalization of HOSE cells and may represent an important premalignant change in ovarian carcinogenesis.

  10. Invasiveness of mouse embryos to human ovarian cancer cells HO8910PM and the role of MMP-9

    PubMed Central

    2012-01-01

    Background Our previous work found that mouse embryos could invade malignant cancer cells. In the process of implantation, embryo trophoblast cells express matrix metalloproteinases and the invasive ability of trophoblast cells is proportional to matrix metalloproteinase-9 protein expression. So the purpose of this study is to observe the effects of mouse embryos on human ovarian cancer cells in the co-culture environment in vitro and explore the possible mechanism of matrix metalloproteinase-9. Methods Several groups of human ovarian cancer cells HO8910PM were co-cultured with mouse embryos for different time duration, after which the effects of mouse embryos on morphology and growth behavior of HO8910PM were observed under the light microscope real-time or by H.E staining. Apoptosis was detected under laser confocal microscope by Annexin V-EGFP/PI staining in situ. Invasion ability of tumor cells was studied by transwell experiments. After matrix metalloproteinase 9 (MMP −9) activity was inhibited by MMP-9 Inhibitor I, the interaction between mouse embryos and human ovarian cancer cells HO8910PM was observed. Results Mouse embryos were able to invade co-cultured human ovarian cancer cell layer which extended in the bottom of the culture dish, and gradually pushed away tumor cells to form their own growth space. The number of apoptosis tumor cells surrounding the embryo increased under laser confocal microscope. After co-cultured with mouse embryos, tumor cells invasive ability was lowered compared with the control group. After MMP-9 activity was inhibited, the interaction between mouse embryos and HO8910PM cells had no significant difference compared with the normal MMP-9 activity group. Conclusion Mouse embryos were able to invade human ovarian cancer cells in vitro and form their own growth space, promote apoptosis of human ovarian cancer cells and lower their invasive ability. The mouse embryo was still able to invade human ovarian cancer cells after MMP-9

  11. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells

    PubMed Central

    Deng, Youlin; Zhang, Junhui; Wang, Zhongliang; Yan, Zhengjian; Qiao, Min; Ye, Jixing; Wei, Qiang; Wang, Jing; Wang, Xin; Zhao, Lianggong; Lu, Shun; Tang, Shengli; Mohammed, Maryam K.; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Zou, Yulong; Liao, Junyi; Qi, Hongbo; Haydon, Rex C.; Luu, Hue H.; He, Tong-Chuan; Tang, Liangdan

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12–24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID:26639992

  12. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells.

    PubMed

    Deng, Youlin; Zhang, Junhui; Wang, Zhongliang; Yan, Zhengjian; Qiao, Min; Ye, Jixing; Wei, Qiang; Wang, Jing; Wang, Xin; Zhao, Lianggong; Lu, Shun; Tang, Shengli; Mohammed, Maryam K; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Zou, Yulong; Liao, Junyi; Qi, Hongbo; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan; Tang, Liangdan

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12-24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID:26639992

  13. Topographical investigations of human ovarian-carcinoma polymorphic epithelial mucin by scanning tunnelling microscopy.

    PubMed Central

    Roberts, C J; Sekowski, M; Davies, M C; Jackson, D E; Price, M R; Tendler, S J

    1992-01-01

    Human polymorphic epithelial mucin is a high-molecular-mass glycoprotein that associates to provide protection to the epithelial-cell surface and may afford the malignant cell a selective advantage for growth. The scanning-tunnelling-microscopy micrographs obtained in the present study identify the purified human ovarian-carcinoma polymorphic epithelial mucin glycoproteins as rod-shaped molecules of mixed length. The dimensions of the individual molecules range from 25 to 45 nm in length and are 3-4 nm in width. The images further suggest that lateral association of the rods occurs. Images Fig. 1. Fig. 2. PMID:1567366

  14. Genetic modeling of ovarian phenotypes in mice for the study of human polycystic ovary syndrome.

    PubMed

    Feng, Yi; Li, Xin; Shao, Ruijin

    2013-01-01

    Polycystic ovary syndrome (PCOS) presents with a range of clinical complications including hyperandrogenism, polycystic ovaries, chronic oligo/anovulation, infertility, and metabolic alterations related to insulin resistance. Because the mechanism by which this disorder develops is poorly understood, information from experimental models of human disease phenotypes may help to define the mechanisms for the initiation and development of PCOS-related pathological events. The establishment of animal models compatible with human PCOS is challenging, and applying the lessons learned from these models to human PCOS is often complicated. In this mini-review we provide examples of currently available genetic mouse models, their ovarian phenotypes, and their possible relationship to different aspects of human PCOS. Because of the practical and ethical limitations of studying PCOS-related events in humans, our understanding of the mechanisms that contribute to the etiology of human PCOS may be enhanced through further study of these transgenic and knockout mouse models. PMID:23390562

  15. The human Müllerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer

    PubMed Central

    Kersual, Nathalie; Garambois, Véronique; Chardès, Thierry; Pouget, Jean-Pierre; Salhi, Imed; Bascoul-Mollevi, Caroline; Bibeau, Frédéric; Busson, Muriel; Vié, Henri; Clémenceau, Béatrice; Behrens, Christian K; Estupina, Pauline; Pèlegrin, André; Navarro-Teulon, Isabelle

    2014-01-01

    Ovarian cancer has the highest mortality rate among gynecologic malignancies. The monoclonal antibody 12G4 specifically recognizes the human Müllerian inhibiting substance type II receptor (MISRII) that is strongly expressed in human granulosa cell tumors (GCT) and in the majority of human epithelial ovarian cancers (EOC). To determine whether MISRII represents an attractive target for antibody-based tumor therapy, we first confirmed by immunohistochemistry with 12G4 its expression in all tested GCT samples (4/4) and all, but one, EOC human tissue specimens (13/14). We then demonstrated in vitro the internalization of 12G4 in MISRIIhighCOV434 cells after binding to MISRII and its ability to increase the apoptosis rate (FACS, DNA fragmentation) in MISRIIhighCOV434 (GCT) and MISRIImediumNIH-OVCAR-3 (EOC) cells that express different levels of MISRII. A standard 51Cr release assay showed that 12G4 mediates antibody-dependent cell-meditated cytotoxicity. Finally, in vivo assessment of 12G4 anti-tumor effects showed a significant reduction of tumor growth and an increase of the median survival time in mice xenografted with MISRIIhighCOV434 or MISRIImediumNIH-OVCAR-3 cells and treated with 12G4 in comparison to controls treated with an irrelevant antibody. Altogether, our data indicate that MISRII is a new promising target for the control of ovarian GCTs and EOCs. A humanized version of the 12G4 antibody, named 3C23K, is in development for the targeted therapy of MISRII-positive gynecologic cancers. PMID:25517316

  16. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression.

    PubMed Central

    Naylor, M S; Stamp, G W; Foulkes, W D; Eccles, D; Balkwill, F R

    1993-01-01

    The gene for tumor necrosis factor, TNF, was expressed in 45 out of 63 biopsies of human epithelial ovarian cancer. In serous tumors, there was a positive correlation between level of TNF expression and tumor grade. TNF mRNA was found in epithelial tumor cells and infiltrating macrophages, whereas TNF protein localized primarily to a subpopulation of macrophages within and in close proximity to tumor areas. mRNA and protein for the p55 TNF receptor gene localized to the tumor epithelium and tumor, but not to stromal macrophages. The p75 TNF receptor was confined to infiltrating cells. Cells expressing TNF mRNA were also found in ovarian cancer ascites and TNF protein was detected in some ascitic fluids. In 2 out of 12 biopsies of normal ovary, TNF mRNA was detected in a minority of cells in the thecal layer of the corpus luteum. Serum levels of TNF and its soluble receptor did not correlate with extent of TNF expression in matched biopsies. Northern and Southern analysis revealed no gross abnormality of the TNF gene. The coexpression of TNF and its receptor in ovarian cancer biopsies suggests the capacity for autocrine/paracrine action. TNF antagonists may have therapeutic potential in this malignancy. Images PMID:8387543

  17. Effects of HCG on human epithelial ovarian cancer vasculogenic mimicry formation in vivo

    PubMed Central

    GAO, SAINAN; FAN, CHAO; HUANG, HUA; ZHU, CHANGLAI; SU, MIN; ZHANG, YUQUAN

    2016-01-01

    Ovarian cancer is the leading cause of mortality due to gynecological malignancy, and vasculogenic mimicry (VM) formation is correlated with poor prognosis. In a previous study, the present authors observed that human chorionic gonadotropin (HCG) could promote VM formation in three-dimensional OVCAR-3 cell cultures. In order to investigate whether HCG could promote VM formation in ovarian cancer in vivo, the role of OVCAR-3 cells overexpressing or depleted of chorionic gonadotropin, beta polypeptide 5 (CGB5, which is the fifth subunit of β-HCG and was identified as the key part of HCG) were injected into nude mice in the present study, while BeWo cells were used as a positive control. The results demonstrated that overexpressed CGB5 promoted xenografts tumor formation in nude mice, and the results of hematoxylin and eosin and cluster of differentiation (CD)34-periodic acid-Schiff dual staining revealed that CGB5 promoted VM formation. Furthermore, reverse transcription-polymerase chain reaction and immunochemistry staining demonstrated that the expression of the vascular markers CD31, vascular endothelial growth factor and factor VIII was also upregulated in the CGB5-overexpressing xenografts tumors. In addition, the expression of luteinizing hormone receptor (LHR), the receptor of CGB5, was increased in CGB5-overexpressing cells. In conclusion, CGB5 may promote tumor growth and VM formation via activation of the LHR signal transduction pathway, which may support a novel strategy for ovarian cancer therapy. PMID:27347165

  18. Toward in-vivo photoacoustic imaging of human ovarian tissue for cancer detection

    NASA Astrophysics Data System (ADS)

    Aguirre, Andres; Kumavor, Patrick; Ardeshirpour, Yasaman; Sanders, Mary M.; Brewer, Molly; Zhu, Quing

    2011-03-01

    Currently, most of the cancers in the ovary are detected when they have already metastasized to other parts of the body. As a result, ovarian cancer has the highest mortality of all gynecological cancers with a 5-year survival rate of 30% or less [1]. The reason is the lack of reliable symptoms as well as the lack of efficacious screening techniques [2,3]. Thus, there is an urgent need to improve the current diagnostic techniques. We have investigated the potential role of co-registered photoacoustic and ultrasound imaging in ovarian cancer detection. In an effort to bring this technique closer to clinical application, we have developed a co-registered ultrasound and photoacoustic transvaginal probe. A fiber coupling assembly has been developed to deliver the light from around the transducer for reflection geometry imaging. Co-registered ultrasound and photoacoustic images of swine ovaries through vagina wall muscle and human ovaries using the aforementioned probe, demonstrate the potential of photoacoustic imaging to non-invasively detect ovarian cancer in vivo.

  19. Apoptotic pathways in ovarian surface epithelium of human embryos during embryogenesis and carcinogenesis: close relationship of developmental plasticity and neoplasm.

    PubMed

    Caric, Ana; Poljicanin, Ana; Tomic, Snjezana; Vilovic, Katarina; Saraga-Babic, Mirna; Vukojevic, Katarina

    2014-03-01

    Cell differentiation and different pathways of cell death were immunohistochemically analyzed in ovaries of six human embryos, 20 serous borderline tumors (SBT) and ovarian serous carcinomas (OSC) using markers for apoptosis (caspase-3, AIF, TUNEL) and stemness (Oct-4). In the 5-8-week ovaries, caspase-3 was absent in the ovarian surface epithelium (ose) and mildly positive in the ovarian stroma (os), AIF was expressed moderately, while Oct-4 expression gradually decreased during that period. Some ovarian cells expressed only caspase-3 or AIF together with TUNEL, while both caspase-3 and AIF were co-expressed in other ovarian cells. Mild expression of Oct-4 and caspase-3 characterized some cells of SBT, while their expression varied from mild to strong in OSC. AIF displayed mild to strong expression in ose of SBT and moderate to strong expression in OSC, while no expression of AIF was observed in os of both tumors. In the ose of both SBT and OSC, caspase-3 and AIF were co-expressed only occasionally, while AIF and Oct-4 were co-expressed strongly. Our study showed the presence of stemness cells and different pathways of cell death (caspase-3 and AIF-mediated) in the ovarian tissue during development and carcinogenesis, indicating the correlation between developmental plasticity in human embryonic ovaries and OSC.

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

    PubMed

    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.

  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. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer.

    PubMed

    Borgoño, Carla A; Grass, Linda; Soosaipillai, Antoninus; Yousef, George M; Petraki, Constantina D; Howarth, David H C; Fracchioli, Stefano; Katsaros, Dionyssios; Diamandis, Eleftherios P

    2003-12-15

    Human kallikrein gene 14 (KLK14) is a recently discovered member of the tissue kallikrein family of secreted serine proteases, which includes hK3/prostate-specific antigen, the best cancer biomarker to date. Given that KLK14 is hormonally regulated, differentially expressed in endocrine-related cancers, and a prognostic marker for breast and ovarian cancer at the mRNA level, we hypothesize that its encoded protein, hK14, like hK3/prostate-specific antigen, may constitute a new biomarker for endocrine-related malignancies. The objective of this study was to generate immunological reagents for hK14, to develop an ELISA and immunohistochemical techniques to study its expression in normal and cancerous tissues and biological fluids. Recombinant hK14 was produced in Pichia pastoris, purified by affinity chromatography, and injected into mice and rabbits for polyclonal antibody generation. Using the mouse and rabbit antisera, a sandwich-type immunofluorometric ELISA and immunohistochemical methodologies were developed for hK14. The ELISA was sensitive (detection limit of 0.1 micro g/liter), specific for hK14, linear from 0 to 20 micro g/liter with between-run and within-run coefficients of variation of <10%. hK14 was quantified in human tissue extracts and biological fluids. Highest levels were observed in the breast, skin, prostate, seminal plasma, and amniotic fluid, with almost undetectable levels in normal serum. hK14 concentration was higher in 40% of ovarian cancer tissues compared with normal ovarian tissues. Serum hK14 levels were elevated in a proportion of patients with ovarian (65%) and breast (40%) cancers. Immunohistochemical analyses indicated strong cytoplasmic staining of hK14 by the epithelial cells of normal and malignant skin, ovary, breast, and testis. In conclusion, we report the first ELISA and immunohistochemical assays for hK14 and describe its distribution in tissues and biological fluids. Our preliminary data indicate that hK14 is a potential

  3. Gonadotropin binding sites in human ovarian follicles and corpora lutea during the menstrual cycle

    SciTech Connect

    Shima, K.; Kitayama, S.; Nakano, R.

    1987-05-01

    Gonadotropin binding sites were localized by autoradiography after incubation of human ovarian sections with /sup 125/I-labeled gonadotropins. The binding sites for /sup 125/I-labeled human follicle-stimulating hormone (/sup 125/I-hFSH) were identified in the granulosa cells and in the newly formed corpora lutea. The /sup 125/I-labeled human luteinizing hormone (/sup 125/I-hLH) binding to the thecal cells increased during follicular maturation, and a dramatic increase was preferentially observed in the granulosa cells of the large preovulatory follicle. In the corpora lutea, the binding of /sup 125/I-hLH increased from the early luteal phase and decreased toward the late luteal phase. The changes in 3 beta-hydroxysteroid dehydrogenase activity in the corpora lutea corresponded to the /sup 125/I-hLH binding. Thus, the changes in gonadotropin binding sites in the follicles and corpora lutea during the menstrual cycle may help in some important way to regulate human ovarian function.

  4. CHD1L Protein is overexpressed in human ovarian carcinomas and is a novel predictive biomarker for patients survival

    PubMed Central

    2012-01-01

    Background Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. However, the status of CHD1L protein expression in ovarian cancer and its clinical/prognostic significance are obscure. Methods In this study, immunohistochemistry (IHC) for CHD1L was performed on a tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44 metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis was used to evaluate patients’ survival status. Results There is an augmented tendency of CHD1L expression in ovarian carcinoma metastasis than in primary lesions (P<0.05). A significant association was found between positive expression of CHD1L and tumors histological type (P <0.05). By univariate survival analysis of the ovarian carcinoma cohorts, positive expression of CHD1L was significantly correlated with shortened patient survival (mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was evaluated to be a significant and independent prognostic factor in multivariate analysis (P<0.05). Conclusions These findings provide evidence that positive expression of CHD1L protein is significantly correlated with the metastasis proceeding of ovarian carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel prognostic biomarker for patients with ovarian carcinoma. PMID:23020525

  5. BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?

    PubMed Central

    Tagliaferri, Pierosandro; Ventura, Monica; Baudi, Francesco; Cucinotto, Iole; Arbitrio, Mariamena; Di Martino, Maria Teresa; Tassone, Pierfrancesco

    2009-01-01

    Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients. PMID:19825178

  6. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

    PubMed

    Li, Dan; Williams, Jon I; Pietras, Richard J

    2002-04-25

    Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status

  7. 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

    2016-02-01

    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.

  8. [Temporal Pattern of DNA Breaks in Human Ovarian Cancer Cells after Exposure to Nanosecond Electric Pulses].

    PubMed

    Liu, Shaoli; Fu, Xiao; Ren, Xueyi; Yu, Tinghe; Hu, Lima

    2015-10-01

    This study aims to explore the temporal pattern of DNA breaks induced by nanosecond electric pulses (nsEP) in cisplatin-sensitive and cisplatin-resistant human ovarian cancer cells. Human ovarian cancer cells A2780 (cisplatin-sensitive subline) and C30 (cisplatin-resistant subline) were exposed to nsEP. Sham exposed groups were shame exposed to nsEP. Cell viability was determined using CCK-8 assay after 0 h, 4 h, 8 h, 12 h and 24 h, respectively, and the percentage of dead cells was calculated. The DNA break was detected with the alkaline single cell gel electrophoresis (comet assay), and the 75th percentiles of TL (tail length), TM (tail moment) and OTM (Olive tail moment) were measured. Cell viability displayed an early decrease and late increase, with the valley value seen at 8 h. Percentages of cell death and comet-formed in A2780 cells were higher than those in C30 cells (P < 0.05) at 8 h, respectively. TL, TM and OTM in C30 cells were less than those in A2780 cells (P < 0.05). The percentage of comet-formed correlated with that of cell death in either A2780 (r = 0.997, P < 0.05) or C30 (r = 0.998, P < 0.05) cells. DNA breaks induced by nsEP in cisplatin-sensitive cells differred from that in resistant cells, and DNA break resulted in fraction of cell death.

  9. 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

    2016-02-01

    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. PMID:26725849

  10. Antiangiogenic Therapy with Human Apolipoprotein(a) Kringle V and Paclitaxel in a Human Ovarian Cancer Mouse Model12

    PubMed Central

    Yu, Hyun-Kyung; Lee, Ho-Jeong; Yun, Seok-Joong; Lee, Sun-Joo; Langley, Robert R.; Yoon, Yeup; Yi, Lee S.H.; Bae, Duk-Soo; Kim, Jang-Seong; Kim, Sun Jin

    2014-01-01

    INTRODUCTION: The present study compared the effect of combination therapy using human apolipoprotein(a) kringle V (rhLK8) to conventional chemotherapy with paclitaxel for human ovarian carcinoma producing high or low levels of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Human ovarian carcinoma cells producing high (SKOV3ip1) or low (HeyA8) levels of VEGF were implanted into the peritoneal cavity of female nude mice. Seven days later, mice were randomized into four groups: control (vehicle), paclitaxel [5 mg/kg, weekly intraperitoneal (i.p.) injection], rhLK8 (50 mg/kg, daily i.p. injection), or the combination of paclitaxel and rhLK8. Mice were treated for 4 weeks and examined by necropsy. RESULTS: In mice implanted with SKOV3ip1 cells, rhLK8 treatment had no significant effect on tumor incidence or the volume of ascites but induced a significant decrease in tumor weight compared with control mice. Paclitaxel significantly reduced tumor weight and ascites volume, and combination treatment with paclitaxel and rhLK8 had an additive therapeutic effect. Similarly, in HeyA8 mice, the effect of combination treatment on tumor weight and tumor incidence was statistically significantly greater than that of paclitaxel or rhLK8 alone. Immunohistochemical analysis showed a significant decrease in microvessel density and a marked increase of apoptosis in tumor and tumor-associated endothelial cells in response to combination treatment with paclitaxel and rhLK8. CONCLUSION: Collectively, these results suggest that antiangiogenic therapy with rhLK8 in combination with taxane-based conventional chemotherapy could be effective for the treatment of ovarian carcinomas, regardless of VEGF status. PMID:25180060

  11. The pro-adhesive and pro-survival effects of glucocorticoid in human ovarian cancer cells.

    PubMed

    Yin, Lijuan; Fang, Fang; Song, Xinglei; Wang, Yan; Huang, Gaoxiang; Su, Jie; Hui, Ning; Lu, Jian

    2016-07-01

    Cell adhesion to extracellular matrix (ECM) is controlled by multiple signaling molecules and intracellular pathways, and is pivotal for survival and growth of cells from most solid tumors. Our previous works demonstrated that dexamethasone (DEX) significantly enhances cell adhesion and cell resistance to chemotherapeutics by increasing the levels of integrin β1, α4, and α5 in human ovarian cancer cells. However, it is unclear whether the components of ECM or other membrane molecules are also involved in the pro-adhesive effect of DEX in ovarian cancer cells. In this study, we demonstrated that the treatment of cells with DEX did not change the expression of collagens (I, III, and IV), laminin, CD44, and its principal ligand hyaluronan (HA), but significantly increased the levels of intracellular and secreted fibronectin (FN). Inhibiting the expression of FN with FN1 siRNA or blocking CD44, another FN receptor, with CD44 blocking antibody significantly attenuated the pro-adhesion of DEX, indicating that upregulation of FN mediates the pro-adhesive effect of DEX by its interaction with CD44 besides integrin β1. Moreover, DEX significantly enhanced cell resistance to the chemotherapeutic agent paclitaxel (PTX) by activating PI-3K-Akt pathway. Finally, we found that DEX also significantly upregulated the expression of MUC1, a transmembrane glycoprotein. Inhibiting the expression of MUC1 with MUC1 siRNA significantly attenuated the DEX-induced effects of pro-adhesion, Akt-activation, and pro-survival. In conclusion, these results provide new data that upregulation of FN and MUC1 by DEX contributes to DEX-induced pro-adhesion and protects ovarian cancer cells from chemotherapy. PMID:27151574

  12. Gene modification of primary tumor cells for active immunotherapy of human breast and ovarian cancer.

    PubMed

    Philip, R; Clary, B; Brunette, E; Kilinski, L; Murugesh, D; Sorich, M; Yau, J; Lebkowski, J; Lyerly, H K; Philip, M

    1996-01-01

    We have previously shown that cationic liposomes facilitate adeno-associated virus (AAV) plasmid transfections of primary and cultured cell types. To test the clinical feasibility of using genetically modified tumor vaccines for the treatment of breast and ovarian cancers, we have constructed an expression plasmid pMP6IL2 and investigated the use of liposome-mediated gene delivery into primary, uncultured human breast and ovarian tumor cells to produce interleukin 2 (IL-2)-secreting tumor cells. We have demonstrated significant levels of IL-2 expression in tumor cell lines and primary breast and ovarian tumor cells using this AAV-based expression plasmid complexed to cationic liposomes. Transfections with the non-AAV plasmid containing the identical expression cassette as the AAV plasmid induced IL-2 expression in the tumor cell line but failed to produce IL-2 in primary tumor cells. Significant levels of IL-2 were induced with the AAV plasmid regardless of liposome compositions used for transfection. The transfected breast cell line and primary tumor cells were able to express the transgene product for up to 28 days after lethal radiation. The transfection efficiency was comparable for both the tumor cell line and primary tumor cells and ranged from 20 to 50% for both cell types as assessed by intracellular IL-2 staining. Although the primary tumor cell preparations consist of mixed population of cells, at least 40% of the tumor cells expressed the transgene as assessed by immunostaining for IL-2. The ability to efficiently express transgenes in freshly isolated, nondividing tumor cells may potentiate active immunotherapy strategies for gene-based cancer treatment.

  13. 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

  14. Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells.

    PubMed Central

    Obiri, N I; Siegel, J P; Varricchio, F; Puri, R K

    1994-01-01

    It has previously been shown that murine sarcoma cells express high-affinity IL-4 receptors (IL-4R) which are internalized after binding to the ligand (Puri et al., Cancer Res 1991; 51:3011-7). We have also reported that human renal cell carcinoma cells express high-affinity IL-4R, and IL-4 inhibits tumour growth in vitro (Obiri et al., J Clin Invest 1993; 91:88). In this study we investigated the expression and function of IL-4R on other human solid tumours. Human melanoma, ovarian carcinoma and breast carcinoma cell lines were assessed for the cell surface expression of IL-4R by radio-ligand receptor binding and for IL-4R gene expression by Northern blot analysis. Primary cultures of mesothelioma and neurofibrosarcoma cells were similarly investigated. Human melanoma, ovarian carcinoma and breast carcinoma cell lines expressed IL-4R on their cell surface with a dissociation constant (Kd) of 140-549 pM. These tumour lines expressed a single 4 kb species of mRNA for IL-4R. Similarly, primary cultures of mesothelioma and neurofibrosarcoma cells were positive for the IL-4R mRNA by Northern blot analysis. Fresh, non-cultured mesothelioma and neurofibrosarcoma tumour sections were also positive for the presence of IL-4R as determined by immunohistochemistry of frozen sections using anti-IL-4R antibody. In order to study possible functions of IL-4R, we evaluated the effects of IL-4 on cell growth and its effect on MHC antigen expression in the presence or absence of interferon-gamma (IFN-gamma). In tissue culture, IL-4 reduced the growth of tumour cell lines and primary cell cultures studied. IL-4 had very little effect on MHC class I antigen expression on ovarian, breast and melanoma cell lines; however, MHC class II (HLA-DR) expression was enhanced on melanoma and breast carcinoma cells. IL-4 also enhanced the IFN-gamma-induced class II expression on melanoma and breast carcinoma cells. Taken together, our observations indicate that IL-4R are expressed on a variety of

  15. TLR4 activates NF-{kappa}B in human ovarian granulosa tumor cells

    SciTech Connect

    Woods, Dori C.; Johnson, A.L.

    2011-06-17

    Highlights: {yields} TLR4 is expressed in human ovarian granulosa tumor cells. {yields} Acting through TLR4, LPS and HSP60 induce a NF{kappa}B signaling cascade in human ovarian granulosa tumor cells. {yields} NF{kappa}B activation or inhibition did not alter chemosensitivity to TRAIL or cisplatin. -- Abstract: Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-{kappa}B) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to I{kappa}B degradation and activation of NF-{kappa}B. NF-{kappa}B activation was confirmed by nuclear localization of NF-{kappa}B p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-{kappa}B signaling attenuated LPS-induced TNF{alpha} plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-{kappa}B signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-{kappa}B does not sensitize GCTs to TRAIL or cisplatin.

  16. Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro.

    PubMed

    Li, Juan; Liu, Peishu; Mao, Hongluan; Wanga, Ancong; Zhang, Xiaolei

    2009-06-01

    Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world, and the development of drug resistance is a major impediment toward successful treatment of the desease. Emodin has been reported to sensitize human tumor cells to chemotherapeutic agents. The present study investigated whether emodin could overcome chemoresistance of A2780/taxol cells. Cells were treated with different concentration of emodin alone or combined with paclitaxel, then the cell viability was measured by MTT and the apoptosis was determined by flow cytometric analysis. The changes of mRNA and protein were examined by QRT-PCR and Western blotting. The function of P-glycoprotein was also determined by flow cytometry. The results showed that emodin induced apoptosis alone at a high concentration and increased paclitaxel-induced apoptosis at a low concentration. It enhanced the sensitivity of A2780/taxol cells to paclitaxel with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, the results demonstrated a dual role for emodin in the inhibition of drug resistant ovarian tumor growth by increasing paclitaxel cellular concentration and re-sensitizing the resistant cells to paclitaxel. Our results suggest the possibility of an innovative chemotherapeutic strategy that uses emodin in combination with paclitaxel to increase the sensitivity of tumor cells. PMID:19424643

  17. Differential in vitro effects of chemotherapeutic agents on primary cultures of human ovarian carcinoma.

    PubMed

    Kornblith, P; Ochs, R L; Wells, A; Gabrin, M J; Piwowar, J; Chattopadhyay, A; George, L D; Burholt, D

    2004-01-01

    The treatment of ovarian cancer principally relies on the use of platinum and taxane chemotherapeutic agents. Short-term clinical results have been encouraging, but long-term responses remain limited. In this report, an in vitro assay system that utilizes cells grown from human tumor explants has been used to quantitatively evaluate responses to relevant concentrations of alternative chemotherapeutic agents. The results suggest that there are significant differences in the responses of explant-derived cultured cells to the different agents tested. In an evaluation of 276 primary ovarian cancer specimens, five nonstandard drugs were tested in 51 cases. Of these 51 cases, cyclophosphamide had the highest rate of response at 67%, followed by doxorubicin at 61%, gemcitabine at 49%, etoposide at 48%, and topotecan at 14%. Venn diagrams, representing the in vitro responses to the platins and taxanes, as well as the responses to the nonstandard drugs, illustrate that there clearly are distinct differences among patients in a given population. These data underscore the potential importance of evaluating each patient's response to a number of different drugs to optimize the therapeutic decision-making process. PMID:15304154

  18. Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination.

    PubMed

    Little, Deirdre Therese; Ward, Harvey Rodrick Grenville

    2012-09-30

    Premature ovarian failure in a well adolescent is a rare event. Its occurrence raises important questions about causation, which may signal other systemic concerns. This patient presented with amenorrhoea after identifying a change from her regular cycle to irregular and scant periods following vaccinations against human papillomavirus. She declined the oral contraceptives initially prescribed for amenorrhoea. The diagnostic tasks were to determine the reason for her secondary amenorrhoea and then to investigate for possible causes of the premature ovarian failure identified. Although the cause is unknown in 90% of cases, the remaining chief identifiable causes of this condition were excluded. Premature ovarian failure was then notified as a possible adverse event following this vaccination. The young woman was counselled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold potential implications for population health and prompts further inquiry.

  19. Effect of nickel (ni(2+)) on primary human ovarian granulosa cells in vitro.

    PubMed

    Révész, Csaba; Forgács, Zsolt; Lázár, Péter; Mátyás, Szabolcs; Rajczy, Klára; Krizsa, Ferenc; Bernard, Artúr; Gáti, István

    2004-01-01

    Human ovarian granulosa cells obtained from women undergoing in vitro fertilization were exposed to 15.6, 31.25, 62.5, 125, 250, 500, 1000 muM Ni(2+) for 48 h. To determine the site of action of Ni(2+), the granulosa cells were stimulated to produce progesterone (P) by using maximally stimulating amounts of human chorionic gonadotropin (0.1 IU/ml hCG) or dibutyryl cyclic adenosine monophosphate (1 mM db-cAMP). The luteinizing hormone (LH) analog hCG was chosen because resultant P production requires an intact membrane receptor and db-cAMP was used to test for post LH receptor defects caused by Ni(2+). Progesterone content of the culture medium was determined by radioimmunoassay (RIA), and viability of the cells was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction test. Concentration-dependent depression in both hGC and db-cAMP stimulated P production was seen at 15.625 muM or higher concentration of Ni(2+), which is not cytotoxic on human ovarian granulosa cells. The viability of cells was unaffected up to 31.25 muM and decreased significantly at 62.5 muM. Our results show a dose-related depression in stimulated P production of granulosa cells at a dose that does not induce significant cytotoxic action. These data indicate that the effect of Ni(2+) on P production is not due to cytotoxicity, and the cellular site(s) of inhibitory action appears to be subsequent to the membrane receptor and production of cAMP.

  20. The human ovarian cancer cell line CABA I: A peculiar genetic evolution

    PubMed Central

    GIUSTI, ILARIA; CERVELLI, CARLA; D'ASCENZO, SANDRA; DI FRANCESCO, MARIANNA; LIGAS, CLAUDIO; D'ALESSANDRO, ELVIRA; PAPOLA, FRANCO; DOLO, VINCENZA

    2016-01-01

    The objective of this study was to study the human ovarian cancer cell line CABA I by means of short tandem repeats (STR) profiling and cytogenetic analysis in order to prevent future misidentification or cross-contamination and verify its stability during in vitro cultivation. To this end, cells at passages 18 and 38 were analyzed using cytogenetic techniques in order to verify possible chromosomal aberrations and the karyotypic evolution of this cell line; GTG-banding and FISH were also performed. For STR analysis, DNA was extracted using the automated extractor MagNA pure and analyzed by means of PowerPlex 16 HS. STR profiles were analyzed by GeneMapper 3.2.1 software. Whereas comparative cytogenetic analysis of CABA I cells at passage 18 and 38 has demonstrated considerable genetic instability, we found that STR profiles were essentially unaltered in both analyzed passages, suggesting that the STR profile is reliable and could be used for the regular authentication of CABA I over time. It should be emphasized, however, that of the 16 loci generally used in human STR profiles, only 3 were properly detectable in CABA I. The data highlight that the CABA I cell line demonstrates an anomalous STR profile that does not fully adjust the criteria currently used for the identification of human cells; in spite of this, it remains stable during the in vitro maintainance. Moreover, the genetic instability of the CABA I cell line overlaps with those observed in vivo in tumor cells, making it a suitable candidate to analyze, in vitro, the peculiar genetic evolution of ovarian cancer cells. PMID:26934856

  1. L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.

    PubMed

    Hong, Hao; Brown, Christine E; Ostberg, Julie R; Priceman, Saul J; Chang, Wen-Chung; Weng, Lihong; Lin, Paul; Wakabayashi, Mark T; Jensen, Michael C; Forman, Stephen J

    2016-01-01

    New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer. PMID:26761817

  2. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    SciTech Connect

    Kim, Soyeon; Lee, Jae-Jung; Heo, Dae Seog

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR{gamma} ligands

  3. MiR-197 induces Taxol resistance in human ovarian cancer cells by regulating NLK.

    PubMed

    Zou, Dongling; Wang, Dong; Li, Rong; Tang, Ying; Yuan, Li; Long, Xingtao; Zhou, Qi

    2015-09-01

    Chemotherapy is the preferred therapeutic approach for the therapy of advanced ovarian cancer, but 5-year survival rate remains low due to the development of drug resistance. Increasing evidence has documented that microRNAs (miRNAs) act important roles in drug resistance in a variety types of cancer. However, the roles of miRNA in regulating Taxol resistance in ovarian cancer and the detailed mechanism are less reported. We used Taqman probe stem loop real-time PCR to accurately measure the levels of miR-197 in normal ovarian cells, ovarian cancer cells, and Taxol-resistant ovarian cancer cells and found that miR-197 was significantly increased in Taxol-resistant ovarian cancer cells. Enforced expression of miR-197 can promote Taxol resistance, cell proliferation, and invasion of ovarian cancer cells. Meanwhile, repression of miR-197 in ovarian cancer cells can sensitize its response to Taxol and also induced attenuated cell proliferation and invasion ability. Furthermore, investigation of the detailed mechanism showed that the promotion of miR-197 on drug resistance in ovarian cancer cells was partially mediated by downregulating NLK, a negative regulator of WNT signaling pathway. Taken together, our work first demonstrated that miR-197 can confer drug resistance to Taxol, by regulating tumor suppressor, NLK expression in ovarian cancer cells.

  4. Minimal residual disease of leukemia and the quality of cryopreserved human ovarian tissue in vitro.

    PubMed

    Asadi-Azarbaijani, Babak; Sheikhi, Mona; Nurmio, Mirja; Tinkanen, Helena; Juvonen, Vesa; Dunkel, Leo; Hovatta, Outi; Oskam, Irma C; Jahnukainen, Kirsi

    2016-01-01

    Auto-transplant of cryopreserved ovarian tissue in leukemia patients carries a risk to reintroduce malignant cells. Maturation of ovarian follicles in vitro is a promising strategy to overcome the leukemic cell contamination. The follicle development and survival in 14 cryopreserved ovarian tissues with leukemia-specific PCR marker was evaluated after 7 or 14 days culture. Minimal residual disease (MRD) quantification was assessed by real-time quantitative PCR in order to identify the MRD positive (n = 6) and negative (n = 8) samples and to monitor levels of MRD before and after culture. The morphology of ovarian follicles were studied by light microscopy. After culture, no statistical significant differences were detected in follicle densities between MRD positive- and negative samples. Ovarian MRD either decreased below undetectable or fluctuated near the baseline level after 7 and 14 days in culture. This study provides quantitative in vitro evidence that leukemia contamination does not affect the follicle survival in cryopreserved ovarian tissue.

  5. The incidence and mortality of ovarian cancer and their relationship with the Human Development Index in Asia

    PubMed Central

    Razi, Saeid; Ghoncheh, Mahshid; Mohammadian-Hafshejani, Abdollah; Aziznejhad, Hojjat; Mohammadian, Mahdi; Salehiniya, Hamid

    2016-01-01

    Background The incidence and mortality estimates of ovarian cancer based on human development are essential for planning by policy makers. This study is aimed at investigating the standardised incidence rates (SIR) and standardised mortality rates (SMR) of ovarian cancer and their relationship with the Human Development Index (HDI) in Asian countries. Methods This study was an ecologic study in Asia for assessment of the correlation between SIR, age standardised rates (ASR), and HDI and their details, including life expectancy at birth, mean years of schooling, and gross national income (GNI) per capita. We used the correlation bivariate method for assessment of the correlation between ASR and HDI, and its details. Statistical significance was assumed if P < 0.05. All reported P-values were two-sided. Statistical analyses were performed using SPSS (Version 15.0, SPSS Inc.). Results The highest SIR of ovarian cancer was observed in Singapore, Kazakhstan, and Brunei respectively. Indonesia, Brunei, and Afghanistan had the highest SMR. There was a positive correlation between the HDI and SIR (r = 0.143, p = 0.006). Correlation between SMR of ovarian cancer and HDI was not significant (r = 0.005, p = 052.0). Conclusion According to the findings of this study, between the HDI and SIR, there was a positive correlation, but there was no correlation between the SMR and HDI. PMID:27110284

  6. Insulin has a biphasic effect on the ability of human chorionic gonadotropin to induce ovarian cysts in the rat.

    PubMed

    Bogovich, K; Clemons, J; Poretsky, L

    1999-08-01

    Hyperinsulinemia enhances the ability of subovulatory doses of human chorionic gonadotropin (hCG) to induce ovarian follicular cysts in the rat. To determine the relative contribution of these hormones to the development of ovarian cysts, adult female rats were treated with either (1) vehicle alone (controls), (2) a high-fat diet (HFD) to control for the effects of weight gain, (3) 1.5 to 6 IU hCG twice daily plus 6 U insulin (Ins)/d, or (4) 1.5 to 9 U Ins/d plus 3 IU hCG twice daily. On day 23 of the in vivo treatments, all groups that received at least 6 U Ins/d displayed increased body weight compared with control and HFD rats (P < or = .05). No control rats and only one HFD rat displayed ovarian cysts on this day. Plasma estrone (E1) and androstenedione (A4) were elevated in HFD rats with noncystic follicles compared with control rats (P < or = .05). Between 64% and 80% of rats on 6 U Ins/d plus twice-daily injections of 1.5 to 6 IU hCG displayed ovarian cysts on day 23. Plasma estradiol (E2) concentrations for these treatment groups were similar to those of control rats. Of the hormonally treated animals, only those that had ovarian cysts in response to twice-daily injections of 4.5 or 6 IU hCG plus 6 U Ins/d displayed elevated plasma A4 and/or testosterone compared with controls. In contrast, plasma E1 concentrations were elevated on day 23 for animals bearing ovarian cysts in response to increasing doses of hCG plus the fixed dose of 6 U Ins/d. Between 70% and 80% of rats treated twice daily with 3 IU hCG plus a daily dose of 1.5 to 6 U Ins displayed ovarian cysts on day 23. In marked contrast, only 25% of rats treated with this dose of hCG plus 9 U Ins/d developed cystic follicles. Of the plasma steroids tested, only E1 and A4 were elevated in these treatment groups compared with controls. However, these increases in plasma steroid concentrations did not correlate with the dose of insulin. We conclude from these data that, although the mechanisms remain to

  7. Ovarian Cancer

    MedlinePlus

    Ovarian Cancer There are five main types of cancer that affect a woman’s reproductive organs: cervical, ovarian, uterine, ... rare fallopian tube cancer.) This fact sheet about ovarian cancer is part of the Centers for Disease Control ...

  8. Ovarian Cancer

    MedlinePlus

    ... deaths than other female reproductive cancers. The sooner ovarian cancer is found and treated, the better your chance for recovery. But ovarian cancer is hard to detect early. Women with ovarian ...

  9. Low-molecular-weight dextran infusion is more effective for the treatment of hemoconcentration due to severe ovarian hyperstimulation syndrome than human albumin infusion.

    PubMed

    Endo, Toshiaki; Kitajima, Yoshimitsu; Hayashi, Takuhiro; Fujii, Miho; Hata, Hiroshi; Azumaguchi, Atsushi

    2004-11-01

    The most severe complication of ovarian hyperstimulation syndrome (OHSS) is thromboembolism, which is related to hemoconcentration. Dextran 40 infusion has greater effectiveness for the treatment of hemoconcentration due to OHSS than does human albumin infusion. PMID:15533378

  10. Factors regulating the bovine, caprine, rat and human ovarian aromatase promoters in a bovine granulosa cell model.

    PubMed

    Sahmi, Fatiha; Nicola, Edmir S; Zamberlam, Gustavo O; Gonçalves, Paulo D B; Vanselow, Jens; Price, Christopher A

    2014-05-01

    The ovarian promoter of the primate and rodent genes encoding cytochrome P450 aromatase (CYP19A1) are robustly responsive to forskolin in luteinized cell models, whereas the ruminant ovarian promoter is minimally active. We explored this discrepancy by investigating the activity of the bovine ovarian promoter in two bovine granulosa cell models, luteinizing and non-luteinizing cells in vitro. In non-luteinizing cells, both FSH and IGF1 increased abundance of transcripts derived from the ovarian promoter. Comparison of the activity of promoters of several species in response to transcription factors (forskolin, NR5A2, FOXL2) in luteinizing cells demonstrated that a rat ovarian promoter-luciferase reporter was regulated mainly by forskolin (18-fold increase over basal expression) and addition of NR5A2 or FOXL2 had no further effect. Activity of a human promoter was significantly increased by NR5A2 plus forskolin (153-fold) compared with forskolin alone (71-fold over basal); addition of FOXL2 did not significantly increase promoter activity. Forskolin alone provoked minor activation of caprine and bovine promoter reporters (3-fold over basal), and addition of NR5A2 increased activity (7- to 11-fold). When forskolin, NR5A2 and FOXL2 treatments were combined, the activity of the caprine and bovine promoters increased to 20- and 34-fold, respectively. These data suggest that a major reason why CYP19A1 is not expressed in luteinized cells (and the corpus luteum) of ruminants may be the stimulatory effect of FOXL2, which does not appear to be the case in the human and rat. PMID:24556528

  11. A Decision Tree Based Classifier to Analyze Human Ovarian Cancer cDNA Microarray Datasets.

    PubMed

    Tsai, Meng-Hsiun; Wang, Hsin-Chieh; Lee, Guan-Wei; Lin, Yi-Chen; Chiu, Sheng-Hsiung

    2016-01-01

    Ovarian cancer is the deadliest gynaecological disease because of the high mortality rate and there is no any symptom in cancer early stage. It was often the terminal cancer period when patients were diagnosed with ovarian cancer and thus delays a good opportunity of treatment. The current common method for detecting ovarian cancer is blood testing for analyzing the tumor marker CA-125 of serum. However, specificity and sensitivity of CA-125 are insufficient for early detection. Therefore, it has become an urgent issue to look for an efficient method which precisely detects the tumor markers for ovarian cancer. This study aims to find the target genes of ovarian cancer by different algorithms of information science. Feature selection and decision tree were applied to analyze 9600 ovarian cancer-related genes. After screening the target genes, candidate genes will be analyzed by Ingenuity Pathway Analysis (IPA) software to create a genetic pathway model and to understand the interactive relationship in the different pathological stages of ovarian cancer. Finally, this research found 9 oncogenes associated with ovarian cancer and some genes had not been discovered in previous studies. This system will assist medical staffs in diagnosis and treatment at cancer early stage and improve the patient's survival. PMID:26531754

  12. Genetics and biology of human ovarian teratomas. III. Cytogenetics and origins of malignant ovarian germ cell tumors.

    PubMed

    Hoffner, L; Shen-Schwarz, S; Deka, R; Chakravarti, A; Surti, U

    1992-08-01

    This report presents cytogenetic data on three cases of malignant ovarian germ cell tumors. All were diagnosed as malignant teratoma; case 1 with yolk sac elements; case 2 with elements of endodermal sinus tumor, embryonal carcinoma, and choriocarcinoma; and case 3 with yolk sac elements and embryonal carcinoma. Metaphase cells from each tumor, and normal tissue from the host, were karyotyped and scored for centromeric heteromorphisms in an attempt to determine the mechanism of origin. The karyotypes were 79,XXX,+1,+3,-6,+8,+12,+14,-15,+17, +20,+21,+22;49,XX,+8,+12,+22; and 48,XX,+3,+14, respectively. The analysis of centromeric heteromorphisms and DNA fingerprints of host and teratoma using the M13 probe revealed that one case originated from a germ cell before the first meiotic division. Normal host tissue was not available in case 2, but several centromeric markers were heterozygous in the tumor, indicating either meiosis I error or complete failure of germ cell meiosis. In the third case the centromeric heteromorphisms that were heterozygous in the host appeared to be homozygous for certain chromosomes and heterozygous for others in the tumor. These results suggest that germ cell teratomas could arise by the fusion of two ova. PMID:1521236

  13. Pinin interacts with C-terminal binding proteins for RNA alternative splicing and epithelial cell identity of human ovarian cancer cells

    PubMed Central

    Zhang, Yanli; Kwok, Jamie Sui-Lam; Choi, Pui-Wah; Liu, Minghua; Yang, Junzheng; Singh, Margit; Ng, Shu-Kay; Welch, William R.; Muto, Michael G.; Tsui, Stephen KW; Sugrue, Stephen P.; Berkowitz, Ross S.; Ng, Shu-Wing

    2016-01-01

    Unlike many other human solid tumors, ovarian tumors express many epithelial markers at a high level for cell growth and local invasion. The phosphoprotein Pinin plays a key role in epithelial cell identity. We showed that clinical ovarian tumors and ovarian cancer cell lines express a high level of Pinin when compared with normal ovarian tissues and immortalized normal ovarian surface epithelial cell lines. Pinin co-localized and physically interacted with transcriptional corepressor C-terminal binding proteins, CtBP1 and CtBP2, in the nuclei of cancer cells. Knockdown of Pinin in ovarian cancer cells resulted in specific reduction of CtBP1 protein expression, cell adhesion, anchorage-independent growth, and increased drug sensitivity. Whole transcriptomic comparison of next-generation RNA sequencing data between control ovarian cancer cell lines and cancer cell lines with respective knockdown of Pinin, CtBP1, and CtBP2 expression also showed reduced expression of CtBP1 mRNA in the Pinin knockdown cell lines. The Pinin knockdown cell lines shared significant overlap of differentially expressed genes and RNA splicing aberrations with CtBP1 knockdown and in a lesser degree with CtBP2 knockdown cancer cells. Hence, Pinin and CtBP are oncotargets that closely interact with each other to regulate transcription and pre-mRNA alternative splicing and promote cell adhesion and other epithelial characteristics of ovarian cancer cells. PMID:26871283

  14. Cationic chlorophyl derivatives with SOD mimicking activity suppress the proliferation of human ovarian cancer cells.

    PubMed

    Kobayashi, Y; Maniki, M; Nakamura, K

    1996-06-01

    Derivatives of chlorophyl, e.g. Fe-chlorin e6-Na, alpha, beta, gamma, delta-Tetraphenylporphine-tetrasulfonic acid disulfonic acid salt tetrahydrate (Fe-TPPTS) and alpha, beta, gamma, delta-Tetrakis (4-N-trimethylaminophenyl) porphine, tetra (p-toluensulfonate (Fe-TTMAPP), express SOD mimicking activity. Examination was made of suppressive effects of human cancer cell lines by derivatives of chlorophyl. Fe-TPPTS and Fe-TTMAPP suppressed proliferation of the human ovarian cancer cell lines but Fe-chlorin e6-Na failed to suppress the proliferation. Lipid peroxide was increased by application of Fe-TPPTS and Fe-TTMAPP, but decreased by application of Fe-chlorin e6-Na. SOD activity of the cancer cells did not change by application of these drugs. TPPTS and TTMAPP have a cationic charge but Fe-chlorin e6-Na has an anionic charge. It is suggested that charge of these drugs relates to the suppressive effects of the cancer cell proliferation. PMID:10851538

  15. Nilotinib reduced the viability of human ovarian cancer cells via mitochondria-dependent apoptosis, independent of JNK activation.

    PubMed

    Chen, Tze-Chien; Yu, Ming-Chih; Chien, Chih-Chiang; Wu, Ming-Shun; Lee, Yu-Chieh; Chen, Yen-Chou

    2016-03-01

    Nilotinib (AMN) induces apoptosis in various cancer cells; however the effect of AMN on human ovarian cancer cells is still unclear. A reduction in cell viability associated with the occurrence of apoptotic characteristics was observed in human SKOV-3 ovarian cancer cells under AMN but not sorafenib (SORA) or imatinib (STI) stimulation. Activation of apoptotic pathway including increased caspase (Casp)-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein cleavage by AMN was detected with disrupted mitochondrial membrane potential (MMP) accompanied by decreased Bcl-2 protein and increased cytosolic cytochrome (Cyt) c/cleaved Casp-9 protein expressions was found, and AMN-induced cell death was inhibited by peptidyl Casp inhibitors, VAD, DEVD and LEHD. Increased phosphorylated c-Jun N-terminal kinase (JNK) protein expression was detected in AMN- but not SORA- or STI-treated SKOV-3 cells, and the JNK inhibitors, SP600125 and JNKI, showed slight but significant enhancement of AMN-induced cell death in SKOV-3 cells. The intracellular peroxide level was elevated by AMN and H2O2, and N-acetylcysteine (NAC) prevented H2O2- but not AMN-induced peroxide production and apoptosis in SKOV-3 cells. AMN induction of apoptosis with increased intracellular peroxide production and JNK protein phosphorylation was also identified in human A2780 ovarian cancer cells, cisplatin-resistant A2780CP cells, and clear ES-2 cells. The evidence supporting AMN effectively reducing the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis is provided.

  16. RNAi-Mediated Downregulation of FKBP14 Suppresses the Growth of Human Ovarian Cancer Cells.

    PubMed

    Lu, Meng; Miao, Yi; Qi, Lan; Bai, Mingzhu; Zhang, Jiarong; Feng, Youji

    2016-01-01

    FKBP14 belongs to the family of FK506-binding proteins (FKBPs). Altered expression of FKBPs has been reported in several malignancies. This study aimed to reveal the expression profile of FKBP14 in ovarian cancer and evaluate whether FKBP14 is a molecular target for cancer therapy. We found that the FKBP14 mRNA level was significantly higher in ovarian cancer tissues than in normal tissues. FKBP14 expression was then knocked down in two ovarian cancer cell lines, SKOV3 and HO8910 cells, by a lentiviral short hairpin RNA (shRNA) delivery system. Reduced expression of FKBP14 markedly impaired the proliferative ability of ovarian cancer cells. Additionally, ovarian cancer cells infected with FKBP14 shRNA lentivirus tended to arrest in the G0/G1 phase and undergo apoptosis. Moreover, knockdown of FKBP14 induced cell apoptosis via increasing the ratio of Bax to Bcl-2. These results indicated that FKBP14 might be a diagnostic marker for ovarian cancer and could be a potential molecular target for the therapy of ovarian cancer. PMID:27131312

  17. Differential effects of rapalogues, dual kinase inhibitors on human ovarian carcinoma cells in vitro

    PubMed Central

    ROGERS-BROADWAY, KARLY-RAI; CHUDASAMA, DIMPLE; PADOS, GEORGE; TSOLAKIDIS, DIMITRIS; GOUMENOU, ANASTASIA; HALL, MARCIA; KARTERIS, EMMANOUIL

    2016-01-01

    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. PMID:27211906

  18. High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL- and cisplatin-induced apoptosis in human ovarian cancer cells.

    PubMed

    Volkmann, Juliane; Reuning, Ute; Rudelius, Martina; Häfner, Norman; Schuster, Tibor; Becker V Ros, Aaron; Weimer, Joerg; Hilpert, Felix; Kiechle, Marion; Dürst, Matthias; Arnold, Norbert; Schmalfeldt, Barbara; Meindl, Alfons; Ramser, Juliane

    2013-06-15

    Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin αB (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p = 0.001, recurrence-free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10-4.06) and RFS (HR = 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001). Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL- as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anti-cancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from TRAIL-containing therapy. PMID:23225306

  19. DUSP1 induces paclitaxel resistance through the regulation of p-glycoprotein expression in human ovarian cancer cells.

    PubMed

    Kang, Yu-Seon; Seok, Hyun-Jeong; Jeong, Eun-Jeong; Kim, Yuna; Yun, Seok-Joong; Min, Jeong-Ki; Kim, Sun Jin; Kim, Jang-Seong

    2016-09-01

    The heterogeneity and genetic instability of ovarian cancer cells often lead to the development of drug resistance, closely related with the increased cancer-related mortality. In this study, we investigated the role of dual-specificity phosphatase 1 (DUSP1) in the development of the resistance in human ovarian cancer cells against paclitaxel. Overexpression of DUSP1 in HeyA8 human ovarian cancer cells (HeyA8-DUSP1) up-regulated the expression of the drug efflux pump, p-glycoprotein. Consequently, HeyA8-DUSP1 cells are highly resistant to paclitaxel, with the resistance comparable to that of a multi-drug resistance cell line (HeyA8-MDR). Moreover, over expression of DUSP1 significantly increased the activation of p38 MAPK, leaving the activation of ERK1/2 and JNK1/2 unaffected. Pharmacological suppression of p38 MAPK activity prevents the up-regulation of p-glycoprotein expression and the consequent resistance against paclitaxel in HeyA8-DUSP1 cells. By contrast, HeyA8-MDR cells expressed a significantly higher level of DUSP1, but treatment with small interference RNA against DUSP1 significantly suppressed the expression of p-glycoprotein and the resistance against paclitaxel in HeyA8-MDR cells. Ectopic expression of MKK3, an upstream activator of p38 MAPK, significantly up-regulated the expression of p-glycoprotein and increased the consequent resistance against paclitaxel in HeyA8 cells. Collectively, these data indicated that DUSP1 may induce the resistance against paclitaxel through the p38 MAPK-mediated overexpression of p-glycoprotein in human ovarian cancer cells.

  20. DUSP1 induces paclitaxel resistance through the regulation of p-glycoprotein expression in human ovarian cancer cells.

    PubMed

    Kang, Yu-Seon; Seok, Hyun-Jeong; Jeong, Eun-Jeong; Kim, Yuna; Yun, Seok-Joong; Min, Jeong-Ki; Kim, Sun Jin; Kim, Jang-Seong

    2016-09-01

    The heterogeneity and genetic instability of ovarian cancer cells often lead to the development of drug resistance, closely related with the increased cancer-related mortality. In this study, we investigated the role of dual-specificity phosphatase 1 (DUSP1) in the development of the resistance in human ovarian cancer cells against paclitaxel. Overexpression of DUSP1 in HeyA8 human ovarian cancer cells (HeyA8-DUSP1) up-regulated the expression of the drug efflux pump, p-glycoprotein. Consequently, HeyA8-DUSP1 cells are highly resistant to paclitaxel, with the resistance comparable to that of a multi-drug resistance cell line (HeyA8-MDR). Moreover, over expression of DUSP1 significantly increased the activation of p38 MAPK, leaving the activation of ERK1/2 and JNK1/2 unaffected. Pharmacological suppression of p38 MAPK activity prevents the up-regulation of p-glycoprotein expression and the consequent resistance against paclitaxel in HeyA8-DUSP1 cells. By contrast, HeyA8-MDR cells expressed a significantly higher level of DUSP1, but treatment with small interference RNA against DUSP1 significantly suppressed the expression of p-glycoprotein and the resistance against paclitaxel in HeyA8-MDR cells. Ectopic expression of MKK3, an upstream activator of p38 MAPK, significantly up-regulated the expression of p-glycoprotein and increased the consequent resistance against paclitaxel in HeyA8 cells. Collectively, these data indicated that DUSP1 may induce the resistance against paclitaxel through the p38 MAPK-mediated overexpression of p-glycoprotein in human ovarian cancer cells. PMID:27422607

  1. Oxygen consumption rate of early pre-antral follicles from vitrified human ovarian cortical tissue

    PubMed Central

    ISHIKAWA, Takayuki; KYOYA, Toshihiko; NAKAMURA, Yusuke; SATO, Eimei; TOMIYAMA, Tatsuhiro; KYONO, Koichi

    2014-01-01

    The study of human ovarian tissue transplantation and cryopreservation has advanced significantly. Autotransplantation of human pre-antral follicles isolated from cryopreserved cortical tissue is a promising option for the preservation of fertility in young cancer patients. The purpose of the present study was to reveal the effect of vitrification after low-temperature transportation of human pre-antral follicles by using the oxygen consumption rate (OCR). Cortical tissues from 9 ovaries of female-to-male transsexuals were vitrified after transportation (6 or 18 h). The follicles were enzymatically isolated from nonvitrified tissue (group I, 18 h of transportation), vitrified-warmed tissue (group II, 6 and 18 h of transportation) and vitrified-warmed tissue that had been incubated for 24 h (group III, 6 and 18 h of transportation). OCR measurement and the LIVE/DEAD viability assay were performed. Despite the ischemic condition, the isolated pre-antral follicles in group I consumed oxygen, and the mean OCRs increased with developmental stage. Neither the transportation time nor patient age seemed to affect the OCR in this group. Meanwhile, the mean OCR was significantly lower (P < 0.05) in group II but was comparable to that of group I after 24 h of incubation. The integrity of vitrified-warmed primordial and primary follicles was clearly corroborated by the LIVE/DEAD viability assay. These results demonstrate that the OCR can be used to directly estimate the effect of vitrification on the viability of primordial and primary follicles and to select the viable primordial and primary follicles from vitrified-warmed follicles. PMID:25262776

  2. Ovarian hyperstimulation syndrome prevention strategies: reducing the human chorionic gonadotropin trigger dose.

    PubMed

    Kashyap, Sonya; Parker, Kasey; Cedars, Marcelle I; Rosenwaks, Zev

    2010-11-01

    This article reviews the biological plausibility and evidence for the use of a low triggering dose of human chorionic gonadotropin (hCG) in the prevention of ovarian hyperstimulation syndrome (OHSS). A systematic search of the literature revealed very little published data for or against the use of low-dose hCG in the prevention of OHSS after assisted reproductive technology. We have had success at avoiding OHSS as a result of gentle stimulation and low-dose sliding scale hCG trigger based on estradiol (E₂) levels. We therefore present the biological plausibility for such an approach by reviewing the relationship between OHSS, vascular endothelial growth factor, and hCG; the physiology of hCG; the relationship between risk of OHSS and E₂ at trigger; and the physiology of alternative methods of triggering such as recombinant luteinizing hormone and gonadotropin-releasing hormone agonist. We also present the results of a quasi-experimental before and after study of the sliding scale protocol for hCG trigger dose in in vitro fertilization with or without intracytoplasmic sperm injection cycles.

  3. Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy.

    PubMed

    Sun, Yang; Jin, Long; Liu, Jia-Hua; Sui, Yu-Xia; Han, Li-Li; Shen, Xiao-Li

    2016-09-01

    We aimed to determine the effects of the inhibition of enhancer of zeste homolog 2 (EZH2) gene expression on the cisplatin resistance of the human ovarian cancer cell line, SKOV3/DDP, and to identify the underlying mechanisms. SKOV3/DDP cells were stably transfected with pSUPER-EZH2 (EZH2 RNA interference plasmid) or pcDNA3.1-EZH2 (EZH2 gene overexpression plasmid) using the lipofection method. Real-time fluorescence quantitative reverse transcription polymerase chain reaction and western blotting confirmed that EZH2 expression was downregulated in pSUPER-EZH2-transfected cells. Flow cytometry revealed that EZH2 inhibition did not induce apoptosis, but significantly inhibited autophagy. In addition, it significantly increased the expression of the cellular senescence-signaling proteins p14(ARF), p16(INK4a), p53, pRb, and p21, and significantly decreased the expression of cyclin-dependent kinase (CDK)1, CDK2, and H3K27me3. Cellular senescence was characterized by a significant increase in the G0/G1 ratio and the restoration of sensitivity to cisplatin in the drug-resistant cells. These findings suggest that interfering with EZH2 expression can inhibit SKOV3/DDP cell autophagy and reverse resistance to cisplatin. The underlying mechanisms could be associated with the regulation of the cellular senescence-signaling pathway. PMID:27610467

  4. Molecular analysis of selected cell cycle regulatory proteins during aerobic and hypoxic maintenance of human ovarian carcinoma cells

    PubMed Central

    Krtolica, A; Krucher, N A; Ludlow, J W

    1999-01-01

    We have previously reported on the development of an in vitro model system for studying the effect of hypoxia on ovarian carcinoma cell proliferation and invasion (Krtolica and Ludlow, 1996). These data indicate that the cell division cycle is reversibly arrested during the G1 phase. Here, we have continued this study to include the proliferation properties of both aerobic and hypoxic human ovarian carcinoma cells at the molecular level. The growth suppressor product of the retinoblastoma susceptibility gene, pRB, appears to be functional in these cells as determined by SV40 T-antigen binding studies. Additional G1-to-S cell cycle regulatory proteins, cyclins D and E, cyclin-dependent kinases (cdks) 4 and 2, and cdk inhibitors p27 and p18, also appear to be intact based on their apparent molecular weights and cell cycle stage-specific abundance. During hypoxia, there is a decrease in abundance of cyclins D and E, with an increase in p27 abundance. cdk4 activity towards pRB and cdk2 activity towards histone H1 are also decreased. Co-precipitation studies revealed an increased amount of p27 complexing with cyclin E-cdk2 during hypoxia than during aerobic cell growth. In addition, pRB-directed phosphatase activity was found to be greater in hypoxic than aerobic cells. Taken together, a model is suggested to explain hypoxia-induced cell cycle arrest in SKA human ovarian carcinoma cells. © 1999 Cancer Research Campaign PMID:10471034

  5. Molecular analysis of selected cell cycle regulatory proteins during aerobic and hypoxic maintenance of human ovarian carcinoma cells.

    PubMed

    Krtolica, A; Krucher, N A; Ludlow, J W

    1999-08-01

    We have previously reported on the development of an in vitro model system for studying the effect of hypoxia on ovarian carcinoma cell proliferation and invasion (Krtolica and Ludlow, 1996). These data indicate that the cell division cycle is reversibly arrested during the G1 phase. Here, we have continued this study to include the proliferation properties of both aerobic and hypoxic human ovarian carcinoma cells at the molecular level. The growth suppressor product of the retinoblastoma susceptibility gene, pRB, appears to be functional in these cells as determined by SV40 T-antigen binding studies. Additional G1-to-S cell cycle regulatory proteins, cyclins D and E, cyclin-dependent kinases (cdks) 4 and 2, and cdk inhibitors p27 and p18, also appear to be intact based on their apparent molecular weights and cell cycle stage-specific abundance. During hypoxia, there is a decrease in abundance of cyclins D and E, with an increase in p27 abundance. cdk4 activity towards pRB and cdk2 activity towards histone H1 are also decreased. Co-precipitation studies revealed an increased amount of p27 complexing with cyclin E-cdk2 during hypoxia than during aerobic cell growth. In addition, pRB-directed phosphatase activity was found to be greater in hypoxic than aerobic cells. Taken together, a model is suggested to explain hypoxia-induced cell cycle arrest in SKA human ovarian carcinoma cells. PMID:10471034

  6. TLR4 activates NFkB in human ovarian granulosa tumor cells

    PubMed Central

    Woods, Dori C.; White, Yvonne A. R.; Dau, Caroline; Johnson, A.L.

    2011-01-01

    Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFαplus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin. PMID:21616060

  7. Anti-Sp17 monoclonal antibody with antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities against human ovarian cancer cells.

    PubMed

    Song, Jia-xi; Cao, Wang-li; Li, Fang-qiu; Shi, Li-ning; Jia, Xuan

    2012-12-01

    Sperm protein 17 (Sp17) is a cancer testis antigen that has been shown to be overexpressed in a variety of gynecologic malignancies, in particular ovarian cancer. Emerging evidences indicate that Sp17 is involved in tumorigenesis and in the migration of malignant cells. It has been proposed as a useful target for tumor-vaccine strategies and a novel marker to define tumor subsets and predict drug response. However, the antitumor activity of anti-Sp17 monoclonal antibody (anti-Sp17 mAb) has not been investigated. In this study, the in vitro cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities of anti-Sp17 mAb were evaluated using Sp17-positive ovarian cancer cells as targets, Sp17-negative ovarian cancer cells as the control, and healthy human peripheral blood monocytes and healthy human serum as effectors. Our preliminary results indicate that the direct cytotoxicity of anti-Sp17 mAb against the investigated ovarian cancer cells was very weak. However, the cytotoxicity of anti-Sp17 mAb, mediated by peripheral blood mononuclear cells (PBMCs), as ADCC, or by human serum, as CDC, was relatively strong in the Sp17-positive ovarian cancer cells. This finding suggested that anti-Sp17 mAb could be a useful tool against ovarian cancer and may provide insight into the development of low side-effect targeting therapy for this malignant disease.

  8. Paris saponin II inhibits human ovarian cancer cell-induced angiogenesis by modulating NF-κB signaling.

    PubMed

    Yang, Mei; Zou, Juan; Zhu, Hongmei; Liu, Shanling; Wang, He; Bai, Peng; Xiao, Xue

    2015-05-01

    The clinical applications of Rhizoma paridis in traditional Chinese medicine are well known. However, the therapeutic potential of Rhizoma paridis and its active component such as Paris saponin I (polyphyllin D) and Paris saponin II (PSII) (formosanin C) in cancer treatments have not yet been fully explored. Recent studies have demonstrated that PSII and chemoagents exhibit comparable inhibitory affects against human ovarian cancer cell growth. Since NF-κB, a ubiquitous transcription factor that plays an important role in cancer biology, is often associated with gynecological cancers, in the present study, we evaluated the possibility that PSII modulates NF-κB activity and VEGF-mediated angiogenesis and elucidated the molecular mechanisms underlying such effects. We assessed the effects of PSII on NF-κB activity in SKOV3 tumor cells and on tumor cell induced-angiogenesis using standardized angiogenesis in vitro, ex vivo and in vivo assays, western blot analysis and kinase assay. We also assessed the effect of the super-engineered repressor of IĸBα and its effect, in combination with PSII treatment on tumor growth and angiogenesis in xenograft athymic mouse models of ovarian cancer (SKOV3 and SKOV3/mutant IĸBα cells) using color Doppler ultrasound and traditional immunohistochemistry. We showed that PSII suppressed NF-κB activation as a result of the reduction in IKKβ kinase activity on its substrate IκBα and the expression of IKKβ. Compromising NF-κB activation reduced the expression of NF-κB-downstream targets such as VEGF, Bcl-2 and Bcl-xL. Such inhibitory effects at molecular levels appear to compromise tumor growth and angiogenesis. Most importantly, the combination of PSII treatment and constitutive repression of IĸBα activity exhibited marked inhibitory effects against human ovarian cancer cell growth in a xenograft mouse model of ovarian cancer. For the first time, we provide evidence showing that PSII potently inhibits angiogenesis

  9. Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

    PubMed Central

    Connell, Claire M.; Shibata, Atsushi; Tookman, Laura A.; Archibald, Kyra M.; Flak, Magdalena B.; Pirlo, Katrina J.; Lockley, Michelle; Wheatley, Sally P.; McNeish, Iain A.

    2011-01-01

    Oncolytic adenoviruses replicate selectively within and lyse malignant cells. As such, they are being developed as anticancer therapeutics. However, the sensitivity of ovarian cancers to adenovirus cytotoxicity varies greatly, even in cells of similar infectivity. Using both the adenovirus E1A-CR2 deletion mutant dl922-947 and WT adenovirus serotype 5 in a panel of human ovarian cancer cell lines that cover a 3-log range of sensitivity, we observed profound overreplication of genomic DNA only in highly sensitive cell lines. This was associated with the presence of extensive genomic DNA damage. Inhibition of ataxia telangiectasia and Rad3-related checkpoint kinase 1 (ATR-Chk1), but not ataxia telangiectasia mutated (ATM), promoted genomic DNA damage and overreplication in resistant and partially sensitive cells. This was accompanied by increased adenovirus cytotoxicity both in vitro and in vivo in tumor-bearing mice. We also demonstrated that Cdc25A was upregulated in highly sensitive ovarian cancer cell lines after adenovirus infection and was stabilized after loss of Chk1 activity. Knockdown of Cdc25A inhibited virus-induced DNA damage in highly sensitive cells and blocked the effects of Chk1 inhibition in resistant cells. Finally, inhibition of Chk1 decreased homologous recombination repair of virus-induced genomic DNA double-strand breaks. Thus, virus-induced host cell DNA damage signaling and repair are key determinants of oncolytic adenoviral activity, and promoting unscheduled DNA synthesis and/or impeding homologous recombination repair could potentiate the effects of oncolytic adenoviruses in the treatment of ovarian cancer. PMID:21383502

  10. Bacillus intermedius ribonuclease (BINASE) induces apoptosis in human ovarian cancer cells.

    PubMed

    Garipov, Azat R; Nesmelov, Alexander A; Cabrera-Fuentes, Hector A; Ilinskaya, Olga N

    2014-12-15

    The cytotoxic effects of Bacillus intermedius RNase (binase) towards ovarian cancer cells (SKOV3 and OVCAR5) were studied in comparison to normal ovarian epithelial cells (HOSE1 and HOSE2). Binase decreased viability and induced the selective apoptosis of ovarian cancer cells. The apoptosis rate was 50% in SKOV3 and 48% in OVCAR5 cells after 24 h of binase treatment (50 μg/ml). Binase-induced apoptosis in these cell lines was accompanied by caspase-3 activation and poly(ADP-ribose) polymerase fragmentation. Normal ovarian epithelial cells were not affected by binase, except for a slight decrease of HOSE2 cell viability and the appearance of traces of activated caspase-3, but not the poly(ADP-ribose) polymerase 85-kDA fragment. Binase did not induce alteration of EZH2 (enhancer of zeste-homolog-2) protein expression neither, in tumor nor in normal cells. In conclusion, selective binase-induced cell death and apoptosis via poly(ADP-ribose) polymerase fragmentation may serve as a new treatment option against ovarian cancer progression.

  11. Nanosecond electric pulses induce DNA breaks in cisplatin-sensitive and -resistant human ovarian cancer cells.

    PubMed

    Linghu, Lingjuan; Tan, Yafang; Lou, Yi; Hu, Lina; Yang, Hongchun; Yu, Tinghe

    2013-01-11

    Human ovarian cancer cells COC1 and COC1/DDP (cisplatin-resistant subline) were exposed to 6 kV/cm nanosecond electric pulses (nsEP) with a pulse length of 8, 16 or 24 ns. The potential in a subcellular unit was calculated using a multilayer dielectric spherical model, and area under the voltage-time curves (AUC) integrated with a lower limit of 0.2V. Cell viability was determined, and double-stand and total DNA breaks detected with the neutral and alkaline comet assays. nsEP evoked a higher voltage and AUC in nucleoplasm, and the levels in COC1 cells was just above those in COC1/DDP cells. Comets only appeared in the alkaline assay demonstrating single-stand DNA break. Fewer DNA break (16.51% vs. 35.13% at 24 ns, p=0.0150) and more survival (22.42% vs. 13.19% at 24 ns, p=0.0015) occurred in COC1/DDP cells despite an equal electric energy and almost equal cell sizes. 24-ns EP led to higher rates of cell-death and comet. The comet rate correlated with cell-death fraction in either cell line (r=0.5701, p=0.0135; r=0.5110, p=0.0302). There was no a correlation between the tail length, tail moment or Olive tail moment and cell-death rate. The data showed that response of chemosensitive cells differed from that of chemoresistant cells and DNA damage contributed to percent of cell death. PMID:23211598

  12. Human leukocyte antigen-E alleles and expression in patients with serous ovarian cancer

    PubMed Central

    Zheng, Hui; Lu, Renquan; Xie, Suhong; Wen, Xuemei; Wang, Hongling; Gao, Xiang; Guo, Lin

    2015-01-01

    Human leukocyte antigen-E (HLA-E) is one of the most extensively studied non-classical MHC class I molecules that is almost non-polymorphic. Only two alleles (HLA-E*0101 and HLA-E*0103) are found in worldwide populations, and suggested to be functional differences between these variants. The HLA-E molecule can contribute to the escape of cancer cells from host immune surveillance. However, it is still unknown whether HLA-E gene polymorphisms might play a role in cancer immune escape. To explore the association between HLA-E alleles and the susceptibility to serous ovarian cancer (SOC), 85 primary SOC patients and 100 healthy women were enrolled. Here, we indicated that high frequency of HLA-E*0103 allele existed in SOC patients by the allele-specific quantitative real-time PCR method. The levels of HLA-E protein expression in SOC patients with the HLA-E*0103 allele were higher than those with the HLA-E*0101 allele using immunohistochemistry analysis. The cell surface expression and functional differences between the two alleles were verified by K562 cells transfected with HLA-E*0101 or HLA-E*0103 allelic heavy chains. The HLA-E*0103 allele made the transfer of the HLA-E molecule to the cell surface easier, and HLA-E/peptides complex more stable. These differences ultimately influenced the function of natural killer cells, showing that the cells transfected with HLA-E*0103 allele inhibited natural killer cells to lysis. This study reveals a novel mechanism regarding the susceptibility to SOC, which is correlated with the HLA-E*0103 allele. PMID:25711417

  13. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer

    PubMed Central

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-01-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC. PMID:27206315

  14. Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats.

    PubMed

    Poretsky, L; Clemons, J; Bogovich, K

    1992-08-01

    Tonically elevated serum luteinizing hormone (LH) and hyperinsulinemia are prominent features of polycystic ovary syndrome (PCO) in women, but the relative roles of LH and insulin in the pathogenesis of PCO is still unknown. The present study was undertaken to determine the effect(s) hyperinsulinemia might have on the induction of follicular cysts by LH/human chorionic gonadotropin (hCG) in the rat. Beginning on day 85 of age, adult female rats were given one of the following in vivo treatments: (1) vehicle alone; (2) a high-fat diet to control for the effects of weight-gain; (3) up to 6 U insulin per day; (4) 50 micrograms gonadotropin-releasing hormone (GnRH) antagonist (GnRHant) per day; (5) 1.5 IU hCG twice daily; (6) insulin + hCG; (7) insulin + GnRHant; (8) hCG + GnRHant; or (9) hCG + insulin + GnRHant. After 22 days of treatment, animals were killed on day 23, trunk blood was collected, and ovaries were excised for histological study. Regular cycles, assessed by vaginal smears, ceased after 10 days for most animals in treatment groups receiving hCG, but continued in all other treatment groups. All the animals in each hCG-treated group developed either unilateral or bilateral cystic ovaries, while no animals in the groups not receiving hCG developed follicular cysts. More animals from each group treated with both hCG and insulin possessed bilateral ovarian cysts than did rats treated with hCG alone: 80% and 60%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1640871

  15. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    PubMed

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC. PMID:27206315

  16. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    PubMed

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.

  17. Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

    PubMed Central

    Song, De-Gang; Ye, Qunrui; Santoro, Stephen; Fang, Chongyun; Best, Andrew

    2013-01-01

    Abstract NKG2D ligands (NKG2DLs) are widely expressed on ovarian cancers to various degrees, making them attractive targets for immunotherapy. Here, we applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human ovarian cancer cells and evaluated the impact of pharmacological upregulation of NKG2DLs on immune recognition. Various NKG2DLs, including MICA/B and ULBP-1, -2, -3, and -4, were expressed at various levels on the surface of all established ovarian cancer cell lines and primary ovarian cancer samples tested. To redirect human T cells against NKG2DLs, an NKG2DL-specific CAR was generated by fusing the extracellular domain of the NKG2D receptor to the 4-1BB costimulatory and CD3-ζ chain signaling domains. In vitro expansion of chimeric NKG2D CAR T cells was delayed compared with untransduced T cells and control CAR T cells; the likely result of fratricide among activated T cells expressing NKG2DLs. However, NKG2D CAR T cells did expand and were selectively enriched during prolonged culture. In coculture, CD4+ and CD8+ NKG2D CAR T cells specifically recognized and killed NKG2DL-expressing ovarian cancer cell lines but not NKG2DL-negative cells. Notably, pretreatment of ovarian cancer cells expressing moderate to low levels of NKG2DLs with the histone deacetylase inhibitor sodium valproate (VPA) upregulated NKG2DL cell surface expression and consequently enhanced their immune recognition by chimeric NKG2D CAR T cells. Our results demonstrate that VPA-induced upregulation of NKG2DL expression enhances the immune recognition of ovarian cancer cells by engineered NKG2D CAR T cells, and rationalizes the use of VPA in combination with NKG2DL-targeted immunotherapy in ovarian cancer. PMID:23297870

  18. Proteasome Inhibitor YSY01A Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant Human Ovarian Cancer Cells

    PubMed Central

    Huang, Wei; Zhou, Quan; Yuan, Xia; Ge, Ze-mei; Ran, Fu-xiang; Yang, Hua-yu; Qiang, Guang-liang; Li, Run-tao; Cui, Jing-rong

    2016-01-01

    Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome. PMID:27326257

  19. Effect of the WWOX gene on the regulation of the cell cycle and apoptosis in human ovarian cancer stem cells.

    PubMed

    Yan, Hongchao; Tong, Jianye; Lin, Xiaoman; Han, Qiuyu; Huang, Hongxiang

    2015-08-01

    In order to examine new ideas for gene therapy in ovarian cancer, the specific mechanism underlying the effects of the WW domain containing oxidoreductase (WWOX) gene on cell cycle regulation and apoptosis in human ovarian cancer stem cells was investigated. Ovarian cancer stem cells were transfected with a eukaryotic expression vector carrying the WWOX gene in vitro (recombinant plasmid) and cells transfected with the empty plasmid (empty plasmid) or untransfected cells were used as controls. Stably transfected cells were screened and amplified in culture and the WWOX protein was detected by western blot analysis in the three groups of cells. Western blot analysis was performed to detect the expression of cell cycle regulatory proteins cyclin E, cyclin-dependent kinase (CDK) 2, cyclin D1, CDK4 and apoptosis-related protein Wnt-5α and c-Jun N-terminal kinase (JNK), while polymerase chain reaction (PCR) was used to detect alterations in the mRNA expression levels of caspase-3. The results demonstrated that the WWOX protein was stably expressed in cells of the recombinant plasmid group, but was not detected in cells of the empty plasmid group and the control group. Cell proliferation at each time point decreased significantly in the recombinant plasmid group compared with the empty plasmid group and the control group. Flow cytometric analysis demonstrated that the proportion of cells in the G0/G1 phase in the recombinant plasmid group was significantly higher than that of cells in the empty plasmid group and the control group. The rate of apoptosis in the recombinant plasmid group was significantly higher than that of cells in the empty plasmid group and the control group. Western blot analysis demonstrated that the expression levels of cyclin E, CDK2, cyclin D1 and CDK4 in the recombinant plasmid group were significantly lower than those in the empty plasmid group and the control group; however, the expression levels of Wnt-5α and JNK were significantly higher

  20. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    SciTech Connect

    Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan

    2014-02-07

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer.

  1. Snail promotes epithelial-mesenchymal transition and invasiveness in human ovarian cancer cells

    PubMed Central

    Wang, Yu-Lou; Zhao, Xue-Min; Shuai, Zhi-Feng; Li, Chun-Yan; Bai, Qing-Yang; Yu, Xiu-Wen; Wen, Qiu-Ting

    2015-01-01

    There are limited reports with respect to the study on the epithelium-mesenchymal transformation (EMT) mediated by Snail in the ovarian cancer. This study detected the expression of Snail and related EMT markers in the ovarian cancer tissues, and explored the possible molecular mechanism of EMT mediated by Snail in the metastasis of ovarian cancer. The patients diagnosed with ovarian cancer according to the pathology were recruited in this study during 2010-2014. The carcinoma tissue and normal tissue adjacent to carcinoma were surgically obtained from patients. The genes of E-cadherin, β-catenin, Fibronectin and N-cadherin were detected using the RT-PCR. The 64 patients were recruited and diagnosed as ovarian cancer by pathological examination. The expression levels of Snail, Fibronectin and N-cadherin in the stage III and IV were higher than those in the stage I and II, respectively (all P < 0.05). However, the expression levels of E-cadherin and β-catenin decreased along with the stage developed (trend test, both P < 0.05), respectively. The expression of Snail was positively correlated with the expression of Fibronectin, N-cadherin, but negatively correlated with the expression of E-cadherin and β-catenin. The number of A2780 cells entering into the lower compartment in the group of carcinoma tissue were significantly higher than that in the group of normal tissue after transfected with Snail expression vector. While, the invasion ability of A2780 significantly reduced after RNAi-Snail. The correlation between Snail and invasion and metastasis of ovarian cancer and epithelial-mesenchymal transition based on tissue and cell levels, and to some extent explored the molecular mechanism of the EMT process mediated by Snail. PMID:26221280

  2. Ovarian cysts

    MedlinePlus

    ... Functional ovarian cysts are not the same as ovarian tumors, or cysts due to hormone-related conditions such ... Philadelphia, PA: Elsevier; 2016:chap 17. Katz VL. Benign gynecologic lesions. In: Lentz GM, Lobo RA, Gershenson ...

  3. Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy

    PubMed Central

    Zhang, Xi-Feng; Gurunathan, Sangiliyandi

    2016-01-01

    Ovarian cancer is one of the most important malignancies, and the origin, detection, and pathogenesis of epithelial ovarian cancer remain elusive. Although many cancer drugs have been developed to dramatically reduce the size of tumors, most cancers eventually relapse, posing a critical problem to overcome. Hence, it is necessary to identify possible alternative therapeutic approaches to reduce the mortality rate of this devastating disease. To identify alternative approaches, we first synthesized silver nanoparticles (AgNPs) using a novel bacterium called Bacillus clausii. The synthesized AgNPs were homogenous and spherical in shape, with an average size of 16–20 nm, which are known to cause cytotoxicity in various types of human cancer cells, whereas salinomycin (Sal) is able to kill cancer stem cells. Therefore, we selected both Sal and AgNPs to study their combined effect on apoptosis and autophagy in ovarian cancer cells. The cells treated with either Sal or AgNPs showed a dose-dependent effect with inhibitory concentration (IC)-50 values of 6.0 µM and 8 µg/mL for Sal and AgNPs, respectively. To determine the combination effect, we measured the IC25 values of both Sal and AgNPs (3.0 µM and 4 µg/mL), which showed a more dramatic inhibitory effect on cell viability and cell morphology than either Sal or AgNPs alone. The combination of Sal and AgNPs had more pronounced effect on cytotoxicity and expression of apoptotic genes and also significantly induced the accumulation of autophagolysosomes, which was associated with mitochondrial dysfunction and loss of cell viability. Our data show a strong synergistic interaction between Sal and AgNPs in tested cancer cells. The combination treatment increased the therapeutic potential and demonstrated the relevant targeted therapy for the treatment of ovarian cancer. Furthermore, we provide, for the first time, a mode of action for Sal and AgNPs in ovarian cancer cells: enhanced apoptosis and autophagy. PMID:27536105

  4. Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy.

    PubMed

    Zhang, Xi-Feng; Gurunathan, Sangiliyandi

    2016-01-01

    Ovarian cancer is one of the most important malignancies, and the origin, detection, and pathogenesis of epithelial ovarian cancer remain elusive. Although many cancer drugs have been developed to dramatically reduce the size of tumors, most cancers eventually relapse, posing a critical problem to overcome. Hence, it is necessary to identify possible alternative therapeutic approaches to reduce the mortality rate of this devastating disease. To identify alternative approaches, we first synthesized silver nanoparticles (AgNPs) using a novel bacterium called Bacillus clausii. The synthesized AgNPs were homogenous and spherical in shape, with an average size of 16-20 nm, which are known to cause cytotoxicity in various types of human cancer cells, whereas salinomycin (Sal) is able to kill cancer stem cells. Therefore, we selected both Sal and AgNPs to study their combined effect on apoptosis and autophagy in ovarian cancer cells. The cells treated with either Sal or AgNPs showed a dose-dependent effect with inhibitory concentration (IC)-50 values of 6.0 µM and 8 µg/mL for Sal and AgNPs, respectively. To determine the combination effect, we measured the IC25 values of both Sal and AgNPs (3.0 µM and 4 µg/mL), which showed a more dramatic inhibitory effect on cell viability and cell morphology than either Sal or AgNPs alone. The combination of Sal and AgNPs had more pronounced effect on cytotoxicity and expression of apoptotic genes and also significantly induced the accumulation of autophagolysosomes, which was associated with mitochondrial dysfunction and loss of cell viability. Our data show a strong synergistic interaction between Sal and AgNPs in tested cancer cells. The combination treatment increased the therapeutic potential and demonstrated the relevant targeted therapy for the treatment of ovarian cancer. Furthermore, we provide, for the first time, a mode of action for Sal and AgNPs in ovarian cancer cells: enhanced apoptosis and autophagy. PMID:27536105

  5. Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways.

    PubMed

    Wu, Rong; Hendrix-Lucas, Neali; Kuick, Rork; Zhai, Yali; Schwartz, Donald R; Akyol, Aytekin; Hanash, Samir; Misek, David E; Katabuchi, Hidetaka; Williams, Bart O; Fearon, Eric R; Cho, Kathleen R

    2007-04-01

    One histologic subtype of ovarian carcinoma, ovarian endometrioid adenocarcinoma (OEA), frequently harbors mutations that constitutively activate Wnt/beta-catenin-dependent signaling. We now show that defects in the PI3K/Pten and Wnt/beta-catenin signaling pathways often occur together in a subset of human OEAs, suggesting their cooperation during OEA pathogenesis. Deregulation of these two pathways in the murine ovarian surface epithelium by conditional inactivation of the Pten and Apc tumor suppressor genes results in the formation of adenocarcinomas morphologically similar to human OEAs with 100% penetrance, short latency, and rapid progression to metastatic disease in upwards of 75% of mice. The biological behavior and gene expression patterns of the murine cancers resemble those of human OEAs with defects in the Wnt/beta-catenin and PI3K/Pten pathways.

  6. Ovarian Cyst

    MedlinePlus

    ... accurate way to tell if a woman has ovarian cancer. For example, some women who do have ovarian cancer have a normal CA-125 level. Also, this ... for women who show signs or symptoms of ovarian cancer or who have genetic mutations that increase the ...

  7. Docosahexaenoic Acid Modulates Invasion and Metastasis of Human Ovarian Cancer via Multiple Molecular Pathways

    PubMed Central

    Wang, Ying-Chun; Wu, Yi-Nan; Wang, Su-Li; Lin, Qing-Hua; He, Ming-Fang; Liu, Qiao-lin; Wang, Jin-Hua

    2016-01-01

    Objective We investigated the effect of docosahexaenoic acid (DHA) on the invasion and metastasis of ovarian cancer cells (A2780, HO8910, and SKOV-3). Methods Cytotoxicity assay was performed to determine the optimal doses of DHA in this experiment. The effects of DHA on invasion ability were assessed by invasion assay. The expressions of messenger RNA and/or proteins associated with invasion or metastasis were detected by quantitative Real Time-Polymerase Chain Reaction or Western blot. The effect of DHA on cell metastasis was assessed in xenograft model of zebrafish. Results Docosahexaenoic acid and α-linolenic acid could reduce the cell vitalities in dose-dependent manner. However, DHA inhibited the invasion and metastasis of ovarian cancer cells, but α-linolenic acid did not (**P < 0.01). Docosahexaenoic acid could downregulate the expressions of WAVE3, vascular endothelial cell growth factor, and MMP-9, and upregulate KISS-1, TIMP-1, and PPAR-γ, which negatively correlated with cell invasion and metastasis (*P < 0.05). Docosahexaenoic acid restrained the development of subintestinal vessels and cancer cell metastasis in xenograft model of zebrafish (**P < 0.01). Conclusions Docosahexaenoic acid inhibited the invasion and metastasis of ovarian cancer cells in vitro and in vivo through the modulation of NF-κB signaling pathway, suggesting that DHA is a promising candidate for ovarian cancer therapy. PMID:27258728

  8. Baicalein inhibits MMP-2 expression in human ovarian cancer cells by suppressing the p38 MAPK-dependent NF-κB signaling pathway.

    PubMed

    Yan, Hao; Xin, Shaobin; Wang, Hui; Ma, Jing; Zhang, Heng; Wei, Hailing

    2015-07-01

    Matrix metalloproteinases (MMPs) secreted by ovarian cancer play essential roles in tumor invasion and metastasis. In this study, we investigated the effect of baicalein, which is isolated from the traditional Chinese herbal medicine Scutellaria baicalensis Georgi, on human ovarian cancer cell lines by measuring MMP-2 expression, invasive potential, and the underlying molecular mechanisms. Analysis of MMP-2 was carried out by western blots and RT-PCR. The invasion ability of ovarian cancer cells was determined using a Transwell invasion assay. Nuclear factor-κB (NF-κB) and p38 MAPK activation was assessed by western blots. The results of the present study showed that baicalein reduced the expression of MMP-2 in a dose-dependent manner and the invasion of ovarian cancer cells was also significantly suppressed by baicalein. We also found that baicalein reduced the activation of NF-κB signaling molecules; in addition, the MMP-2 expression and invasion ability of ovarian cancer cells were abolished with the treatment of the NF-κB inhibitor, pyrrolidine dithiocarbamate. However, the addition of p38 MAPK inhibitor SB203580 significantly reduced the activation of NF-κB; meanwhile, baicalein was shown to exert an inhibitory effect on p38 activation. Furthermore, the MMP-2 expression and invasion ability of ovarian cancer cells were significantly inhibited by SB203580. In conclusion, baicalein inhibits the MMP-2 expression and invasion ability of ovarian cancer cells, possibly by the p38 MAPK-dependent NF-κB signaling pathway; these findings may provide insights into the potential of using baicalein as a therapeutic strategy against ovarian cancer.

  9. Opposing effects of ethanol on pig ovarian adenylyl cyclase desensitized by human choriogonadotropin or isoproterenol.

    PubMed

    Ekstrom, R C; Hunzicker-Dunn, M

    1990-11-01

    Pig ovarian follicular membranes contain a gonadotropin-responsive adenylyl cyclase, which becomes partially desensitized (approximately 40%) upon a 40-min incubation with a saturating concentration of human (h) CG. This in vitro desensitization is time and hormone dependent and also requires the presence of micromolar concentrations of GTP. In this report we show that 10% ethanol present during the desensitization phase of the incubation increases the extent of hCG-induced desensitization of adenylyl cyclase by 2-fold. Ethanol shortened the time necessary to reach maximal hCG-induced desensitization from 20 to 10 min, but had no effect on the dose dependency for GTP. In addition, ethanol had no effect on the affinity of the LH/hCG receptor for 125I-hCG but did cause an increase in the ED50 of hCG for inducing desensitization from 0.25 to 0.75 nM. Interestingly, ethanol decreased the apparent number of LH/hCG-receptor sites by 55%, yet the control hCG-sensitive adenylyl cyclase activity was not reduced. The "hyperdesensitized" state achieved in the presence of ethanol could not be reversed by washing the membranes and incubating them in ethanol-free medium. NaF-sensitive adenylyl cyclase was also not impaired in hCG-desensitized membranes from control or ethanol-treated samples. Thus, hCG-induced desensitization was not due to a defect in the functioning of the stimulatory guanine nucleotide-binding regulatory protein (G8) or catalytic subunits, but rather was caused by an impairment of the coupling of the lutropin (LH)/hCG receptor with G8, which was exacerbated further by ethanol. In spite of the effect of ethanol on hCG-induced desensitization, this agent had an inhibitory effect on isoproterenol-induced desensitization of isoproterenol-responsive luteal adenylyl cyclase. These results indicate that membrane fluidity is important in modulating the structure and functional interaction of the LH/hCG receptor with G8 because ethanol is a well known lipid

  10. Human amniotic epithelial cells can differentiate into granulosa cells and restore folliculogenesis in a mouse model of chemotherapy-induced premature ovarian failure

    PubMed Central

    2013-01-01

    Introduction Ovarian dysfunction frequently occurs in female cancer patients after chemotherapy, but human amniotic epithelial cells (hAECs) that can differentiate into cell types that arise from all three germ layers may offer promise for restoration of such dysfunction. Previous studies confirmed that hAECs could differentiate into cells that express germ cell-specific markers, but at this time hAECs have not been shown to restore ovarian function. Methods To model premature ovarian failure, hAECs infected with lenti-virus carrying green fluorescent protein were injected into the tail vein of mice sterilized with cyclophosphamide and busulphan. hAECs migrated to the mouse ovaries and overall ovarian function was measured using immunohistochemical techniques. Results Seven days to two months after hAECs transplantation, ovarian cells were morphologically restored in sterilized mice. Hemotoxylin and eosin staining revealed that restored ovarian cells developed follicles at all stages. No follicles were observed in control mice at the same time period. Immunostaining with anti-human antigen antibodies and pre-transplantation labeling with green fluorescent protein (GFP) revealed that the grafted hAECs survived and migrated to mouse ovary, differentiating into granulosa cells. Furthermore, the ovarian function marker, anti-Müllerian hormone, was evident in treated mouse ovaries after hAEC transplantation. Conclusions Intravenously injected hAECs reached the ovaries of chemotherapy-treated mice and restored folliculogenesis, data which suggest promise for hAECs for promoting reproductive health and improving the quality of life for female cancer survivors. PMID:24406076

  11. Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts

    PubMed Central

    Topp, M; Hartley, L; Cook, M; Heong, V; Boehm, E; McShane, L; Pyman, J; McNally, O; Ananda, S; Harrell, M; Etemadmoghadam, D; Galletta, L; Alsop, K; Mitchell, G; Fox, SB; Kerr, JB; Hutt, KJ; Kaufmann, SH; Swisher, EM; Bowtell, DD; Wakefield, M; Scott, CL

    2015-01-01

    Introduction Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses. Methods We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγnull recipient mice, completed molecular annotation and assessed platinum sensitivity. Results The success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥100 d, n=4), resistant (progression-free interval <100 d, n=3) or refractory (n=3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2). Conclusions Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC. PMID:24560445

  12. 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

  13. Macranthoside B Induces Apoptosis and Autophagy Via Reactive Oxygen Species Accumulation in Human Ovarian Cancer A2780 Cells.

    PubMed

    Shan, Yu; Guan, Fuqin; Zhao, Xingzeng; Wang, Ming; Chen, Yu; Wang, Qizhi; Feng, Xu

    2016-01-01

    Macranthoside B (MB), a saponin compound in Lonicera macranthoides, can block cell proliferation and induce cell death in several types of cancer cells; however, the precise mechanisms by which MB exerts its anticancer effects remain poorly understood. MB blocked A2780 human ovarian carcinoma cell proliferation both dose- and time-dependently. MB induced apoptosis, with increased poly (ADP-ribose) polymerase (PARP) and caspase-3/9 cleavage. MB also caused autophagy in A2780 cells, with light chain 3 (LC3)-II elevation. Inhibiting MB-induced autophagy with the autophagy inhibitor 3-methyladenine (3-MA) significantly decreased apoptosis, with a reduction of growth inhibition; inhibiting MB-induced apoptosis with the pan-caspase inhibitor Z-VAD-FMK did not decrease autophagy but elevated LC3-II levels, indicating that MB-induced autophagy is cytotoxic and may be upstream of apoptosis. Furthermore, MB increased intracellular reactive oxygen species (ROS) levels, with activated 5' adenosine monophosphate-activated protein kinase (AMPK), decreased mammalian target of rapamycin (mTOR) and P70S6 kinase phosphorylation, and increased PARP and caspase-3/9 cleavage, and LC3-II elevation; treatment with the ROS scavenger N-acetyl cysteine and the AMPK inhibitor Compound C diminished this effect. Therefore, the ROS/AMPK/mTOR pathway mediates the effect of MB on induction of apoptosis via autophagy in human ovarian carcinoma cells. PMID:26943028

  14. Moderate Ovarian Stimulation Does Not Increase the Incidence of Human Embryo Chromosomal Abnormalities in in Vitro Fertilization Cycles

    PubMed Central

    Bosch, Ernesto; Alamá, Pilar; Rubio, Carmen; Rodrigo, Lorena; Pellicer, Antonio

    2012-01-01

    Context: A high chromosomal abnormalities rate has been observed in human embryos derived from in vitro fertilization (IVF) treatments. The real incidence in natural cycles has been poorly studied, so whether this frequency may be induced by external factors, such as use of gonadotropins for ovarian stimulation, remains unknown. Design: We conducted a prospective cohort study in a University-affiliated private infertility clinic with a comparison between unstimulated and stimulated ovarian cycles in the same women. Preimplantation genetic screening by fluorescence in situ hybridization was performed in all viable d 3 embryos. Objective: The primary objective was to compare the incidence of embryo chromosomal abnormalities in an unstimulated cycle and in an ulterior moderate ovarian stimulated cycle. Secondary outcome measures were embryo quality, blastocyst rate of biopsied embryos, number of normal blastocysts per donor, type of chromosomal abnormalities, and clinical outcome. Results: One hundred eighty-five oocyte donors were initially recruited for the unstimulated cycle, and preimplantation genetic screening could be performed in 51 of them, showing 35.3% of embryo chromosomal abnormalities. Forty-six of them later completed a stimulated cycle. The sperm donor sample was the same for both cycles. The proportion of embryos displaying abnormalities in the unstimulated cycle was 34.8% (16 of 46), whereas it was 40.6% (123 of 303) in the stimulated cycle with risk difference = 5.8 [95% confidence interval (CI) = −20.6–9.0], and relative risk = 1.17 (95% CI = 0.77–1.77) (P = 0.45). When an intrasubject comparison was made, the abnormalities rate was 34.8% (95% CI = 20.5–49.1) in the unstimulated cycle and 38.2% (95% CI = 30.5–45.8) in the stimulated cycle [risk difference = 3.4 (95% CI = −17.9–11.2); P = 0.64]. No differences were observed for embryo quality and type of chromosomal abnormalities. Conclusions: Moderate ovarian stimulation in young

  15. Establishment of an orthotopic transplantation tumor model in nude mice using a drug-resistant human ovarian cancer cell line with a high expression of c-Kit.

    PubMed

    Yi, Cunjian; Zhang, Lei; Li, Li; Liu, Xiangqiong; Ling, Shengrong; Zhang, Fayun; Liang, Wei

    2014-12-01

    The resistance of ovarian cancer to platinum-based chemotherapy is a critical issue in the clinical setting. The present study aimed to establish animal models to replicate this clinical condition, as well as to investigate the resistance mechanisms of ovarian cancer. A cisplatin (DDP)-resistant human ovarian cancer cell line, SKOV3/DDP, was screened, validated and injected subcutaneously into the neck of female nude mice. Following tumor establishment, the tumor was collected and cut into small sections, which were subsequently implanted into the ovaries of other nude mice. The growth of the orthotopic tumors was observed and the tumor-bearing mice were sacrificed and dissected. The orthotopic and metastatic tumor tissues were collected, sectioned, stained with hematoxylin and eosin and analyzed. In the present study, 16 nude mice underwent orthotopic transplantation surgery and a tumor model was successfully established in 14/16 of the mice, with an in situ tumor formation rate of 87.5%. Following euthanasia, a laparotomy demonstrated the tumor formation at the site of transplantation, as well as varying degrees of metastasis to additional organs and tissues. Therefore, the present study successfully established an orthotopic tumor transplantation model in nude mice using a c-Kit-positive DDP-resistant human ovarian cancer cell line. This model may represent a useful tool for investigating the resistance mechanism of ovarian cancer, as well as evaluating the efficacy of therapeutic strategies.

  16. A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol.

    PubMed

    Oun, Rabbab; Plumb, Jane A; Wheate, Nial J

    2014-05-01

    The anticancer drug cisplatin was encapsulated within the cucurbit[7]uril macrocycle to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB[7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth.

  17. The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes.

    PubMed

    Zhao, Mengjing; Wei, Cai; Yang, Xue; Zhou, Juan; Wang, Jing; Gu, Fang; Lei, Ting; Qin, Yide

    2016-04-01

    Some bioactive peptides derived from natural resources or synthesized by rational design have been proved to have very good anticancer effect. We studied the inhibition of PGPIPN, a hexapeptide derived from bovine β-casein, on the invasion and metastasis of human ovarian cancer cells in vitro and its molecular mechanism. The human ovarian cancer cells studied include the cell line SKOV3 as well as the primary ovarian cancer cells from ovarian tumor tissues of 37 patients at initial debulking surgery, diagnosed as serous ovarian adenocarcinoma. We showed that PGPIPN inhibited the invasion of ovarian cancer cells with Transwell chamber assay, the migration of ovarian cancer cells with cell scratch assay and colony formation of ovarian cancer cells. The expression (mRNAs and proteins) of genes relevant to invasion and metastasis, MTA1, and NM23H1 were analyzed by real-time PCR and western blotting. PGPIPN repressed the expression of MTA1, and promoted NM23H1. The effects of PGPIPN were dose-dependent. Thus, our study suggests that PGPIPN is a potential therapeutic agent for adjuvant therapy of human malignant ovarian tumors.

  18. Positive Selection in Bone Morphogenetic Protein 15 Targets a Natural Mutation Associated with Primary Ovarian Insufficiency in Human

    PubMed Central

    Meslin, Camille; Monestier, Olivier; Di Pasquale, Elisa; Pascal, Géraldine; Persani, Luca; Fabre, Stéphane

    2013-01-01

    Bone Morphogenetic Protein 15 (BMP15) is a TGFβ-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. Alterations of the BMP15 gene have been found associated with different ovarian phenotypic effects depending on the species, from sterility to increased prolificacy in sheep, slight subfertility in mouse or associated with primary ovarian insufficiency (POI) in women. To investigate the evolving role of BMP15, a phylogenetic analysis of this particular TGFβ family member was performed. A maximum likelihood phylogenetic tree of several TGFβ/BMP family members expressed by the ovary showed that BMP15 has a very strong divergence and a rapid evolution compared to others. Moreover, among 24 mammalian species, we detected signals of positive selection in the hominidae clade corresponding to F146, L189 and Y235 residues in human BMP15. The biological importance of these residues was tested functionally after site directed-mutagenesis in a COV434 cells luciferase assay. By replacing the positively selected amino acid either by alanine or the most represented residue in other studied species, only L189A, Y235A and Y235C mutants showed a significant increase of BMP15 signaling when compared to wild type. Additionally, the Y235C mutant was more potent than wild type in inhibiting progesterone secretion of ovine granulosa cells in primary culture. Interestingly, the Y235C mutation was previously identified in association with POI in women. In conclusion, this study evidences that the BMP15 gene has evolved faster than other members of the TGFß family and was submitted to a positive selection pressure in the hominidae clade. Some residues under positive selection are of great importance for the normal function of the protein and thus for female fertility. Y235 represents a critical residue in the determination of BMP15 biological activity, thus indirectly confirming its role in the onset of POI in

  19. Positive selection in bone morphogenetic protein 15 targets a natural mutation associated with primary ovarian insufficiency in human.

    PubMed

    Auclair, Sylvain; Rossetti, Raffaella; Meslin, Camille; Monestier, Olivier; Di Pasquale, Elisa; Pascal, Géraldine; Persani, Luca; Fabre, Stéphane

    2013-01-01

    Bone Morphogenetic Protein 15 (BMP15) is a TGFβ-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. Alterations of the BMP15 gene have been found associated with different ovarian phenotypic effects depending on the species, from sterility to increased prolificacy in sheep, slight subfertility in mouse or associated with primary ovarian insufficiency (POI) in women. To investigate the evolving role of BMP15, a phylogenetic analysis of this particular TGFβ family member was performed. A maximum likelihood phylogenetic tree of several TGFβ/BMP family members expressed by the ovary showed that BMP15 has a very strong divergence and a rapid evolution compared to others. Moreover, among 24 mammalian species, we detected signals of positive selection in the hominidae clade corresponding to F146, L189 and Y235 residues in human BMP15. The biological importance of these residues was tested functionally after site directed-mutagenesis in a COV434 cells luciferase assay. By replacing the positively selected amino acid either by alanine or the most represented residue in other studied species, only L189A, Y235A and Y235C mutants showed a significant increase of BMP15 signaling when compared to wild type. Additionally, the Y235C mutant was more potent than wild type in inhibiting progesterone secretion of ovine granulosa cells in primary culture. Interestingly, the Y235C mutation was previously identified in association with POI in women. In conclusion, this study evidences that the BMP15 gene has evolved faster than other members of the TGFß family and was submitted to a positive selection pressure in the hominidae clade. Some residues under positive selection are of great importance for the normal function of the protein and thus for female fertility. Y235 represents a critical residue in the determination of BMP15 biological activity, thus indirectly confirming its role in the onset of POI in

  20. Endothelin-1/endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis.

    PubMed

    Teoh, Jian-peng; Park, Kyoung-mi; Wang, Yongchao; Hu, Qiuping; Kim, Sangmi; Wu, Guangyu; Huang, Shuang; Maihle, Nita; Kim, Il-man

    2014-12-01

    The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.

  1. Cranberry Proanthocyanidins are Cytotoxic to Human Cancer Cells and Sensitize Platinum-Resistant Ovarian Cancer Cells to Paraplatin

    PubMed Central

    Singh, Ajay P.; Singh, Rakesh K.; Kim, Kyu Kwang; Satyan, K. S.; Nussbaum, Roger; Torres, Monica; Brard, Laurent; Vorsa, Nicholi

    2010-01-01

    Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1–4 linkages containing between 2–8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC50 = 79–479 μg/mL) but were non-cytotoxic to lung fibroblast cells (IC50 > 1000 μg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 μg/ ml) resulted in a significant reduction of the paraplatin IC50 value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells. PMID:19172579

  2. A novel uPAg-KPI fusion protein inhibits the growth and invasion of human ovarian cancer cells in vitro

    PubMed Central

    ZHAO, LI-PING; XU, TIAN-MIN; KAN, MU-JIE; XIAO, YE-CHEN; CUI, MAN-HUA

    2016-01-01

    Urokinase-type plasminogen activator (uPA) acts by breaking down the basement membrane and is involved in cell proliferation, migration and invasion. These actions are mediated by binding to the uPA receptor (uPAR) via its growth factor domain (GFD). The present study evaluated the effects of uPAg-KPI, a fusion protein of uPA-GFD and a kunitz protease inhibitor (KPI) domain that is present in the amyloid β-protein precursor. Using SKOV-3 cells, an ovarian cancer cell line, we examined cell viability, migration, invasion and also protein expression. Furthermore, we examined wound healing, and migration and invasion using a Transwell assay. Our data showed that uPAg-KPI treatment reduced the viability of ovarian cancer SKOV-3 cells in both a concentration and time-dependent manner by arresting tumor cells at G1/G0 phase of the cell cycle. The IC50 of uPAg-KPI was 0.5 µg/µl after 48 h treatment. At this concentration, uPAg-KPI also inhibited tumor cell colony formation, wound closure, as well as cell migration and invasion capacity. At the protein level, western blot analysis demonstrated that uPAg-KPI exerted no significant effect on the expression of total extracellular signal-regulated kinase (ERK)1/ERK2 and AKT, whereas it suppressed levels of phosphorylated ERK1/ERK2 and AKT. Thus, we suggest that this novel uPAg-KPI fusion protein reduced cell viability, colony formation, wound healing and the invasive ability of human ovarian cancer SKOV-3 cells in vitro by regulating ERK and AKT signaling. Further studies using other cell lines will confirm these findings. PMID:27035617

  3. [The establishment of human ovarian carcinoma cell line HO-8910 and its characteristics].

    PubMed

    Mou, H Z; Xu, S H; Zhang, Y Y

    1994-03-01

    A cell line designated HO-8910 was established in vitro from the ascitic fluid of a patient with poorly-differentiated ovarian papillary serous cyst-adenocarcinoma. The cell line grew well through 130 passages and showed malignant epithelial morphology under light and electron microscopes. The chromosome number varied widely from 45 to 300 and its model was 54(42%); The DNA index was 1.45 as measured by FCM method; Both of them showed aneuploidy. The cell line has the ability to secrete steroid sex hormones and also has hormone receptors. When transplanted into nude mice, the xenograft has similar pathological characteristic to the original. It is expected that this cell line would be of great help in the future study on ovarian carcinoma.

  4. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer.

    PubMed

    Zhang, Hui; Liu, Tao; Zhang, Zhen; Payne, Samuel H; Zhang, Bai; McDermott, Jason E; Zhou, Jian-Ying; Petyuk, Vladislav A; Chen, Li; Ray, Debjit; Sun, Shisheng; Yang, Feng; Chen, Lijun; Wang, Jing; Shah, Punit; Cha, Seong Won; Aiyetan, Paul; Woo, Sunghee; Tian, Yuan; Gritsenko, Marina A; Clauss, Therese R; Choi, Caitlin; Monroe, Matthew E; Thomas, Stefani; Nie, Song; Wu, Chaochao; Moore, Ronald J; Yu, Kun-Hsing; Tabb, David L; Fenyö, David; Bafna, Vineet; Wang, Yue; Rodriguez, Henry; Boja, Emily S; Hiltke, Tara; Rivers, Robert C; Sokoll, Lori; Zhu, Heng; Shih, Ie-Ming; Cope, Leslie; Pandey, Akhilesh; Zhang, Bing; Snyder, Michael P; Levine, Douglas A; Smith, Richard D; Chan, Daniel W; Rodland, Karin D

    2016-07-28

    To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT. PMID:27372738

  5. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer.

    PubMed

    Zhang, Hui; Liu, Tao; Zhang, Zhen; Payne, Samuel H; Zhang, Bai; McDermott, Jason E; Zhou, Jian-Ying; Petyuk, Vladislav A; Chen, Li; Ray, Debjit; Sun, Shisheng; Yang, Feng; Chen, Lijun; Wang, Jing; Shah, Punit; Cha, Seong Won; Aiyetan, Paul; Woo, Sunghee; Tian, Yuan; Gritsenko, Marina A; Clauss, Therese R; Choi, Caitlin; Monroe, Matthew E; Thomas, Stefani; Nie, Song; Wu, Chaochao; Moore, Ronald J; Yu, Kun-Hsing; Tabb, David L; Fenyö, David; Bafna, Vineet; Wang, Yue; Rodriguez, Henry; Boja, Emily S; Hiltke, Tara; Rivers, Robert C; Sokoll, Lori; Zhu, Heng; Shih, Ie-Ming; Cope, Leslie; Pandey, Akhilesh; Zhang, Bing; Snyder, Michael P; Levine, Douglas A; Smith, Richard D; Chan, Daniel W; Rodland, Karin D

    2016-07-28

    To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT.

  6. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma

    PubMed Central

    Shen, G H; Ghazizadeh, M; Kawanami, O; Shimizu, H; Jin, E; Araki, T; Sugisaki, Y

    2000-01-01

    The influence of vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) on prognosis and the relationship between VEGF expression and MVD in ovarian carcinoma are not well defined. We studied VEGF expression in parallel with MVD by immunohistochemistry in 94 ovarian tumours (64 malignant, 13 borderline, and 17 benign) and correlated the results with the clinicopathologic prognostic factors of the disease to clarify their significance in this disease. Assessment of VEGF mRNA isoforms by RT-PCR was also performed. Of the malignant, borderline, and benign ovarian tumours respectively, two (3%), four (31%) and 16 (94%) were negative, 31 (48%), seven (54%) and one (6%) had low expressions, and 31 (48%), two (15%) and none (0%) had high expressions of VEGF. There were significant associations between the VEGF expression and disease stage (P = 0.002), histologic grade (P = 0.0004), and patient outcome (P = 0.0002). MVD did not correlate significantly with the clinicopathologic parameters. Likewise, no correlation was found between MVD and VEGF expression. The survival of patients with high VEGF expression was significantly worse than that of patients with low and negative VEGF expression (P = 0.0004). Multivariate analysis revealed that disease stage and VEGF expression were significant and independent prognostic indicators of overall survival time (P = 0.008 and P = 0.006 respectively). These findings suggest that in conjunction with the established clinicopathologic prognostic parameters of ovarian carcinoma, VEGF expression may enhance the predictability of patients at high risk for tumour progression who are potential candidates for further aggressive therapy. © 2000 Cancer Research Campaign PMID:10901370

  7. 3D texture analysis for classification of second harmonic generation images of human ovarian cancer

    PubMed Central

    Wen, Bruce; Campbell, Kirby R.; Tilbury, Karissa; Nadiarnykh, Oleg; Brewer, Molly A.; Patankar, Manish; Singh, Vikas; Eliceiri, Kevin. W.; Campagnola, Paul J.

    2016-01-01

    Remodeling of the collagen architecture in the extracellular matrix (ECM) has been implicated in ovarian cancer. To quantify these alterations we implemented a form of 3D texture analysis to delineate the fibrillar morphology observed in 3D Second Harmonic Generation (SHG) microscopy image data of normal (1) and high risk (2) ovarian stroma, benign ovarian tumors (3), low grade (4) and high grade (5) serous tumors, and endometrioid tumors (6). We developed a tailored set of 3D filters which extract textural features in the 3D image sets to build (or learn) statistical models of each tissue class. By applying k-nearest neighbor classification using these learned models, we achieved 83–91% accuracies for the six classes. The 3D method outperformed the analogous 2D classification on the same tissues, where we suggest this is due the increased information content. This classification based on ECM structural changes will complement conventional classification based on genetic profiles and can serve as an additional biomarker. Moreover, the texture analysis algorithm is quite general, as it does not rely on single morphological metrics such as fiber alignment, length, and width but their combined convolution with a customizable basis set. PMID:27767180

  8. Multispectral fluorescence imaging of human ovarian and Fallopian tube tissue for early stage cancer detection

    NASA Astrophysics Data System (ADS)

    Tate, Tyler; Baggett, Brenda; Rice, Photini; Watson, Jennifer; Orsinger, Gabe; Nymeyer, Ariel C.; Welge, Weston A.; Keenan, Molly; Saboda, Kathylynn; Roe, Denise J.; Hatch, Kenneth; Chambers, Setsuko; Black, John; Utzinger, Urs; Barton, Jennifer

    2015-03-01

    With early detection, five year survival rates for ovarian cancer are over 90%, yet no effective early screening method exists. Emerging consensus suggests that perhaps over 50% of the most lethal form of the disease, high grade serous ovarian cancer, originates in the Fallopian tube. Cancer changes molecular concentrations of various endogenous fluorophores. Using specific excitation wavelengths and emissions bands on a Multispectral Fluorescence Imaging (MFI) system, spatial and spectral data over a wide field of view can be collected from endogenous fluorophores. Wavelength specific reflectance images provide additional information to normalize for tissue geometry and blood absorption. Ratiometric combination of the images may create high contrast between neighboring normal and abnormal tissue. Twenty-six women undergoing oophorectomy or debulking surgery consented the use of surgical discard tissue samples for MFI imaging. Forty-nine pieces of ovarian tissue and thirty-two pieces of Fallopian tube tissue were collected and imaged with excitation wavelengths between 280 nm and 550 nm. After imaging, each tissue sample was fixed, sectioned and HE stained for pathological evaluation. Comparison of mean intensity values between normal, benign, and cancerous tissue demonstrate a general trend of increased fluorescence of benign tissue and decreased fluorescence of cancerous tissue when compared to normal tissue. The predictive capabilities of the mean intensity measurements are tested using multinomial logistic regression and quadratic discriminant analysis. Adaption of the system for in vivo Fallopian tube and ovary endoscopic imaging is possible and is briefly described.

  9. Genetics and biology of human ovarian teratomas. I. Cytogenetic analysis and mechanism of origin.

    PubMed

    Surti, U; Hoffner, L; Chakravarti, A; Ferrell, R E

    1990-10-01

    One hundred and two benign, mature ovarian teratomas and two immature, malignant teratomas were karyotyped and scored for centromeric heteromorphisms as part of an ongoing project to determine the chromosomal karyotype and the genetic origin of ovarian teratomas and to assess their utility for gene-centromere mapping. Karyotypic analysis of the benign cases revealed 95 46,XX teratomas and 7 chromosomally abnormal teratomas (47,XXX, 47,XX,+8 [two cases], 47,XX,+15, 48,XX,+7,+12 91,XXXX,-13 [mosaic], 47,XX,-15,+21,+mar). Our study reports on the first cases of tetraploidy and structural rearrangement in benign ovarian teratomas. The two immature cases had modal chromosome numbers of 78 and 49. Centromeric heteromorphisms that were heterozygous in the host were homozygous in 65.2% (n = 58) of the benign teratomas and heterozygous in the remaining 34.8% (n = 31). Chromosome 13 heteromorphisms were the most informative, with 72.7% heterozygosity in hosts. The cytogenetic data indicate that 65% of teratomas are derived from a single germ cell after meiosis I and failure of meiosis II (type II) or endoreduplication of a mature ovum (type III); 35% arise by failure of meiosis I (type I) or mitotic division of premeiotic germ cells (type IV). PMID:2220805

  10. Multispectral fluorescence imaging of human ovarian and fallopian tube tissue for early-stage cancer detection

    NASA Astrophysics Data System (ADS)

    Tate, Tyler H.; Baggett, Brenda; Rice, Photini F. S.; Koevary, Jennifer Watson; Orsinger, Gabriel V.; Nymeyer, Ariel C.; Welge, Weston A.; Saboda, Kathylynn; Roe, Denise J.; Hatch, Kenneth D.; Chambers, Setsuko K.; Utzinger, Urs; Barton, Jennifer Kehlet

    2016-05-01

    With early detection, 5-year survival rates for ovarian cancer exceed 90%, yet no effective early screening method exists. Emerging consensus suggests over 50% of the most lethal form of the disease originates in the fallopian tube. Twenty-eight women undergoing oophorectomy or debulking surgery provided informed consent for the use of surgical discard tissue samples for multispectral fluorescence imaging. Using multiple ultraviolet and visible excitation wavelengths and emissions bands, 12 fluorescence and 6 reflectance images of 47 ovarian and 31 fallopian tube tissue samples were recorded. After imaging, each sample was fixed, sectioned, and stained for pathological evaluation. Univariate logistic regression showed cancerous tissue samples had significantly lower intensity than noncancerous tissue for 17 image types. The predictive power of multiple image types was evaluated using multivariate logistic regression (MLR) and quadratic discriminant analysis (QDA). Two MLR models each using two image types had receiver operating characteristic curves with area under the curve exceeding 0.9. QDA determined 56 image type combinations with perfect resubstituting using as few as five image types. Adaption of the system for future in vivo fallopian tube and ovary endoscopic imaging is possible, which may enable sensitive detection of ovarian cancer with no exogenous contrast agents.

  11. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen.

    PubMed

    Fishman, D A; Kearns, A; Chilukuri, K; Bafetti, L M; O'Toole, E A; Georgacopoulos, J; Ravosa, M J; Stack, M S

    1998-01-01

    Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the

  12. Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

    PubMed

    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. PMID:27091429

  13. Application of microwave-assisted micro-solid-phase extraction for determination of parabens in human ovarian cancer tissues.

    PubMed

    Sajid, Muhammad; Basheer, Chanbasha; Narasimhan, Kothandaraman; Choolani, Mahesh; Lee, Hian Kee

    2015-09-01

    Parabens (alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in food, cosmetics and pharmaceutical products. However, weak estrogenicity of some parabens has been reported in several studies, which provided the impetus for this work. Here, a simple and efficient analytical method for quantifying parabens in cancer tissues has been developed. This technique involves the simultaneous use of microwave-assisted solvent extraction (MASE) and micro-solid phase extraction (μ-SPE), in tandem with high performance liquid chromatography (HPLC/UV) analysis for the determination of parabens. The pollutants studied included four parabens (methyl, ethyl, propyl and butyl parabens). Optimization of the experimental parameters for MASE and μ-SPE was performed. Good relative standard deviation (%RSD) ranged from 0.09 to 2.81% and high enrichment factors (27-314) were obtained. Coefficients of determination (r(2)) up to 0.9962 were obtained across a concentration range of 5.0-200ngg(-1). The method detection limits for parabens ranged from 0.005 to 0.0244ngg(-1). The procedure was initially tested on prawn samples to demonstrate its feasibility on a complex biological matrix. Preliminary studies on human ovarian cancer (OC) tissues showed presence of parabens. Higher levels of parabens were detected in malignant ovarian tumor tissues compared to benign tumor tissue samples.

  14. Overexpression of long non-coding RNA HOTAIR leads to chemoresistance by activating the Wnt/β-catenin pathway in human ovarian cancer.

    PubMed

    Li, Jing; Yang, Siqin; Su, Ning; Wang, Yuan; Yu, Jinjin; Qiu, Haifeng; He, Xiaoying

    2016-02-01

    Overexpression of HOTAIR (HOX antisense intergenic RNA) is significantly correlated with tumor progression and poor prognosis in human ovarian cancer. However, the underlying mechanisms are largely unknown. In the present study, we investigated the roles of HOTAIR in the initiation and chemoresistance of ovarian cancer. As our data show, HOTAIR overexpression promoted cell cycle progression (and thus cell proliferation) by activating the wnt/β-catenin signaling pathway. Likewise, knockdown of HOTAIR suppressed cell proliferation and arrested cell cycle at G1 phase via inhibition of wnt/β-catenin signaling. Moreover, the results of primary culture demonstrated that elevated HOTAIR expression correlated positively with chemoresistance in ovarian cancer. In vitro and in vivo, HOTAIR induced cellular resistance to cisplatin by activating the wnt/β-catenin pathway, which could be reversed by pre-treatment with the wnt/β-catenin inhibitor, XAV939. In conclusion, HOTAIR promotes the initiation and chemoresistance of ovarian cancer by activating wnt/β-catenin signaling, suggesting that HOTAIR might be a potent therapeutic target for ovarian cancer treatment. PMID:26341496

  15. Viability of human ovarian tissue confirmed 5 years after freezing with spontaneous ice-formation by autografting and chorio-allantoic membrane culture.

    PubMed

    Isachenko, Vladimir; Orth, Ingrid; Isachenko, Evgenia; Mallmann, Peter; Peters, Doris; Schmidt, Torsten; Morgenstern, Bernd; Foth, Dolores; Hanstein, Bettina; Rahimi, Gohar

    2013-06-01

    To achieve optimal and uniform outcomes, slow cooling protocols for human ovarian tissues generally initiate ice formation at high sub-zero temperatures (-6 to -9 °C). The aim of the study was to investigate the function of ovarian tissue that had unintentionally self seeded at -20 °C during the freezing step, by examining its development following chicken embryonic chorioallantoic membrane (CAM) grafting and after transplantation back to the patient. Ovarian tissue was frozen in 6% (v/v) dimethyl sulfoxide, 6% (v/v) ethylene glycol and 0.15M sucrose which had self-seeded at -20 °C. Five years after cryopreservation, 8 pieces were thawed and transplanted back to the patient. Two small (1 × 2 × 1 mm) pieces of this thawed tissue were cultured in a CAM-system for 5 days to assess the tissue viability. The autografted ovarian tissue re-established spontaneous menstrual bleeding within five months and raised serum 17-β Estradiol from 19 to 330 pg/ml. Ultrasound revealed a dominant follicle at the site of the transplanted tissue in the follicular phase after the menstrual bleed. Analysis of the CAM cultured tissue established that 88% of the primordial follicles are degenerated and there was limited in growth of blood vessels. In conclusion, in spite of the damage caused by the cryopreservation with spontaneous ice-formation the viability could be confirmed by CAM culture and the restoration of ovarian function after auto-transplantation.

  16. Minireview: Human Ovarian Cancer: Biology, Current Management, and Paths to Personalizing Therapy

    PubMed Central

    Romero, Ignacio

    2012-01-01

    More than 90% of ovarian cancers have been thought to arise from epithelial cells that cover the ovarian surface or, more frequently, line subserosal cysts. Recent studies suggest that histologically similar cancers can arise from the fimbriae of Fallopian tubes and from deposits of endometriosis. Different histotypes are observed that resemble epithelial cells from the normal Fallopian tube (serous), endometrium (endometrioid), cervical glands (mucinous), and vaginal rests (clear cell) and that share expression of relevant HOX genes which drive normal gynecological differentiation. Two groups of epithelial ovarian cancers have been distinguished: type I low-grade cancers that present in early stage, grow slowly, and resist conventional chemotherapy but may respond to hormonal manipulation; and type II high-grade cancers that are generally diagnosed in advanced stage and grow aggressively but respond to chemotherapy. Type I cancers have wild-type p53 and BRCA1/2, but have frequent mutations of Ras and Raf as well as expression of IGFR and activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Virtually all type II cancers have mutations of p53, and almost half have mutation or dysfunction of BRCA1/2, but other mutations are rare, and oncogenesis appears to be driven by amplification of several growth-regulatory genes that activate the Ras/MAPK and PI3K pathways. Cytoreductive surgery and combination chemotherapy with platinum compounds and taxanes have improved 5-yr survival, but less than 40% of all stages can be cured. Novel therapies are being developed that target high-grade serous cancer cells with PI3Kness or BRCAness as well as the tumor vasculature. Both in silico and animal models are needed that more closely resemble type I and type II cancers to facilitate the identification of novel targets and to predict response to combinations of new agents. PMID:22416079

  17. Psammoma bodies in two types of human ovarian tumours: a mineralogical study

    NASA Astrophysics Data System (ADS)

    Fanlu, Meng; Changqiu, Wang; Yan, Li; Anhuai, Lu; Fang, Mei; Jianying, Liu; Jingyun, Du; Yan, Zhang

    2015-06-01

    Psammoma body (PB) is a common form of calcification in pathological diagnosis and closely relevant to tumours. This paper focuses on the mineralogical characteristics of PBs in ovarian serous cancer and teratoma by using polarization microscope (POM), environmental scanning electron microscope (ESEM), micro-Fourier transform infrared spectroscopy (micro-FT-IR), transmission electron microscope (TEM), micro-area synchrotron radiation X-ray powder diffraction (μ-SRXRD) and fluorescence (μ-SRXRF). Both the PBs in tissues and separated from eight typical cases were investigated. POM and ESEM observation revealed the inside-out growth pattern of PBs. μ-SRXRD and micro-FT-IR results demonstrated the dominant mineral phase of PBs in ovarian serous cancer and teratoma was AB-type carbonate hydroxyapatite (Ca10[(PO4)6-x-y(CO3)x(HPO4 2-)y][(OH)2-u(CO3)u] with 0 ≤ x,y,u ≤ 2). As observed by ESEM and TEM, the layer-rich PBs in teratoma were up to 70 μm and mainly consisted of 5 nm-wide, 5-12 nm-long columnar crystals; the PBs in ovarian serous cancer with a maximum diameter of 35 μm were composed of slightly longer columnar crystals and granulates with 20-100 nm in diameter. The selected area electron diffraction patterns showed dispersed polycrystalline diffraction rings with arching behavior of (002) diffraction, indicating the aggregated nanocrystals grew in the preferred orientation of (002) face. The EDX and μ-SRXRF results together indicated the existence of Na, Mg, Zn and Sr in PBs. These detailed mineralogical characteristics may help uncover the nature of the pathological PBs in ovary.

  18. Erratum to: Psammoma bodies in two types of human ovarian tumours: a mineralogical study

    NASA Astrophysics Data System (ADS)

    Meng, Fanlu; Wang, Changqiu; Li, Yan; Lu, Anhuai; Mei, Fang; Liu, Jianying; Du, Jingyun; Zhang, Yan

    2015-06-01

    Psammoma body (PB) is a common form of calcification in pathological diagnosis and closely relevant to tumours. This paper focuses on the mineralogical characteristics of PBs in ovarian serous cancer and teratoma by using polarization microscope (POM), environmental scanning electron microscope (ESEM), micro-Fourier transform infrared spectroscopy (micro-FT-IR), transmission electron microscope (TEM), micro-area synchrotron radiation X-ray powder diffraction (μ-SRXRD) and fluorescence (μ-SRXRF). Both the PBs in tissues and separated from eight typical cases were investigated. POM and ESEM observation revealed the inside-out growth pattern of PBs. μ-SRXRD and micro-FT-IR results demonstrated the dominant mineral phase of PBs in ovarian serous cancer and teratoma was AB-type carbonate hydroxyapatite (Ca10[(PO4)6-x-y(CO3)x(HPO4)y][(OH)2-u(CO3)u] with 0 ≤ x,y,u ≤ 2). As observed by ESEM and TEM, the layer-rich PBs in teratoma were up to 70 μm and mainly consisted of 5 nm-wide, 5-12 nm-long columnar crystals; the PBs in ovarian serous cancer with a maximum diameter of 35 μm were composed of slightly longer columnar crystals and granulates with 20-100 nm in diameter. The selected area electron diffraction patterns showed dispersed polycrystalline diffraction rings with arching behavior of (002) diffraction, indicating the aggregated nanocrystals grew in the preferred orientation of (002) face. The EDX and μ-SRXRF results together indicated the existence of Na, Mg, Zn and Sr in PBs. These detailed mineralogical characteristics may help uncover the nature of the pathological PBs in ovary.

  19. Establishment of human ovarian serous carcinomas cell lines in serum free media.

    PubMed

    Pan, Zhuangyu; Hooley, Jeffrey; Smith, Douglas H; Young, Peter; Roberts, Penelope E; Mather, Jennie P

    2012-03-01

    Ovarian cancers are the fifth leading cause of cancer death among US woman. The majority of ovarian cancers belong to a category of serous adenocarcinomas. This type of cancer is often diagnosed at a late stage of the disease. Surgical debulking, followed by chemotherapy is the current treatment. Half of all patients will die within 5 years of diagnosis of the disease. Poor survival may be due to disease progression as a consequence of development of drug resistance, cancer cell heterogeneity within the tumor, or the persistence of cancer stem cells. Cancer stem cells (CSC) are defined as a minority cell type in the tumor, which retains the capacity, through asymmetric division, for self-renewal as well as differentiation into multiple cell types. Through this process, CSC can regenerate the entire tumor phenotype and subsequent metastases. Initial in vitro work in the area of solid tumor CSC biology has focused on the isolation and propagation of cells with CSC-like properties from breast and colon tumors. Breast and colon cell lines with CSC-like properties have been isolated and maintained in vitro for extended periods of time. The in vitro maintenance of these CSC requires growth in hormone-supplemented serum-free media and the use of matrix or growth as tumor spheres (Roberts, Ricci-Vitiani et al., Cammareri et al.). Based on the pioneering work generating breast and colon CSC, our lab has begun to develop methods for the establishment cell lines with CSC-like properties from additional solid tumors. In this article, we describe methods, using defined medium, which allow for the successful establishment of continuous cell cultures from a minority cell type within serous ovarian cancers. The cell lines established using these methods grow in serum-free hormone-supplemented medium either as a monolayer on a matrix, or as tumor spheres in suspension. These cells express markers previously reported for tumor stem cells, including CD44 and CD133, and form tumors

  20. Human epididymis protein 4 expression positively correlated with miR-21 and served as a prognostic indicator in ovarian cancer.

    PubMed

    Chen, Yong; Chen, Qingquan; Liu, Qicai; Gao, Feng

    2016-06-01

    Ovarian cancer is the most common cause of gynecological malignancy-related mortality. Human epididymis protein 4 (HE4) is a useful biomarker for ovarian cancer when either used alone or in combination with carbohydrate antigen 125 (CA125). What is more, aberrant expression of microRNA-21 (miR-21) has been shown to be involved in oncogenesis, but the relationship between miR-21 and HE4 in ovarian cancer is not clear. Tumor and adjacent tumor tissues from 43 patients with ovarian cancer were examined. Real-time polymerase chain reaction (RT-PCR) was used to detect the expression of HE4 in the carcinoma and adjacent tissues. The associations between HE4 and tumor biological characters were discussed. TaqMan(®) MicroRNA (miRNA) assays were employed to detect the expression of miR-21 in the ovarian carcinoma. In ovarian cancer, the expression of HE4 messenger RNA (mRNA) in cancer tissues was higher than adjacent tumor tissues (P < 0.0001), which was 1.299-fold of adjacent tumor tissues. And, the expression of miR-21 was also up-regulated which was significantly different in the ovarian cancer (the positive rate was 76.74 %). There was a significantly positive correlation between miR-21 and HE4 expression (r = 0.283 and P = 0.066 for HE4 mRNA, r = 0.663 and P < 0.0001 for serum HE4). There was also a significant correlation between miR-21 and tumor grade (r = 0.608, P < 0.0001). Significantly, patients with recent recurrence (less than 6 months, n = 17) have a higher miR-21 expression than those with no recent recurrence. Therefore, HE4 and miR-21 may play an important role in the development and progression of ovarian cancer and they may serve as prognostic indicators in ovarian cancer.

  1. Novel methods of treating ovarian infertility in older and POF women, testicular infertility, and other human functional diseases.

    PubMed

    Bukovsky, Antonin

    2015-02-25

    In vitro maturation (IVM) and in vitro fertilization (IVF) technologies are facing with growing demands of older women to conceive. Although ovarian stem cells (OSCs) of older women are capable of producing in vitro fresh oocyte-like cells (OLCs), such cells cannot respond to IVM and IVF due to the lack of granulosa cells required for their maturation. Follicular renewal is also dependent on support of circulating blood mononuclear cells. They induce intermediary stages of meiosis (metaphase I chromosomal duplication and crossover, anaphase, telophase, and cytokinesis) in newly emerging ovarian germ cells, as for the first time demonstrated here, induce formation of granulosa cells, and stimulate follicular growth and development. A pretreatment of OSC culture with mononuclear cells collected from blood of a young healthy fertile woman may cause differentiation of bipotential OSCs into both developing germ and granulosa cells. A small blood volume replacement may enable treatment of ovarian infertility in vivo. The transferred mononuclear cells may temporarily rejuvenate virtually all tissues, including improvement of the function of endocrine tissues. Formation of new follicles and their development may be sufficient for IVM and IVF. The novel proposed in vitro approaches may be used as a second possibility. Infertility of human males affects almost a half of the infertility cases worldwide. Small blood volume replacement from young healthy fertile men may also be easy approach for the improvement of sperm quality in older or other affected men. In addition, body rejuvenation by small blood volume replacement from young healthy individuals of the same sex could represent a decline of in vitro methodology in favor of in vivo treatment for human functional diseases. Here we propose for the first time that blood mononuclear cells are essential for rejuvenation of those tissues, where immune system components participate in an appropriate division and differentiation

  2. The influence of nanotexturing of poly(lactic-co-glycolic acid) films upon human ovarian cancer cell attachment

    NASA Astrophysics Data System (ADS)

    Yaşayan, Gökçen; Xue, Xuan; Collier, Pamela; Clarke, Philip; Alexander, Morgan R.; Marlow, Maria

    2016-06-01

    In this study, we have produced nanotextured poly(lactic-co-glycolic acid) (PLGA) films by using polystyrene (PS) particles as a template to make a polydimethylsiloxane mould against which PLGA is solvent cast. Biocompatible, biodegradable and nanotextured PLGA films were prepared with PS particles of diameter of 57, 99, 210, and 280 nm that produced domes of the same dimension in the PLGA surface. The effect of the particulate monolayer templating method was investigated to enable preparation of the films with uniformly ordered surface nanodomes. Cell attachment of a human ovarian cancer cell line (OVCAR3) alone and co-cultured with mesenchymal stem cells (MSCs) was evaluated on flat and topographically nano-patterned surfaces. Cell numbers were observed to increase on the nanotextured surfaces compared to non-textured surfaces both with OVCAR3 cultures and OVCAR3-MSC co-cultures at 24 and 48 h time points.

  3. Ovarian Cysts

    MedlinePlus

    ... or if the cyst does not go away. Birth control pills can help prevent new cysts. A health problem that may involve ovarian cysts is polycystic ovary syndrome (PCOS). Women with PCOS can have high levels of male hormones, irregular or no periods and small ovarian ...

  4. MiR-145 is downregulated in human ovarian cancer and modulates cell growth and invasion by targeting p70S6K1 and MUC1

    SciTech Connect

    Wu, Huijuan; Xiao, ZhengHua; Wang, Ke; Liu, Wenxin; Hao, Quan

    2013-11-29

    Highlights: •MiR-145 is downregulated in human ovarian cancer. •MiR-145 targets p70S6K1 and MUC1. •p70S6K1 and MUC1 are involved in miR-145 mediated tumor cell growth and cell invasion, respectively. -- Abstract: MicroRNAs (miRNAs) are a family of small non-coding RNA molecules that regulate gene expression at post-transcriptional levels. Previous studies have shown that miR-145 is downregulated in human ovarian cancer; however, the roles of miR-145 in ovarian cancer growth and invasion have not been fully demonstrated. In the present study, Northern blot and qRT-PCR analysis indicate that miR-145 is downregulated in ovarian cancer tissues and cell lines, as well as in serum samples of ovarian cancer, compared to healthy ovarian tissues, cell lines and serum samples. Functional studies suggest that miR-145 overexpression leads to the inhibition of colony formation, cell proliferation, cell growth viability and invasion, and the induction of cell apoptosis. In accordance with the effect of miR-145 on cell growth, miR-145 suppresses tumor growth in vivo. MiR-145 is found to negatively regulate P70S6K1 and MUC1 protein levels by directly targeting their 3′UTRs. Importantly, the overexpression of p70S6K1 and MUC1 can restore the cell colony formation and invasion abilities that are reduced by miR-145, respectively. MiR-145 expression is increased after 5-aza-CdR treatment, and 5-aza-CdR treatment results in the same phenotype as the effect of miR-145 overexpression. Our study suggests that miR-145 modulates ovarian cancer growth and invasion by suppressing p70S6K1 and MUC1, functioning as a tumor suppressor. Moreover, our data imply that miR-145 has potential as a miRNA-based therapeutic target for ovarian cancer.

  5. AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer

    PubMed Central

    Pépin, David; Sosulski, Amanda; Zhang, Lihua; Wang, Dan; Vathipadiekal, Vinod; Hendren, Katherine; Coletti, Caroline M.; Yu, Aaron; Castro, Cesar M.; Birrer, Michael J.; Gao, Guangping; Donahoe, Patricia K.

    2015-01-01

    To improve ovarian cancer patient survival, effective treatments addressing chemoresistant recurrences are particularly needed. Mullerian inhibiting substance (MIS) has been shown to inhibit the growth of a stem-like population of ovarian cancer cells. We have recently engineered peptide modifications to human MIS [albumin leader Q425R MIS (LRMIS)] that increase production and potency in vitro and in vivo. To test this novel therapeutic peptide, serous malignant ascites from highly resistant recurrent ovarian cancer patients were isolated and amplified to create low-passage primary cell lines. Purified recombinant LRMIS protein successfully inhibited the growth of cancer spheroids in vitro in a panel of primary cell lines in four of six patients tested. Adeno-associated virus (AAV) -delivered gene therapy has undergone a clinical resurgence with a good safety profile and sustained gene expression. Therefore, AAV9 was used as a single i.p. injection to deliver LRMIS to test its efficacy in inhibiting growth of palpable tumors in patient-derived ovarian cancer xenografts from ascites (PDXa). AAV9-LRMIS monotherapy resulted in elevated and sustained blood concentrations of MIS, which significantly inhibited the growth of three of five lethal chemoresistant serous adenocarcinoma PDXa models without signs of measurable or overt toxicity. Finally, we tested the frequency of MIS type II receptor expression in a tissue microarray of serous ovarian tumors by immunohistochemistry and found that 88% of patients bear tumors that express the receptor. Taken together, these preclinical data suggest that AAV9-LRMIS provides a potentially well-tolerated and effective treatment strategy poised for testing in patients with chemoresistant serous ovarian cancer. PMID:26216943

  6. Effect of targeted ovarian cancer therapy using amniotic fluid mesenchymal stem cells transfected with enhanced green fluorescent protein-human interleukin-2 in vivo

    PubMed Central

    YOU, QI; YAO, YUAN; ZHANG, YUANLONG; FU, SONGBIN; DU, MEI; ZHANG, GUANGMEI

    2015-01-01

    The aim of the present study was to investigate the effect of using amniotic fluid mesenchymal stem cells (AF-MSCs) in targeted ovarian cancer therapy in vivo. AF-MSCs were isolated from human second trimester AF and a plasmid, enhanced green fluorescent protein-human interleukin-2 (pEGFP-hIL-2) was formed. The plasmid was stably transfected into the AF-MSCs and the cells were intravenously injected into ovarian cancer nude mice models. Following stable transfection of the vector, tumor formation, and the expression and activity of hIL-2 were investigated, and microscopic pathological examinations of the tumor were performed. It was found that AF-MSCs exhibited high motility during migration in vivo, and the vector, pEGFP-hIL-2 can be stably transfected into AF-MSCs. Following stable transfection, this type of stem cell is able to successfully transport the therapeutic gene, IL-2, migrate to the ovarian cancer tumor site to secrete the functional IL-2 and treat the tumor. Thus, AF-MSCs may serve as transporters for therapeutic genes targeting ovarian tumor sites and, therefore, be involved in the treatment of tumors. PMID:26179662

  7. Effect of targeted ovarian cancer therapy using amniotic fluid mesenchymal stem cells transfected with enhanced green fluorescent protein-human interleukin-2 in vivo.

    PubMed

    You, Qi; Yao, Yuan; Zhang, Yuanlong; Fu, Songbin; Du, Mei; Zhang, Guangmei

    2015-10-01

    The aim of the present study was to investigate the effect of using amniotic fluid mesenchymal stem cells (AF-MSCs) in targeted ovarian cancer therapy in vivo. AF-MSCs were isolated from human second trimester AF and a plasmid, enhanced green fluorescent protein‑human interleukin‑2 (pEGFP‑hIL‑2) was formed. The plasmid was stably transfected into the AF‑MSCs and the cells were intravenously injected into ovarian cancer nude mice models. Following stable transfection of the vector, tumor formation, and the expression and activity of hIL‑2 were investigated, and microscopic pathological examinations of the tumor were performed. It was found that AF‑MSCs exhibited high motility during migration in vivo, and the vector, pEGFP‑hIL‑2 can be stably transfected into AF‑MSCs. Following stable transfection, this type of stem cell is able to successfully transport the therapeutic gene, IL-2, migrate to the ovarian cancer tumor site to secrete the functional IL-2 and treat the tumor. Thus, AF-MSCs may serve as transporters for therapeutic genes targeting ovarian tumor sites and, therefore, be involved in the treatment of tumors.

  8. Isolation of small SSEA-4-positive putative stem cells from the ovarian surface epithelium of adult human ovaries by two different methods.

    PubMed

    Virant-Klun, Irma; Skutella, Thomas; Hren, Matjaz; Gruden, Kristina; Cvjeticanin, Branko; Vogler, Andrej; Sinkovec, Jasna

    2013-01-01

    The adult ovarian surface epithelium has already been proposed as a source of stem cells and germinal cells in the literature, therefore it has been termed the "germinal epithelium". At present more studies have confirmed the presence of stem cells expressing markers of pluripotency in adult mammalian ovaries, including humans. The aim of this study was to isolate a population of stem cells, based on the expression of pluripotency-related stage-specific embryonic antigen-4 (SSEA-4) from adult human ovarian surface epithelium by two different methods: magnetic-activated cell sorting and fluorescence-activated cell sorting. Both methods made it possible to isolate a similar, relatively homogenous population of small, SSEA-4-positive cells with diameters of up to 4  μm from the suspension of cells retrieved by brushing of the ovarian cortex biopsies in reproductive-age and postmenopausal women and in women with premature ovarian failure. The immunocytochemistry and genetic analyses revealed that these small cells--putative stem cells--expressed some primordial germ cell and pluripotency-related markers and might be related to the in vitro development of oocyte-like cells expressing some oocyte-specific transcription factors in the presence of donated follicular fluid with substances important for oocyte growth and development. The stemness of these cells needs to be further researched.

  9. Effects of metoclopramide-induced hyperprolactinemia during early follicular development on human ovarian function.

    PubMed

    Kauppila, A; Kirkinen, P; Orava, M; Vihko, R

    1984-11-01

    Nine healthy women, aged 25 to 36 yr, were treated with metoclopramide (MC) (10 mg orally three times daily) from the first to the sixth day of their cycle (treatment A) for two successive cycles (n = 18) and six of these women later received MC from -3 to the fifth day of the menstrual cycle (treatment B) during one or two cycles (n = 10), to investigate the effects of hyperprolactinemia during the early phase of ovarian follicular growth. Comparisons were performed with control cycles in the same women. The treatment cycles were characterized by low serum concentrations of LH during the early follicular phase and at midcycle, low early follicular phase serum testosterone (T) levels and high luteal phase T and free T index values, with no significant differences between A and B treatment modalities. We classified the treatment cycles into two categories, seriously disturbed and normal or only slightly disturbed, on the basis of ultrasonographic findings and midcycle estradiol (E2) and luteal phase progesterone (P) concentrations. Folliculogenesis was seriously disturbed in 11 of the 28 treatment cycles (39%). During these cycles, midcycle serum LH and the LH to FSH ratio were lowered, luteal phase LH and FSH increased, midcycle E2 and luteal phase P and the P to E2 ratio decreased, luteal phase T and the free T index and androstenedione increased, and luteal phase 5 alpha-dihydrotestosterone decreased. During the early follicular phase and at midcycle the ratios of T to E2 and androstenedione to E2 were increased, and at midcycle and during the luteal phase of the cycle the ratio of T to 5 alpha-dihydrotestosterone was increased. These changes in steroid hormones were probably of ovarian origin since the serum concentrations of dehydroepiandrosterone sulfate and sex hormone-binding globulin were similar in seriously disturbed and control cycles. Four of the nine study subjects were hyperprolactinemia sensitive (disturbed folliculogenesis) and five

  10. Identification of high-risk patients by human epididymis protein 4 levels during follow-up of ovarian cancer

    PubMed Central

    STEFFENSEN, KARINA DAHL; WALDSTRØM, MARIANNE; BRANDSLUND, IVAN; LUND, BENTE; SØRENSEN, SARAH MEJER; PETZOLD, MAX; JAKOBSEN, ANDERS

    2016-01-01

    The majority of ovarian cancer patients with advanced disease at diagnosis will relapse following primary treatment, with a dismal prognosis. Monitoring the levels of serum markers in patients under follow-up may be essential for the early detection of relapse, and for distinguishing high-risk patients from those with less aggressive disease. The aim of the present study was to investigate the possible predictive value of human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) in relation to recurrence of epithelial ovarian cancer by measuring the two markers during follow-up subsequent to surgery and adjuvant first-line carboplatin/paclitaxel chemotherapy. Serum HE4 and CA125 were analyzed in 88 epithelial ovarian cancer patients at the end of treatment and consecutively during follow-up. The patients were divided into a high-risk and a low-risk group based on having an increase in HE4 and CA125 levels above or below 50% during follow-up, relative to the baseline (end-of-treatment) level. Disease recurrence was detected in 55 patients during follow-up. Patients with an increase in HE4 of >50% at 3- and 6-month follow-up compared to the end-of-treatment sample had significantly poorer progression-free survival (PFS) [hazard ratio (HR), 2.82 (95% CI, 0.91–8.79; P=0.0052) and HR, 7.71 (95% CI, 3.03–19.58; P<0.0001), respectively]. The corresponding 3- and 6-month biomarker assessments for increased CA125 levels (>50%) showed HRs of 1.86 (95% CI, 0.90–3.80; P=0.0512) and 2.55 (95% CI, 1.39–4.68; P=0.0011), respectively. Multivariate analysis confirmed HE4 as a predictor of short PFS, with an HR of 8.23 (95% CI, 3.28–20.9; P<0.0001) at 6-month follow-up. The increase of CA125 was not a significant prognostic factor in multivariate analysis for PFS. In conclusion, HE4 appears to be a sensitive marker of recurrence and instrumental in risk assessment during the first 6 months of follow-up. PMID:27313725

  11. Long-Time Cooling before Cryopreservation Decreased Translocation of Phosphatidylserine (Ptd-L-Ser) in Human Ovarian Tissue

    PubMed Central

    2015-01-01

    Objectives To translocation (externalization) of phosphatidylserine lead at least the five negative effects observed during cells cryopreservation: hypoxia, increasing of intracellular Ca2+, osmotic disruption of cellular membranes, generation of reactive oxygen species (ROS) and lipid peroxidation. The aim of this study was to test the intensiveness of the phosphatidylserine translocation immediately after thawing and after 45 d xenografting of human ovarian tissue, which was either frozen just after operative removal from patient or cooled before cryopreservation to 5°C for 24 h and then frozen. Materials and Methods Ovarian fragments from twelve patients were divided into small pieces in form of cortex with medulla, and randomly divided into the following four groups. Pieces of Group 1 (n=30) were frozen immediately after operation, thawed and just after thawing their quality was analyzed. Group 2 pieces (n=30) after operation were cooled to 5°C for 24 h, then frozen after 24 h pre-cooling to 5°C, thawed and just after thawing their quality was analyzed. Group 3 pieces (n=30) were frozen immediately after operation without pre-cooling, thawed, transplanted to SCID mice and then, after 45 d of culture their quality was analyzed. Group 4 pieces (n=30) were frozen after 24 h pre-cooling to 5°C, thawed, transplanted to SCID mice and then, after 45 d their quality was analyzed. The effectiveness of the pre-freezing cooling of tissuewas evaluated by the development of follicles (histology) and by intensiveness of translocation of phosphatidylserine (FACS with FITC-Annexin V and Propidium Iodide). Results For groups 1, 2, 3 and 4 the mean densities of follicles per 1 mm3 was 19.0, 20.2, 12.9, and 12.2, respectively (P1-2, 3-4 >0.1). For these groups, 99%, 98%, 88% and 90% preantral follicles, respectively were morphologically normal (P1-2, 3-4 >0.1). The FACS analysis showed significantly decreased intensiveness of translocation of phosphatidylserine after pre

  12. Synchronization of ovulation with human chorionic gonadotropin in lactating dairy cows with ovarian cysts during heat stress.

    PubMed

    Navanukraw, Chainarong; Khanthusaeng, Vilaivan; Kraisoon, Aree; Suwannarit, Duangkamon; Jarassaeng, Chaiwat; Aiumlamai, Suneerat

    2015-06-01

    A study was conducted during hot season to determine the effect of synchronization of ovulation with human chorionic gonadotropin (hCG) on fertility of lactating dairy cows with ovarian cysts. Non cyclic Holstein dairy cows (n = 80) were stratified by parity and diagnosed as having an ovarian cyst. The cows were further identified as follicular or luteal cysts according to the plasma progesterone (P4) concentration and the cystic image of ultrasonography. Cystic cows were randomly assigned to receive treatments (Ovsynch as the control or Ovsynch plus 3000 IU hCG). All cows were artificially inseminated at 16-18 h after the second gonadotropin releasing hormone injection. Cows supplemented with hCG had a greater number of corpus luteum (1.8 ± 0.2 and 0.8 ± 0.3; P < 0.05) and had greater P4 concentration on day 12 than those control cows (6.3 ± 0.3 and 3.9 ± 0.4 ng/ml; P < 0.05). Concentration of cortisol did not differ between groups of cystic cows. No significant differences were found in overall conception rates between the treatments; however, significantly greater conception rate (P = 0.03) was observed in cows with luteal cysts receiving Ovsynch plus hCG. This study highlights that administration of hCG following the Ovsynch-based timed artificial insemination (AI) is more effective than the control Ovsynch by which the hCG affects corpus luteum (CL) development, P4 concentration, and thus improves conception rate in dairy cows with luteal cysts. PMID:25863956

  13. Ovarian Cancer FAQ

    MedlinePlus

    ... Ovarian Cancer Patient Education FAQs Ovarian Cancer Patient Education Pamphlets - Spanish Ovarian Cancer FAQ096, April 2015 PDF Format Ovarian ... Your Practice Patient Safety & Quality Payment Reform (MACRA) Education & Events Annual ... Pamphlets Teen Health About ACOG About Us Leadership & ...

  14. EZH2-specific microRNA-98 inhibits human ovarian cancer stem cell proliferation via regulating the pRb-E2F pathway.

    PubMed

    Liu, Te; Hou, Lengchen; Huang, Yongyi

    2014-07-01

    The Polycomb group protein, enhancer of zeste homolog 2 (EZH2), plays an important role in transcriptional regulation through chromatin remodeling and interactions with other transcription factors to control cell proliferation and embryonic development. Previous study has shown that EZH2 is important for cell cycle regulation and is highly expressed in human ovarian cancer. Loss of EZH2 inhibits growth of ovarian cancer as well as other human carcinomas. In this study, an expression plasmid of EZH2-targeted microRNA-98 was constructed and transfected into human ovarian cancer stem cells (OCSCs). Seventy-two hours after transfection, cell growth was inhibited and arrested at the G0/G1 transition. p21(CIPI/WAF1) was up-regulated, while the CDK2/cyclin E complex and c-Myc were down-regulated. Most importantly, expression levels of E2F1, retinoblastoma protein (pRb), and histone deacetylase 1 (HDAC1) in the pRb-E2F signaling pathway had changed. Furthermore, microRNA-98 suppressed the growth of OCSCs xenograft tumors. Our findings suggest that EZH2-specific microRNA-98 can effectively inhibit cell proliferation in vitro and regulate the pRb-E2F pathway in human OCSCs.

  15. Ovarian hypofunction

    MedlinePlus

    ... may be caused by genetic factors such as chromosome abnormalities. It may also occur with certain autoimmune disorders that disrupt the normal function of the ovaries. Chemotherapy and radiation therapy can also cause ovarian hypofunction.

  16. Ovarian Cysts

    MedlinePlus

    ... information Endometriosis fact sheet Ovarian cancer fact sheet Polycystic ovary syndrome fact sheet The javascript used in this widget ... ovaries make many small cysts. This is called polycystic ovary syndrome (PCOS). PCOS can cause problems with the ovaries ...

  17. Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

    PubMed Central

    Grunewald, T G P; Kammerer, U; Winkler, C; Schindler, D; Sickmann, A; Honig, A; Butt, E

    2007-01-01

    LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration. In the present work, we analysed the effect of LASP-1 on biology and function of human ovarian cancer cell line SKOV-3 using small interfering RNA technique (siRNA).Transfection with LASP-1-specific siRNA resulted in a reduced protein level of LASP-1 in SKOV-3 cells. The siRNA-treated cells were arrested in G2/M phase of the cell cycle and proliferation of the tumour cells was suppressed by 60–90% corresponding to around 70% of the cells being transfected successfully as seen by immunofluorescence. Moreover, transfected tumour cells showed a 40% reduced migration. LASP-1 silencing is accompanied by a reduced binding of the LASP-1-binding partner zyxin to focal contacts without changes in actin stress fibre and microtubule organisation or focal adhesion morphology as observed by immunofluorescence. In contrast, silencing of zyxin is not influencing cell migration and had neither influence on LASP-1 expression nor actin cytoskeleton and focal contact morphology suggesting that LASP-1 is necessary and sufficient for recruiting zyxin to focal contacts.The data provide evidence for an essential role of LASP-1 in tumour cell growth and migration, possibly through influencing zyxin localization. PMID:17211471

  18. Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

    PubMed Central

    2015-01-01

    A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 μg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 °C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinoma (HT-29), the prodrug administered intraperitoneally was effective in reducing or eliminating xenograft tumors at dose levels as low as 0.3 mg/kg when given daily and at 0.9 mg/kg when given less frequently. When given via intraperitoneal and oral routes at daily doses of 0.6 and 0.9 mg/kg, the prodrug was also effective and well tolerated in a mouse model of human ovarian cancer (A2780). PMID:26596892

  19. Limitations of the clonal agar assay for the assessment of primary human ovarian tumour biopsies.

    PubMed Central

    Bertoncello, I.; Bradley, T. R.; Campbell, J. J.; Day, A. J.; McDonald, I. A.; McLeish, G. R.; Quinn, M. A.; Rome, R.; Hodgson, G. S.

    1982-01-01

    114 biopsy specimens from 70 patients with ovarian carcinoma at all stages of disease were submitted for assessment of clonogenic capacity in agar. A highly significant correlation was found between agar clonogenicity and patient survival after biopsy. However, problems related to inherent tumour heterogeneity, quality of sample and tissue disaggregation indicate that this technique may have limited applicability in the routine assessment of patients. Only 41 biopsy specimens (36%) from 31 patients (44.3%) complied with the prerequisite criteria for agar clonogenic assessment, namely: (a) the confirmed presence of malignant cells in the biopsy, (b) the ability to prepare a single-cell suspension, and (c) adequate viable cell numbers for assay. Furthermore, although the dominant patterns of agar clonogenic growth could be identified and correlated with stage of disease, the heterogeneity in both initial clonogenic capacity and "self-renewal" capacity assessed by the ability of primary clones to propagate in liquid culture and reclone in agar was too inconsistent for the assay to be used as a prognostic index for the individual patient. Images Figure PMID:7093117

  20. In vivo Magnetic Resonance Metabolic and Morphofunctional Fingerprints in Experimental Models of Human Ovarian Cancer

    PubMed Central

    Canese, Rossella; Mezzanzanica, Delia; Bagnoli, Marina; Indraccolo, Stefano; Canevari, Silvana; Podo, Franca; Iorio, Egidio

    2016-01-01

    Epithelial ovarian cancer (EOC) is the gynecological malignancy with the highest death rate, characterized by frequent relapse and onset of drug resistance. Disease diagnosis and therapeutic follow-up could benefit from application of molecular imaging approaches, such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), able to monitor metabolic and functional alterations and investigate the underlying molecular mechanisms. Here, we overview the quantitative alterations that occur during either orthotopic or subcutaneous growth of preclinical EOC models. A common feature of 1H MR spectra is the presence of a prominent peak due to total choline-containing metabolites (tCho), together with other metabolic alterations and MRI-detected morphofunctional patterns specific for different phenotypes. The tCho signal, already present at early stages of tumor growth, and changes of diffusion-weighted MRI parameters could serve as markers of malignancy and/or tumor response to therapy. The identification by MRS and MRI of biochemical and physiopathological fingerprints of EOC disease in preclinical models can represent a basis for further developments of non-invasive MR approaches in the clinical setting. PMID:27446810

  1. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer.

    PubMed

    Odunsi, Kunle; Matsuzaki, Junko; James, Smitha R; Mhawech-Fauceglia, Paulette; Tsuji, Takemasa; Miller, Austin; Zhang, Wa; Akers, Stacey N; Griffiths, Elizabeth A; Miliotto, Anthony; Beck, Amy; Batt, Carl A; Ritter, Gerd; Lele, Shashikant; Gnjatic, Sacha; Karpf, Adam R

    2014-01-01

    The cancer-testis/cancer-germline antigen NY-ESO-1 is a vaccine target in epithelial ovarian cancer (EOC), but its limited expression is a barrier to vaccine efficacy. As NY-ESO-1 is regulated by DNA methylation, we hypothesized that DNA methyltransferase (DNMT) inhibitors may augment NY-ESO-1 vaccine therapy. In agreement, global DNA hypomethylation in EOC was associated with the presence of circulating antibodies to NY-ESO-1. Pre-clinical studies using EOC cell lines showed that decitabine treatment enhanced both NY-ESO-1 expression and NY-ESO-1-specific CTL-mediated responses. Based on these observations, we performed a phase I dose-escalation trial of decitabine, as an addition to NY-ESO-1 vaccine and doxorubicin liposome (doxorubicin) chemotherapy, in 12 patients with relapsed EOC. The regimen was safe, with limited and clinically manageable toxicities. Both global and promoter-specific DNA hypomethylation occurred in blood and circulating DNAs, the latter of which may reflect tumor cell responses. Increased NY-ESO-1 serum antibodies and T cell responses were observed in the majority of patients, and antibody spreading to additional tumor antigens was also observed. Finally, disease stabilization or partial clinical response occurred in 6/10 evaluable patients. Based on these encouraging results, evaluation of similar combinatorial chemo-immunotherapy regimens in EOC and other tumor types is warranted.

  2. Contamination of human ovarian follicular fluid and serum by chlorinated organic compounds in three Canadian cities.

    PubMed Central

    Jarrell, J F; Villeneuve, D; Franklin, C; Bartlett, S; Wrixon, W; Kohut, J; Zouves, C G

    1993-01-01

    OBJECTIVES: To determine the extent of contamination of ovarian follicular fluid and serum samples in women undergoing in-vitro fertilization and to study the effect of the contaminants on reproductive outcome. DESIGN: Inception cohort study. PATIENTS: Seventy-four women undergoing in-vitro fertilization at three regional clinics in Halifax, Hamilton, Ont., and Vancouver. MAIN OUTCOME MEASURES: Follicular fluid and serum levels of contaminants, cleavage rates and time to cleavage of first egg. RESULTS: Five chlorinated organic chemicals were frequently found in the two types of samples: alpha-chlordane (ALCH), dichlorochlorophenylethylene (DDE), heptachloroepoxide-oxychlordane (OXCH), hexachlorobenzene (HCB) and polychlorinated biphenyl (PCB). The levels were generally low. Regional differences between the three clinics were present. Samples from the Halifax clinic had the lowest frequency and level of contamination. The source of drinking water (well, bottled or municipal) was an important confounder. The concentrations of the five contaminants did not affect the cleavage rate or the time to cleavage of the first egg. CONCLUSION: Trace amounts of toxic and persistent chlorinated organic chemicals found in the follicular fluid of Canadian women undergoing in-vitro fertilization did not seem to have any adverse biologic effect on the rate of fertilization and the time to cleavage. Reasons for regional differences in the concentrations of contaminants require further study. PMID:8462054

  3. Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75.

    PubMed Central

    Yano, T; Pinski, J; Halmos, G; Szepeshazi, K; Groot, K; Schally, A V

    1994-01-01

    Female athymic nude mice bearing xenografts of OV-1063 human epithelial ovarian cancer cell line were treated with potent luteinizing hormone (LH)-releasing hormone (LH-RH) antagonist SB-75 (Cetrorelix; [Ac-D-Nal(2)1, D-Phe(4 CI)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH in which Ac-D-Nal(2) = N-acetyl-3-(2-naphthyl)-D-alanine, D-Phe(4CI) = 4-chloro-D-phenylalanine, D-Pal(3) = 3-(3-pyridyl)-D-alanine, and D-Cit = D-Citrulline) or with the agonist [D-Trp6]LH-RH. In the first experiment, SB-75 and [D-Trp6]LH-RH were administered in the form of microcapsules releasing 60 and 25 micrograms/day, respectively. In the second study, the analogs were given by daily s.c. injections in doses of 100 micrograms/day. In both experiments, tumor growth, as measured by reduction in tumor volume, percentage change in tumor volume, tumor burden, and increase in tumor doubling time, was significantly inhibited by treatment with SB-75 but not with [D-Trp6]LH-RH. Uterine and ovarian weights were reduced and serum LH levels decreased by administration of either analog. Chronic treatment with SB-75 greatly reduced the concentration of receptors for epidermal growth factor and insulin-like growth factor I in tumor cell membranes, a phenomenon that might be related to tumor growth inhibition. It is possible that the antitumoral effects of SB-75 on OV-1063 ovarian cancers are exerted not only through the suppression of the pituitary-gonadal axis, but also directly. In view of its strong inhibitory effect on the growth of OV-1063 ovarian cancers in vivo, the potent LH-RH antagonist SB-75 might be considered for possible hormonal therapy of advanced epithelial ovarian carcinoma. PMID:7518926

  4. In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors.

    PubMed

    Roomi, M W; Monterrey, J C; Kalinovsky, T; Rath, M; Niedzwiecki, A

    2010-03-01

    Matrix metalloproteinases (MMPs) secreted by cervical and ovarian cancer, especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect of cytokines, mitogens, inducers and inhibitors on MMP-2 and MMP-9 expression in cervical and ovarian cancer cell lines. Human cervical (HeLa and DoTc2-4510) and ovarian (SK-OV-3) cell lines were cultured in appropriate media. At near confluence, the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography and quantitated by densitometry. HeLa and SK-OV-3 cell lines expressed MMP-2 whereas DoTc2-4510 cells expressed MMP-9. Treatment of cervical cancer cell lines (HeLa and DoTc2-4510) with PMA had no effect on MMP-2 expression and a moderate stimulatory effect in ovarian cancer cell line SK-OV-3. MMP-9 was stimulated by phorbol 12-myristate 13-acetate in HeLa cells and enhanced in DoTc2-4510. Tumor necrosis factor-alpha and interleukin-1beta, had slight inhibitory effect on HeLa cell expression of MMP-2 while lipopolysaccharide stimulated MMP-2 in HeLa cells. Doxycycline, epigallocatechin gallate, a nutrient mixture, actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited MMP-2 in HeLa and SK-OV-3 cell lines and inhibited MMP-9 in DoTc2-4510. Our results show that cytokines, mitogens, inducers and inhibitors have an up or down regulatory effect on MMP-2 and MMP-9 expression in ovarian and cervical cancer cell lines, suggesting these agents may be effective strategies to treat these cancers.

  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. Investigation of human cationic antimicrobial protein-18 (hCAP-18), lactoferrin and CD163 as potential biomarkers for ovarian cancer

    PubMed Central

    2013-01-01

    Background Epithelial ovarian cancer is one of the leading causes of gynaecological cancer morbidity and mortality in women. Early stage ovarian cancer is usually asymptomatic, therefore, is often first diagnosed when it is widely disseminated. Currently available diagnostics lack the requisite sensitivity and specificity to be implemented as community-based screening tests. The identification of additional biomarkers may improve the diagnostic efficiency of multivariate index assays. The aims of this study were to characterise and compare the ovarian tissue immunohistochemical localisation and plasma concentrations of three putative ovarian cancer biomarkers: human cationic antimicrobial protein-18 (hCAP-18); lactoferrin; and CD163 in normal healthy women and women with ovarian cancer. Methods In this case–control cohort study, ovarian tissue and blood samples were obtained from 164 women (73 controls, including 28 women with benign pelvic masses; 91 cancer, including 21 women with borderline tumours). Localisation of each antigen within the ovary was assessed by immunohistochemistry and serum concentrations determined by ELISA assays. Results Immunoreactive (ir) hCAP-18 and lactoferrin were identified in epithelial cells, while CD163 was predominately localised in stromal cells. Tissue ir CD163 increased significantly (P<0.05) with disease grade. Median plasma concentrations of soluble (s)CD163 were significantly greater in the cases (3220 ng/ml) than in controls (2488 ng/ml) (P< 0.01). Median plasma concentrations of hCAP-18 and lactoferrin were not significantly different between cases and controls. The classification efficiency of each biomarker (as determined by the area under the receiver operator characteristic curve; AUC) was: 0.67± 0.04; 0.62 ± 0.08 and 0.51 ± 0.07 for sCD163, hCAP-18 and lactoferrin, respectively. When the 3 biomarkers were modelled using stochastic gradient boosted logistic regression, the AUC increased to 0.95 ± 0.03. Conclusions

  7. Inhibitory effect of ethyl acetate extract of the shaggy inc cap medicinal mushroom, Coprinus comatus (Higher Basidiomycetes) fruit bodies on cell growth of human ovarian cancer.

    PubMed

    Rouhana-Toubi, Amal; Wasser, Solomon P; Agbarya, Abed; Fares, Fuad

    2013-01-01

    In a previous study, we screened organic extracts of different mushroom mycelia and picked ethyl acetate extract of Coprinus comatus as one of the most active extracts against human ovarian cancer cells. In the current study, we extracted a dry powder of C. comatus fruit bodies using ethyl acetate and examined its effect on the viability of three cell lines originated from human ovarian cancer (ES-2, SKOV-3, and SW-626). This extract was active against all tested cell lines, in a dose-dependent manner (concentrations 50-200 µg/mL, P<0.01). In an attempt to segregate the active fraction, we subjected the extract to chromatography on a silica gel column. The effect of six different fractions and of the crude extract on the viability of ES-2 cells was examined after exposure time of 24 h. Fraction F (last eluted) was significantly more effective than crude extract in the reduction of cell viability (P<0.01). Fraction F was also significantly more active than crude extract in the reduction of viability of SKOV-3 cells. We next identified some of the compounds of fraction F (mainly fatty acids) by gas chromatography-mass spectrometry. In summary, ethyl acetate extract of C. comatus reduced viability of three lines of human ovarian cancer. Fractionation of this extract by a silica gel column enabled the selection of a fraction significantly more active than the original extract. PMID:24266371

  8. 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

  9. Taxol produced from endophytic fungi induces apoptosis in human breast, cervical and ovarian cancer cells.

    PubMed

    Wang, Xin; Wang, Chao; Sun, Yu-Ting; Sun, Chuan-Zhen; Zhang, Yue; Wang, Xiao-Hua; Zhao, Kai

    2015-01-01

    Currently, taxol is mainly extracted from the bark of yews; however, this method can not meet its increasing demand on the market because yews grow very slowly and are a rare and endangered species belonging to first- level conservation plants. Recently, increasing efforts have been made to develop alternative means of taxol production; microbe fermentation would be a very promising method to increase the production scale of taxol. To determine the activities of the taxol extracted from endophytic fungus N. sylviforme HDFS4-26 in inhibiting the growth and causing the apoptosis of cancer cells, on comparison with the taxol extracted from the bark of yew, we used cellular morphology, cell counting kit (CCK-8) assay, staining (HO33258/PI and Giemsa), DNA agarose gel electrophoresis and flow cytometry (FCM) analyses to determine the apoptosis status of breast cancer MCF-7 cells, cervical cancer HeLa cells and ovarian cancer HO8910 cells. Our results showed that the fungal taxol inhibited the growth of MCF-7, HeLa and HO8910 cells in a dose-and time-dependent manner. IC50 values of fungal taxol for HeLa, MCF-7 and HO8910 cells were 0.1-1.0 μg/ml, 0.001-0.01 μg/ml and 0.01- 0.1 μg/ml, respectively. The fungal taxol induced these tumor cells to undergo apoptosis with typical apoptotic characteristics, including morphological changes for chromatin condensation, chromatin crescent formation, nucleus fragmentation, apoptotic body formation and G2/M cell cycle arrest. The fungal taxol at the 0.01-1.0 μg/ ml had significant effects of inducing apoptosis between 24-48 h, which was the same as that of taxol extracted from yews. This study offers important information and a new resource for the production of an important anticancer drug by endofungus fermentation. PMID:25640339

  10. Taxol produced from endophytic fungi induces apoptosis in human breast, cervical and ovarian cancer cells.

    PubMed

    Wang, Xin; Wang, Chao; Sun, Yu-Ting; Sun, Chuan-Zhen; Zhang, Yue; Wang, Xiao-Hua; Zhao, Kai

    2015-01-01

    Currently, taxol is mainly extracted from the bark of yews; however, this method can not meet its increasing demand on the market because yews grow very slowly and are a rare and endangered species belonging to first- level conservation plants. Recently, increasing efforts have been made to develop alternative means of taxol production; microbe fermentation would be a very promising method to increase the production scale of taxol. To determine the activities of the taxol extracted from endophytic fungus N. sylviforme HDFS4-26 in inhibiting the growth and causing the apoptosis of cancer cells, on comparison with the taxol extracted from the bark of yew, we used cellular morphology, cell counting kit (CCK-8) assay, staining (HO33258/PI and Giemsa), DNA agarose gel electrophoresis and flow cytometry (FCM) analyses to determine the apoptosis status of breast cancer MCF-7 cells, cervical cancer HeLa cells and ovarian cancer HO8910 cells. Our results showed that the fungal taxol inhibited the growth of MCF-7, HeLa and HO8910 cells in a dose-and time-dependent manner. IC50 values of fungal taxol for HeLa, MCF-7 and HO8910 cells were 0.1-1.0 μg/ml, 0.001-0.01 μg/ml and 0.01- 0.1 μg/ml, respectively. The fungal taxol induced these tumor cells to undergo apoptosis with typical apoptotic characteristics, including morphological changes for chromatin condensation, chromatin crescent formation, nucleus fragmentation, apoptotic body formation and G2/M cell cycle arrest. The fungal taxol at the 0.01-1.0 μg/ ml had significant effects of inducing apoptosis between 24-48 h, which was the same as that of taxol extracted from yews. This study offers important information and a new resource for the production of an important anticancer drug by endofungus fermentation.

  11. NF-kappaB activation contributes to anthracycline resistance pathway in human ovarian carcinoma cell line A2780.

    PubMed

    Salvatore, Carmela; Camarda, Grazia; Maggi, Carlo Alberto; Goso, Cristina; Manzini, Stefano; Binaschi, Monica

    2005-09-01

    The development of chemoresistance is a major obstacle for successful anticancer therapy. Understanding the molecular mechanisms leading to chemoresistance is a rational step to improve the therapeutic efficacy of cytotoxic drugs. Since anthracyclines play an important role in cancer chemotherapy, we have generated a human ovarian tumor cell line resistant to sabarubicin (MEN 10755), the newest anthracycline molecule in clinical development. Expression of the transporter protein MRP that affected sabarubicin uptake, and a reduced DNA topoisomerase II content in A2780/saba cells was observed. Since the poisoning of DNA topoisomerase II results in DNA damage, which is a critical signal for NF-kappaB activation, we explored if this transcription factor has a role in the chemoresistance to anthracyclines. We showed a reduced NF-kappaB activation in the resistant cell line. Moreover, qualitative changes in NF-kappaB dimer formation between the two cell lines were observed. In agreement with the hypothesis of a role of NF-kappaB in mediating drug resistance, we showed that the pharmacological inhibition of NF-kappaB activation attenuated drug resistance in A2780/saba cells whereas it had no effect in A2780 cells. Altogether, these findings show that anthracycline resistance in A2780 cell lines is due to the coexpression of several molecular mechanisms.

  12. Survival and growth of human preantral follicles after cryopreservation of ovarian tissue, follicle isolation and short-term xenografting.

    PubMed

    Paulini, Fernanda; Vilela, Janice M V; Chiti, Maria Costanza; Donnez, Jacques; Jadoul, Pascale; Dolmans, Marie-Madeleine; Amorim, Christiani A

    2016-09-01

    In women, chemotherapy and radiotherapy can be harmful to the ovaries, causing loss of endocrine and reproductive functions. When gonadotoxic treatment cannot be delayed, ovarian tissue cryobanking is the only way of preserving fertility. This technique, however, is not advisable for patients with certain types of cancer, because of the risk of reintroducing malignant cells present in the cryopreserved tissue. Our objective is therefore to develop a transplantable artificial ovary. To this end, cryopreserved human preantral follicles were isolated and embedded in fibrin formulations prepared with 50 mg/ml fibrinogen and 10 IU/ml thrombin supplemented or not with 3% hyaluronic acid, and respectively xenografted to specially created right and left peritoneal pockets in eight nude mice. On days 0 and 7, the animals were killed and the matrices retrieved. On day 7, no difference was observed in the recovery rate of follicles embedded in fibrin alone (23.4%) or fibrin-hyaluronic acid (20.5%). Ki67 staining confirmed growth of the grafted follicles and terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling assay revealed 100% of the follicles to be viable in both groups on day 7. In conclusion, fibrin seems to be a promising material for creation of an artificial ovary, supporting follicle survival and development. PMID:27210771

  13. Synthesis and cytotoxicity of three trans-palladium complexes containing planaramine ligands in human ovarian tumor models.

    PubMed

    Mazumder, Mohammed Ehsanul Hoque; Beale, Philip; Chan, Charles; Yu, Jun Qing; Huq, Fazlul

    2012-10-01

    The present study deals with the synthesis, characterization, and activity against human ovarian cancer cell lines A2780, A2780(cisR), A2780(ZD0473R), and SKOV-3 of three trans-planaramine-palladium(II) complexes of the form trans-PdL(2)Cl(2), coded as EH1, EH3, and EH4, for which L = 2-methylpyridine, imidazole, and 1,2-α-imidazopyridine, respectively. The cellular accumulation of palladium, palladium-DNA binding levels, and the nature of interactions of the compounds with salmon sperm and pBR322 plasmid DNA were also determined. All three compounds were found to be less active than cisplatin, but unlike cisplatin they were found to be equally or more active against the resistant cell lines A2780(cisR) and A2780(ZD0473R) than against the parent cell line A2780. Among the three palladium complexes, EH4 (which has the bulkiest carrier ligand) was found to be most active, in line with the highest cellular accumulation of palladium and highest level of palladium-DNA binding resulting from the compound. EH4 was also found to cause the greatest conformational change to pBR322 plasmid DNA. The results of this study illustrate structure-activity relationships; in particular, they support the idea that the decreased reactivity of trans-palladium complexes through the introduction of bulky ligands can make them more active against tumors.

  14. A comparison of hyperthermia cisplatin sensitization in human ovarian carcinoma and glioma cell lines sensitive and resistant to cisplatin treatment.

    PubMed

    Raaphorst, G P; Doja, S; Davis, L; Stewart, D; Ng, C E

    1996-01-01

    Two pairs of human tumor cell lines (glioma and ovarian carcinoma (OvCa) each having a parental cell line and cisplatin-resistant variant, were evaluated for (a) cisplatin response, (b) hyperthermia response, and (c) combined hyperthermia and cisplatin response. The two resistant lines had comparable resistant responses while for the parental lines, the OvCa was more sensitive than the glioma to cisplatin doses up to 14 microgram/ml. For the hyperthermia response, the OvCa parental line was more resistant than the variant line at low-temperature hyperthermia (41 degrees C or 42 degrees C) but became more sensitive at high temperature (45 degree C). For the glioma, the parental line was more sensitive to hyperthermia at all temperatures tested. Hyperthermia caused sensitization to cisplatin in all cell lines but was generally greater in the glioma cell lines. In the OvCa system, hyperthermia had a slightly greater sensitizing effect on the resistant cell lines, while in the glioma the opposite was true. The degree of sensitization increased with hyperthermia temperature. In summary, the results showed that there is no cross- resistance for hyperthermia and cisplatin, that the degree of thermal sensitization is not reduced in cisplatin- resistant cell lines, and that cisplatin thermal sensitization is cell-line and temperature dependent. Thus, hyperthermia can effectively improve tumor cell response to cisplatin and may be useful in overcoming resistance to cisplatin.

  15. Ovarian cancer.

    PubMed

    Matulonis, Ursula A; Sood, Anil K; Fallowfield, Lesley; Howitt, Brooke E; Sehouli, Jalid; Karlan, Beth Y

    2016-01-01

    Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. PMID:27558151

  16. The presence of centrioles and centrosomes in ovarian mature cystic teratoma cells suggests human parthenotes developed in vitro can differentiate into mature cells without a sperm centriole

    SciTech Connect

    Lee, Bo Yon; Shim, Sang Woo; Kim, Young Sun; Kim, Seung Bo

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer The sperm centriole is the progenitor of centrosomes in all somatic cells. Black-Right-Pointing-Pointer Centrioles and centrosomes exist in parthenogenetic ovarian teratoma cells. Black-Right-Pointing-Pointer Without a sperm centriole, parthenogenetic oocytes produce centrioles and centrosomes. Black-Right-Pointing-Pointer Parthenogenetic human oocytes can develop and differentiate into mature cells. -- Abstract: In most animals, somatic cell centrosomes are inherited from the centriole of the fertilizing spermatozoa. The oocyte centriole degenerates during oogenesis, and completely disappears in metaphase II. Therefore, the embryos generated by in vitro parthenogenesis are supposed to develop without any centrioles. Exceptional acentriolar and/or acentrosomal developments are possible in mice and in some experimental cells; however, in most animals, the full developmental potential of parthenogenetic cells in vitro and the fate of their centrioles/centrosomes are not clearly understood. To predict the future of in vitro human parthenogenesis, we explored the centrioles/centrosomes in ovarian mature cystic teratoma cells by immunofluorescent staining and transmission electron microscopy. We confirmed the presence of centrioles and centrosomes in these well-known parthenogenetic ovarian tumor cells. Our findings clearly demonstrate that, even without a sperm centriole, parthenotes that develop from activated oocytes can produce their own centrioles/centrosomes, and can even develop into the well-differentiated mature tissue.

  17. The presence of centrioles and centrosomes in ovarian mature cystic teratoma cells suggests human parthenotes developed in vitro can differentiate into mature cells without a sperm centriole.

    PubMed

    Lee, Bo Yon; Shim, Sang Woo; Kim, Young Sun; Kim, Seung Bo

    2011-11-18

    In most animals, somatic cell centrosomes are inherited from the centriole of the fertilizing spermatozoa. The oocyte centriole degenerates during oogenesis, and completely disappears in metaphase II. Therefore, the embryos generated by in vitro parthenogenesis are supposed to develop without any centrioles. Exceptional acentriolar and/or acentrosomal developments are possible in mice and in some experimental cells; however, in most animals, the full developmental potential of parthenogenetic cells in vitro and the fate of their centrioles/centrosomes are not clearly understood. To predict the future of in vitro human parthenogenesis, we explored the centrioles/centrosomes in ovarian mature cystic teratoma cells by immunofluorescent staining and transmission electron microscopy. We confirmed the presence of centrioles and centrosomes in these well-known parthenogenetic ovarian tumor cells. Our findings clearly demonstrate that, even without a sperm centriole, parthenotes that develop from activated oocytes can produce their own centrioles/centrosomes, and can even develop into the well-differentiated mature tissue.

  18. Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(−/−) FORKO mice

    PubMed Central

    Ghadami, M.; El-Demerdash, E.; Salama, S.A.; Binhazim, A.A.; Archibong, A.E.; Chen, X.; Ballard, B.R.; Sairam, M.R.; Al-Hendy, A.

    2010-01-01

    A homozygous missense mutation, C566T, in the follicle stimulation hormone receptor (FSHR) gene has been linked to premature ovarian failure. The disease leads to infertility in a normal karyotype female with an elevated follicle stimulating hormone (FSH) and decreased serum estrogen level. Female mice carrying mutated FSHR gene, called follitropin receptor knockout (FORKO), display similar phenotype and are sterile because of a folliculogenesis block at a primary stage. We investigated the effects of bilateral intra-ovarian injection of an adenovirus expressing a normal copy of human FSHR on the reproductive system of 6–10 weeks female FORKO mice. Ad-LacZ was injected directly into each ovary of the control group. Animals were sacrificed at 2, 4, 8 and 12 weeks post-injection and tissues collected for evaluation. Treated mice showed estrogenic changes in daily vaginal smear whereas control animals remained fixated in the diestrus stage. Histological evaluation showed on average 26 ± 4 follicles/ovary in treated group with 8 ± 2 follicles at the antral stage compared with only 5 ± 2 with zero follicles at antral stage in Ad-LacZ control mice. There was no significant change in serum level of progesterone, however, estrogen level increased 2–3-fold (P < 0.02) and FSH decreased by up to 50% (P < 0.04) in treated animals. FSHR mRNA was detected in the ovaries of the treated group. In conclusion, intra-ovarian injection of an adenovirus expressing human FSHR gene is able to restore FSH responsiveness and reinitiate ovarian folliculogenesis as well as resume estrogen production in female FORKO mice. Ad-LacZ injections indicate the absence of systemic viral dissemination or germ line transmission of adenovirus DNA to offspring. PMID:20086006

  19. Delivery of Constitutively Active Mutant MKK6(E) With TAT-OSBP Induces Apoptosis in Human Ovarian Carcinoma HO8910 Cells.

    PubMed

    Liao, Hua; Kang, Jia-li; Jiang, Wen-yan; Deng, Cui; Yuan, Jin; Shuai, Rong

    2015-11-01

    Biologically active peptides and proteins are novel agents that show promise in the development of anticancer drugs. Their relatively low cell permeability and poor tumor selectivity, however, impede their widespread applicability. In this study, we evaluated the tumor selectivity, cellular internalization, and biological activity of a cell-permeable ovarian cancer cell-specific therapeutic protein consisting of TAT-OSBP and constitutively active MKK6(E), an upstream kinase of the p38 signaling pathway that mediates cellular apoptosis. OSBP, a 7-amino-acid peptide with high affinity for human ovarian cancer HO8910 cells, was conjugated to the cell-penetrating peptide (TAT) to form a tumor-selective peptide (TAT-OSBP), which was further conjugated with EGFP or MKK6(E). Flow cytometry and fluorescent microscopy were performed to evaluate the tumor-targeted penetration of TAT-OSBP-EGFP. The inhibitory effects of TAT-OSBP-MKK6(E) were determined by cell proliferation and apoptosis assays. The internalization efficiency of TAT-OSBP-EGFP was significantly higher than that of TAT-EGFP. TAT-OSBP-EGFP selectively penetrated HO8910 cells. TAT-OSBP-MKK6(E) fusion protein inhibited cancer cell growth to varying degrees, with the highest level of inhibition in HO8910 cells. Moreover, TAT-OSBP-MKK6(E) significantly induced apoptosis of HO8910 cells. However, there was no significant difference in apoptosis in the normal ovarian epithelial cells treated with either TAT-OSBP-MKK6(E) or TAT-MKK6(E). Our results demonstrate that TAT-OSBP-MKK6(E) is a novel artificially designed molecule, which induces apoptosis and selectively targets human ovarian carcinoma HO8910 cells. Our study provides novel insights that may aid in the development of a new generation of anticancer drugs. PMID:26495757

  20. Purification of granulosa cells from human ovarian follicular fluid using granulosa cell aggregates.

    PubMed

    Quinn, M C J; McGregor, S B; Stanton, J L; Hessian, P A; Gillett, W R; Green, D P L

    2006-01-01

    Human follicular fluid can provide a source of human granulosa cells for scientific study. However, removing potentially contaminating cells, such as white and red blood cells, is important for molecular and in vitro studies. We have developed a purification technique for human granulosa cells based on the selection of cellular aggregates. Human granulosa cells from 21 IVF patients were collected. A 50% Percoll gradient was used to remove red blood cells, and granulosa cell aggregates were collected, washed and processed for histology, electron microscopy, flow cytometry analysis, cell culture and RNA extraction. Granulosa cell aggregates were found to be homogeneous and free of white blood cells after histological and electron microscopic analysis. White blood cell contamination, measured by flow cytometry, was found to be between 2 and 4%. Polymerase chain reaction analysis revealed expression of known human granulosa cell genes and a white blood cell marker. Human granulosa cells grown in vitro showed flattened fibroblast-like morphology with lipid droplets consistent with previous reports. Cultured cells expressed the FSH receptor. Selection of human granulosa cell aggregates following centrifugation through a Percoll gradient provides an efficient method of selecting granulosa cells, suitable for both molecular and in vitro studies.

  1. Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer.

    PubMed

    Kim, Sun-Jin; Kim, Jang Seong; Kim, Seung Wook; Brantley, Emily; Yun, Seok Joong; He, Junqin; Maya, Marva; Zhang, Fahao; Wu, Qiuyu; Lehembre, François; Regenass, Urs; Fidler, Isaiah J

    2011-02-01

    Potential treatments for ovarian cancers that have become resistant to standard chemotherapies include modulators of tumor cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice. Mice with established disease were treated with vehicle (control), paclitaxel (weekly, intraperitoneal injections), macitentan (daily oral administrations), or a combination of paclitaxel and macitentan. Treatment with paclitaxel decreased tumor weight and volume of ascites. Combination therapy with macitentan and paclitaxel reduced tumor incidence and further reduced tumor weight and volume of ascites when compared with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but alone had no effect on tumor incidence or ascites. Immunohistochemical analyses revealed that treatment with macitentan and macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of paclitaxel. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. Collectively, these results show that administration of macitentan in combination with paclitaxel prevents the progression of ovarian cancer in the peritoneal cavity of nude mice in part by inhibiting survival pathways of both tumor cells and tumor-associated endothelial cells.

  2. Ras-induced epigenetic inactivation of the RRAD (Ras-related associated with diabetes) gene promotes glucose uptake in a human ovarian cancer model.

    PubMed

    Wang, Yan; Li, Guiling; Mao, Fengbiao; Li, Xianfeng; Liu, Qi; Chen, Lin; Lv, Lu; Wang, Xin; Wu, Jinyu; Dai, Wei; Wang, Guan; Zhao, Enfeng; Tang, Kai-Fu; Sun, Zhong Sheng

    2014-05-16

    RRAD (Ras-related associated with diabetes) is a small Ras-related GTPase that is frequently inactivated by DNA methylation of the CpG island in its promoter region in cancer tissues. However, the role of the methylation-induced RRAD inactivation in tumorigenesis remains unclear. In this study, the Ras-regulated transcriptome and epigenome were profiled by comparing T29H (a Ras(V12)-transformed human ovarian epithelial cell line) with T29 (an immortalized but non-transformed cell line) through reduced representation bisulfite sequencing and digital gene expression. We found that Ras(V12)-mediated oncogenic transformation was accompanied by RRAD promoter hypermethylation and a concomitant loss of RRAD expression. In addition, we found that the RRAD promoter was hypermethylated, and its transcription was reduced in ovarian cancer versus normal ovarian tissues. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in demethylation in the RRAD promoter and restored RRAD expression in T29H cells. Additionally, treatment with farnesyltransferase inhibitor FTI277 resulted in restored RRAD expression and inhibited DNA methytransferase expression and activity in T29H cells. By employing knockdown and overexpression techniques in T29 and T29H, respectively, we found that RRAD inhibited glucose uptake and lactate production by repressing the expression of glucose transporters. Finally, RRAD overexpression in T29H cells inhibited tumor formation in nude mice, suggesting that RRAD is a tumor suppressor gene. Our results indicate that Ras(V12)-mediated oncogenic transformation induces RRAD epigenetic inactivation, which in turn promotes glucose uptake and may contribute to ovarian cancer tumorigenesis.

  3. Novel monofunctional platinum (II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells, distinct from cisplatin

    PubMed Central

    Guo, Wen-Jie; Zhang, Yang-Miao; Zhang, Li; Huang, Bin; Tao, Fei-Fei; Chen, Wei; Guo, Zi-Jian; Xu, Qiang; Sun, Yang

    2013-01-01

    Failure to engage apoptosis appears to be a leading mechanism of resistance to traditional platinum drugs in patients with ovarian cancer. Therefore, an alternative strategy to induce cell death is needed for the chemotherapy of this apoptosis-resistant cancer. Here we report that autophagic cell death, distinct from cisplatin-induced apoptosis, is triggered by a novel monofunctional platinum (II) complex named Mono-Pt in human ovarian carcinoma cells. Mono-Pt-induced cell death has the following features: cytoplasmic vacuolation, caspase-independent, no nuclear fragmentation or chromatin condensation, and no apoptotic bodies. These characteristics integrally indicated that Mono-Pt, rather than cisplatin, initiated a nonapoptotic cell death in Caov-3 ovarian carcinoma cells. Furthermore, incubation of the cells with Mono-Pt but not with cisplatin produced an increasing punctate distribution of microtubule-associated protein 1 light chain 3 (LC3), and an increasing ratio of LC3-II to LC3-I. Mono-Pt also caused the formation of autophagic vacuoles as revealed by monodansylcadaverine staining and transmission electron microscopy. In addition, Mono-Pt-induced cell death was significantly inhibited by the knockdown of either BECN1 or ATG7 gene expression, or by autophagy inhibitors 3-methyladenine, chloroquine and bafilomycin A1. Moreover, the effect of Mono-Pt involved the AKT1-MTOR-RPS6KB1 pathway and MAPK1 (ERK2)/MAPK3 (ERK1) signaling, since the MTOR inhibitor rapamycin increased, while the MAPK1/3 inhibitor U0126 decreased Mono-Pt-induced autophagic cell death. Taken together, our results suggest that Mono-Pt exerts anticancer effect via autophagic cell death in apoptosis-resistant ovarian cancer. These findings lead to increased options for anticancer platinum drugs to induce cell death in cancer. PMID:23580233

  4. Ras-induced epigenetic inactivation of the RRAD (Ras-related associated with diabetes) gene promotes glucose uptake in a human ovarian cancer model.

    PubMed

    Wang, Yan; Li, Guiling; Mao, Fengbiao; Li, Xianfeng; Liu, Qi; Chen, Lin; Lv, Lu; Wang, Xin; Wu, Jinyu; Dai, Wei; Wang, Guan; Zhao, Enfeng; Tang, Kai-Fu; Sun, Zhong Sheng

    2014-05-16

    RRAD (Ras-related associated with diabetes) is a small Ras-related GTPase that is frequently inactivated by DNA methylation of the CpG island in its promoter region in cancer tissues. However, the role of the methylation-induced RRAD inactivation in tumorigenesis remains unclear. In this study, the Ras-regulated transcriptome and epigenome were profiled by comparing T29H (a Ras(V12)-transformed human ovarian epithelial cell line) with T29 (an immortalized but non-transformed cell line) through reduced representation bisulfite sequencing and digital gene expression. We found that Ras(V12)-mediated oncogenic transformation was accompanied by RRAD promoter hypermethylation and a concomitant loss of RRAD expression. In addition, we found that the RRAD promoter was hypermethylated, and its transcription was reduced in ovarian cancer versus normal ovarian tissues. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in demethylation in the RRAD promoter and restored RRAD expression in T29H cells. Additionally, treatment with farnesyltransferase inhibitor FTI277 resulted in restored RRAD expression and inhibited DNA methytransferase expression and activity in T29H cells. By employing knockdown and overexpression techniques in T29 and T29H, respectively, we found that RRAD inhibited glucose uptake and lactate production by repressing the expression of glucose transporters. Finally, RRAD overexpression in T29H cells inhibited tumor formation in nude mice, suggesting that RRAD is a tumor suppressor gene. Our results indicate that Ras(V12)-mediated oncogenic transformation induces RRAD epigenetic inactivation, which in turn promotes glucose uptake and may contribute to ovarian cancer tumorigenesis. PMID:24648519

  5. Benign epithelial ovarian tumours-cancer precursors or markers for ovarian cancer risk?

    PubMed

    Jordan, Susan; Green, Adèle; Webb, Penelope

    2006-06-01

    The natural history of the development of epithelial ovarian cancer remains obscure and no effective screening test exists. In several human malignancies progression from benign to invasive tumour occurs, but this sequence has not been established for epithelial ovarian cancer. We have reviewed epidemiological, histopathological and molecular studies of benign epithelial ovarian tumours to assess the evidence for and against such a progression in ovarian cancer. These data suggest that a diagnosis of a benign ovarian cyst or tumour is associated with an increased risk of ovarian cancer later in life. Current evidence also suggests that benign serous tumours can progress to low-grade serous cancer and that benign mucinous tumours can progress to mucinous cancer. The more common high-grade serous ovarian cancers are likely to arise de novo.

  6. Induction of gamma-glutamyl transpeptidase mRNA by platinum complexes in a human ovarian carcinoma cell line.

    PubMed

    el-akawi, Z; Zdanowicz, J; Creaven, P J; Abu-hadid, M; Perez, R; Pendyala, L

    1996-01-01

    Elevation of glutathione (GSH) is widely observed in cellular resistance to platinum agents. Our previous studies have shown that sublines of human ovarian carcinoma cell line A2780, which exhibited low levels of resistance to oxaliplatin, showed elevated steady state levels of mRNA and activity of gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2), but not of gamma-glutamylcysteine synthetase (gamma-GCS, EC 6.3.2.2) [El-akawi et al., Cancer Lett. 105:5-14; 1966]. To understand this phenomenon better, we have studied the effect of single exposures of oxaliplatin or cisplatin on the mRNA expression of gamma-GT and gamma-GCS in A2780 cells. The mRNAs of gamma-GT and gamma-GCS were measured by reverse transcriptase PCR, with quantitation of the PCR product by HPLC; mRNA levels are expressed as ratios to beta-actin mRNA, used as an endogenous standard. GSH was measured by HPLC. The gamma-GT activity was measured by a colorimetric assay. Single exposures of cells to oxaliplatin induced a time- and concentration-dependent increase in the mRNA of gamma-GT, but not of gamma-GCS. Cisplatin also induced an elevation in gamma-GT mRNA, but to a lower degree. The gamma-GT enzyme activity increased corresponding to the elevation in mRNA expression. The gamma-GT-induced cells showed an increase in cellular GSH when incubated in medium containing GSH. The data suggest that a) single, brief exposures to pharmacologically relevant concentrations of platinum complexes induce elevation in mRNA of gamma-GT, b) elevation in gamma-GT mRNA translates into elevated gamma-GT activity and increase in GSH salvage, and c) the degree of induction of gamma-GT mRNA differs between platinum complexes.

  7. Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

    PubMed Central

    Chao, Yi-Ning; Sun, David; Peng, Yen-Chun; Wu, Yuh-Lin

    2016-01-01

    Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE2) and IL-8. GHRP-2 promoted the degradation of PDD-induced COX-2 and IL-8 proteins with the involvement of proteasomal and lysosomal pathways. PDD-mediated COX-2 production acts via the p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways; PDD-mediated IL-8 production acts via the p38, JNK and ERK pathways. GHRP-2 reduced the PDD-induced phosphorylation of p38 and JNK and activator protein 1 (AP-1) reporter activation and PDD-induced NF-κB nuclear translocation and reporter activation. The inhibitors of mitogen-activated protein kinase phosphatase-1 (MKP-1) and protein phosphatase 2 (PP2A) reduced the inhibitory effect of GHRP-2 on PDD-induced COX-2 and IL-8 expression. Our findings demonstrate an anti-inflammatory role for ghrelin (GHRP-2) in PKC-mediated inflammation of granulosa cells, at least in part, due to its inhibitory effect on PKC-induced activation of p38, JNK and NF-κB, possibly by targeting to MKP-1 and PP2A. PMID:27548147

  8. Isolation and characterization of an IGROV-1 human ovarian cancer cell line made resistant to Ecteinascidin-743 (ET-743)

    PubMed Central

    Erba, E; Bergamaschi, D; Bassano, L; Ronzoni, S; Liberti, G Di; Muradore, I; Vignati, S; Faircloth, G; Jimeno, J; D'Incalci, M

    2000-01-01

    By exposing Igrov-1 human ovarian cancer cells to increasing concentrations of Ecteinascidin-743 (ET-743), either for a short or prolonged time, we obtained sublines resistant to ET-743 which overexpress Pgp. The most resistant clone (Igrov-1/25 ET) was evaluated for biological and pharmacological characterizations. The increased Pgp levels of Igrov-1/25 ET were not due to amplification of the mdr-1 gene but to increased mRNA levels. No increase in other multidrug resistance-related proteins such as MRP or LRP was observed in Igrov-1/25 ET. The IC50values of ET-743 against Igrov-1/25 ET was approximately 50 times higher than the parental cell line. Resistance was not reversed while maintaining the cell line in drug-free medium for at least 24 months. Igrov-1/25 ET was cross-resistant to Doxorubicin and VP16 while it was equally sensitive to L-PAM, MNNG, CPT and only marginally less sensitive to Cis-DDP and Oxaliplatin compared to the parental cell line. Igrov-1/25 ET exposed to Doxorubicin retained this drug much less, mainly because of a more efficient drug efflux. The cyclosporine analogue SDZ PSC-833 reversed the resistance of Igrov-1/25 ET to ET-743, without any enhancement of the drug activity against the parental Igrov-1 cell line. Igrov-1/25 ET exhibits typical features of cell lines overexpressing the mdr-1 gene and can be a potentially useful tool in selecting ET-743 non-cross-resistant analogues as well as to investigate methods to counteract resistance to this drug. © 2000 Cancer Research Campaign PMID:10817511

  9. Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility

    SciTech Connect

    Lu, Renquan; Sun, Xinghui; Xiao, Ran; Zhou, Lei; Gao, Xiang; Guo, Lin

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer We generated stable transduced HE4 overexpression and knockdown cells. Black-Right-Pointing-Pointer HE4 was associated with EOC cell adhesion and motility. Black-Right-Pointing-Pointer HE4 might have some effects on activation of EGFR-MAPK signaling pathway. Black-Right-Pointing-Pointer HE4 play an important role in EOC tumorigenicity. -- Abstract: Human epididymis protein 4 (HE4) is a novel and specific biomarker for epithelial ovarian cancer (EOC). We previously demonstrated that serum HE4 levels were significantly elevated in the majority of EOC patients but not in subjects with benign disease or healthy controls. However, the precise mechanism of HE4 protein function is unknown. In this study, we generated HE4-overexpressing SKOV3 cells and found that stably transduced cells promoted cell adhesion and migration. Knockdown of HE4 expression was achieved by stable transfection of SKOV3 cells with a construct encoding a short hairpin DNA directed against the HE4 gene. Correspondingly, the proliferation and spreading ability of HE4-expressed cells were inhibited by HE4 suppression. Mechanistically, impaired EGFR and Erk1/2 phosphorylation were observed in cells with HE4 knockdown. The phosphorylation was restored when the knockdown cells were cultured in conditioned medium containing HE4. Moreover, in vivo tumorigenicity showed that HE4 suppression markedly inhibited the growth of tumors. This suggests that expression of HE4 is associated with cancer cell adhesion, migration and tumor growth, which can be related to its effects on the EGFR-MAPK signaling pathway. Our results provide evidence of the cellular and molecular mechanisms that may underlie the motility-promoting role of HE4 in EOC progression. The role of HE4 as a target for gene-based therapy might be considered in future studies.

  10. Silencing of the TGF-β1 Gene Increases the Immunogenicity of Cells from Human Ovarian Carcinoma

    PubMed Central

    Wei, Huafeng; Liu, Pu; Swisher, Elizabeth; Yip, Yuen Yee; Tse, Jee Hang; Agnew, Kathy; Hellström, Karl Erik; Hellström, Ingegerd

    2012-01-01

    Cells from many tumors produce transforming growth factor (TGF)-βwhich facilitates their escape from control by the immune system. We previously reported that non-immunogenic cells from either of two transplantable mouse tumors became effective as therapeutic tumor vaccines after lentivirus-mediated shRNA interference to ‘silence’the TGF-β1 gene. We now show that cells from in vitro cultured human ovarian carcinomas (OvC) make large amounts of TGF-β1 and that this can be prevented by ‘silencing’ the TGF-β1 gene. We further show that in vitro sensitization of peripheral blood mononuclear cells (PBMC) in the presence of either mitomycin-treated OvC cells whose TGF-β1 gene was silenced or in vitro matured dendritic cells (DC) which had been pulsed with homogenates from OvC cells with silenced TGF-β1 generated a stronger Th1/Tc1 immune response to the respective WT OvC and also to the OvC antigens mesothelin and HE4 as measured by ELIspot assays. The percentage of interferon (IFN)-γ and tumor necrosis factor (TNF)-α-producing CD4+ and CD8+ T cells increased while there were fewer cells expressing markers characteristic for regulatory T cells or myeloid derived suppressor cells. Similar results were obtained when PBMC from a patient with OvC were sensitized to DC pulsed with homogenate from autologous TGF-β1-silenced tumor cells, and a cytolytic lymphocyte response was generated to autologous OvC cells. Our results support clinical evaluation of TGF-β1-silenced tumor vaccines for immunotherapy of OvC. PMID:22421944

  11. Purification, characterization, and amino-terminal sequence of rat ovarian receptor for luteinizing hormone/human choriogonadotropin.

    PubMed

    Roche, P C; Ryan, R J

    1989-03-15

    The luteinizing hormone (LH)/human choriogonadotropin (hCG) receptor of rat ovary was solubilized with Lubrol PX in the presence of 20% glycerol and protease inhibitors, and purified by one-step affinity chromatography. Purified receptor had a specific hCG binding capacity of 4900 pmol/mg protein, and displayed a single class of high affinity binding sites (Ka = 6.20 X 10(9) M-1). An 11,200-fold purification over the starting crude homogenate was achieved. The purified LH/hCG receptor was identified by sodium dodecyl sulfate-gel electrophoresis and silver staining as a single protein of 92 kDa. The ability of the purified 92-kDa protein to specifically bind hormone was demonstrated by electroblotting onto Immobilon P membrane, incubation with 125I-labeled hCG, and autoradiography of the blot. In addition to a 92-kDa band, ligand blotting also yielded a 170-kDa band representing receptor dimer. Covalent cross-linking of hCG, with isotope in either the alpha- or beta-subunit, to membrane-bound receptor produced complexes that contained a single receptor component of approximately 92 kDa. The cross-linking studies indicated that both subunits interact with receptor and also suggested receptor dimer formation. Following sodium dodecyl sulfate-electrophoresis, purified receptor was electroblotted onto polyethylenimine-treated glass fiber filters for direct microsequencing in a gas-phase sequenator. Eleven cycles of sequence analysis yielded the unique sequence: NH2-Arg-Glu-Leu-Ser-Gly-Ser-Leu-XXX-Pro-Glu-Pro-COOH. These results indicate that the rat ovarian LH/hCG receptor is a protein of 92 kDa which can be easily purified in microgram amounts. This study also describes a relatively simple technique for electroblotting and microsequencing that should be applicable to other membrane-bound hormone receptors. PMID:2925659

  12. Drug resistance features and S-phase fraction as possible determinants for drug response in a panel of human ovarian cancer xenografts

    PubMed Central

    Kolfschoten, G M; Hulscher, T M; Pinedo, H M; Boven, E

    2000-01-01

    Multidrug resistance (MDR) and more specifically the expression of P-glycoprotein (Pgp) have been studied extensively in vitro. Unfortunately, it appears that the predictive value of MDR recognized in vitro is mostly an incorrect measure to determine the responsiveness of a particular tumour in the clinic. This misunderstood or overvalued role of MDR might explain the failure of strategies to reverse Pgp function by the use of modulators in solid tumours. To obtain more insight in in vivo drug resistance we investigated a panel of 15 human ovarian cancer xenografts consisting of the most common histological subtypes known in ovarian cancer patients. The response rate to cisplatin, cyclophosphamide and doxorubicin in the xenografts resembled the results of phase II trials with these agents in ovarian cancer patients. This resemblance justifies drug resistance studies in this experimental in vivo human tumour system. We determined the expression levels of MDR 1, MRP 1, LRP and topoisomerase IIα mRNA by the RNase protection assay and the presence of MRP1 and LRP proteins by immunohistochemistry. The S-phase fraction was investigated as a separate parameter by flow cytometry. In none of the 15 ovarian cancer xenografts was MDR 1 expression detectable. The expression levels of MRP 1 and LRP were low to moderate and resembled the presence of the MRP1 and LRP proteins. There was a weak, inverse relationship between the expression levels of LRP and sensitivity to cisplatin and cyclophosphamide (r = –0.44 and –0.45), but not to doxorubicin. The levels of topoisomerase IIα varied among the xenografts (0.73–2.66) and failed to correlate with doxorubicin resistance (r = 0.14). The S-phase fraction, however, showed a relation with the sensitivity to cisplatin (r = 0.66). Among the determinants studied in ovarian cancer in vivo, LRP mRNA and the S-phase fraction were the best predictive factors for drug response and most specifically for the activity of cisplatin.

  13. Oridonin effectively reverses cisplatin drug resistance in human ovarian cancer cells via induction of cell apoptosis and inhibition of matrix metalloproteinase expression.

    PubMed

    Ma, Shihong; Tan, Wenhua; Du, Botao; Liu, Wei; Li, Weijia; Che, Dehong; Zhang, Guangmei

    2016-04-01

    Cisplatin is a first generation platinum‑based chemotherapeutic agent, however, the extensive application of cisplatin inevitably results in drug resistance, which is a major obstacle in cancer chemotherapy. The aim of the present study was to investigate the efficiency of reversing cisplatin‑resistance with the use of combination therapy with oridonin and cisplatin in human ovarian cancer cells, and attempt to reduce the side effects of the therapeutic agents when used alone. The half maximal inhibitory concentration (IC50) values of cisplatin were determined in cisplatin‑sensitive and cisplatin‑resistant ovarian cancer cells using an MTT assay. IC50 values of cisplatin in A2780, A2780/DDP, SKOV3 and SKOV3/DDP cells were significantly decreased in a time‑dependent manner. The antitumor effect of oridonin in A2780/DDP cells was also detected by the MTT assay and the inhibitory effects of oridonin increased in a dose‑ and time‑dependent manner. A2780/DDP cells were treated with 20 µM oridonin in combination with increasing concentrations of cisplatin for 48 h, and the result demonstrated that oridonin synergistically increased the antitumor effects of cisplatin in A2780/DDP cells. Notably, the combination treatment of oridonin and cisplatin effectively reversed cisplatin resistance and the IC50 values were significantly decreased from 50.97 µM and 135.20 to 26.12 µM and 73.00 µM in A2780/DDP and SKOV3/DDP cells at 48 h, respectively. Furthermore, oridonin induced cell apoptosis in a dose‑dependent manner and promoted cell‑cycle arrest at the G0/G1 phase in ovarian cancer cells. Oridonin and cisplatin synergistically increased the cell apoptosis rate of A2780/DDP cells, which was detected by fluorescence‑activated cell sorting analysis. Downregulated expression levels of Bcl‑2 and upregulated the expression of Bax protein were demonstrated by western blot analysis, further indicating increased apoptosis. In addition, the expression levels of

  14. Oncolytic reovirus against ovarian and colon cancer.

    PubMed

    Hirasawa, Kensuke; Nishikawa, Sandra G; Norman, Kara L; Alain, Tommy; Kossakowska, Anna; Lee, Patrick W K

    2002-03-15

    Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy. PMID:11912142

  15. What Is Ovarian Cancer?

    MedlinePlus

    ... the key statistics about ovarian cancer? What is ovarian cancer? Cancer starts when cells in the body begin ... section . Other cancers that are similar to epithelial ovarian cancer Primary peritoneal carcinoma Primary peritoneal carcinoma (PPC) is ...

  16. Monoclonal antibodies reactive with human breast or ovarian carcinoma: In vivo applications

    SciTech Connect

    Thor, A.D.; Edgerton, S.M. )

    1989-10-01

    Monoclonal antibodies (MoAbs) are unique and useful bioprobes that allow in vivo targeting of membrane-associated or circulating antigens. Most of the clinical trials to date have used low dosages of radiolabeled MoAb given in a single dose. Newer studies have included antibody fragments, repeated injections, intraperitoneal (IP) administration, and other labels such as 90Y. Clinical MoAb trials are often arduous, expensive, and time-consuming to perform. Before human use, animal studies and extensive MoAb characterization are required. The production of pharmaceutical grade, radiolabeled MoAb is technically difficult and costly. Clinical trials require administrative and patient consent as well as extensive written protocols. These studies necessitate interdepartmental and intradepartmental cooperation and coordination. Furthermore, the use of in vivo radiolabeled probes impacts many levels of health care providers from janitorial, nursing, and technical staff to laboratories and physicians. Simple blood tests or disposal of body excretions may concern nursing or technical staff with the possibility of radiation exposure. The responsibility for study design, personnel involvement, and prospective use in patients without a definitive cancer diagnosis ultimately rests with the physician. While many issues have been addressed, additional clinical trials, consideration of safety issues, and standardization between institutions will be necessary before the use of radiolabeled MoAb for diagnosis, management, or therapy of human tumors becomes routine. Continued cooperation and funding should ensure its achievement. 136 references.

  17. Comparative gene expression profiling in human cumulus cells according to ovarian gonadotropin treatments.

    PubMed

    Assou, Said; Haouzi, Delphine; Dechaud, Hervé; Gala, Anna; Ferrières, Alice; Hamamah, Samir

    2013-01-01

    In in vitro fertilization cycles, both HP-hMG and rFSH gonadotropin treatments are widely used to control human follicle development. The objectives of this study are (i) to characterize and compare gene expression profiles in cumulus cells (CCs) of periovulatory follicles obtained from patients stimulated with HP-hMG or rFSH in a GnRH antagonist cycle and (ii) to examine their relationship with in vitro embryo development, using Human Genome U133 Plus 2.0 microarrays. Genes that were upregulated in HP-hMG-treated CCs are involved in lipid metabolism (GM2A) and cell-to-cell interactions (GJA5). Conversely, genes upregulated in rFSH-treated CCs are implicated in cell assembly and organization (COL1A1 and COL3A1). Interestingly, some genes specific to each gonadotropin treatment (NPY1R and GM2A for HP-hMG; GREM1 and OSBPL6 for rFSH) were associated with day 3 embryo quality and blastocyst grade at day 5, while others (STC2 and PTX3) were related to in vitro embryo quality in both gonadotropin treatments. These genes may prove valuable as biomarkers of in vitro embryo quality. PMID:24151596

  18. Cytotoxic effect of Alpinia scabra (Blume) Náves extracts on human breast and ovarian cancer cells

    PubMed Central

    2013-01-01

    Background Alpinia scabra, locally known as 'Lengkuas raya’, is an aromatic, perennial and rhizomatous herb from the family Zingiberaceae. It is a wild species which grows largely on mountains at moderate elevations in Peninsular Malaysia, but it can also survive in the lowlands like in the states of Terengganu and Northern Johor. The present study reports the cytotoxic potential of A. scabra extracts from different parts of the plant. Methods The experimental approach in the present study was based on a bioassay-guided fractionation. The crude methanol and fractionated extracts (hexane, chloroform and water) from different parts of A. scabra (leaves, rhizomes, roots and pseudo stems) were prepared prior to the cytotoxicity evaluation against human ovarian (SKOV-3) and hormone-dependent breast (MCF7) carcinoma cells. The identified cytotoxic extracts were then subjected to chemical investigations in order to identify the active ingredients. A normal human lung fibroblast cell line (MRC-5) was used to determine the specificity for cancerous cells. The cytotoxic extracts and fractions were also subjected to morphological assessment, DNA fragmentation analysis and DAPI nuclear staining. Results The leaf (hexane and chloroform) and rhizome (chloroform) extracts showed high inhibitory effect against the tested cells. Ten fractions (LC1-LC10) were yielded after purification of the leaf chloroform extract. Fraction LC4 which showed excellent cytotoxic activity was further purified and resulted in 17 sub-fractions (VLC1-VLC17). Sub-fraction VLC9 showed excellent cytotoxicity against MCF7 and SKOV-3 cells but not toxic against normal MRC-5 cells. Meanwhile, eighteen fractions (RC1-RC18) were obtained after purification of the rhizome chloroform extract, of which fraction RC5 showed cytotoxicity against SKOV-3 cells with high selectivity index. There were marked morphological changes when observed using phase-contrast inverted microscope, DAPI nuclear staining and also DNA

  19. Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer.

    PubMed

    Masoumi-Moghaddam, Samar; Amini, Afshin; Wei, Ai-Qun; Robertson, Gregory; Morris, David L

    2015-08-01

    Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase signaling, deregulation of which has been implicated in the pathophysiology of cancer. In the present study, the expression status of Spry2 and Spry4 proteins and its clinical relevance in human epithelial ovarian cancer (EOC) were investigated retrospectively. We examined the immunohistochemical expression of Spry2 and Spry4 in matched tumor and normal tissue samples from 99 patients. The expression of ERK, p-ERK, Ki67, fibroblast growth factor-2, vascular endothelial growth factor and interleukin-6 and their correlation with Sprouty homologs were also evaluated. Moreover, the correlation between Spry2 and Spry4 and the clinicopathological characteristics were analyzed along with their predictive value for overall survival (OS) and disease-free survival (DFS). Our data indicated significant downregulation of Spry2 and Spry4 in tumor tissues (p < 0.0001). A significant inverse correlation was evident between Spry2 and p-ERK/ERK (p = 0.048), Ki67 (p = 0.011), disease stage (p = 0.013), tumor grade (p = 0.003), recurrence (p < 0.001) and post-treatment ascites (p = 0.001), individually. It was found that Spry2 low-expressing patients had significantly poorer OS (p = 0.002) and DFS (p = 0.004) than those with high expression of Spry2. Multivariate analysis showed that high Spry2 (p = 0.018), low stage (p = 0.049) and no residual tumor (p =0.006) were independent prognostic factors for a better OS. With regard to DFS, high Spry2 (p = 0.044) and low stage (p = 0.046) remained as independent predictors. In conclusion, we report for the first time significant downregulation of Spry2 and Spry4 proteins in human EOC. Spry2 expression was revealed to significantly impact tumor behavior with predictive value as an independent prognostic factor for survival and recurrence.

  20. Application of interferon modulators to overcome partial resistance of human ovarian cancers to VSV-GP oncolytic viral therapy

    PubMed Central

    Dold, Catherine; Rodriguez Urbiola, Carles; Wollmann, Guido; Egerer, Lisa; Muik, Alexander; Bellmann, Lydia; Fiegl, Heidelinde; Marth, Christian; Kimpel, Janine; von Laer, Dorothee

    2016-01-01

    Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed that in vitro this antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report the in vivo enhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response. PMID:27738655

  1. Photodynamic action of LED-activated pyropheophorbide-α methyl ester in cisplatin-resistant human ovarian carcinoma cells

    NASA Astrophysics Data System (ADS)

    Tan, Y.; Xu, C. S.; Xia, X. S.; Yu, H. P.; Bai, D. Q.; He, Y.; Leung, A. W. N.

    2009-04-01

    Cisplatin-resistance is a major obstacle for the successful therapy to ovarian cancer, and exploring novel approach to deactivate cisplatin-resistant ovarian cells will improve the clinical outcomes. Our present study showed that there was no dark cytotoxicity of MPPa in the COC1/DDP cells at the dose of 0.25 - 4 μM, and LED-activated MPPa resulted in drug dose- and light-dependent cytotoxicity. Apoptotic rate 6 h after LED-activated MPPa (2 μM) increased to 16.71% under the light energy of 1 J/cm2. Confocal laser scanning microscopy showed that MPPa mainly localized in the intracellular membrane system, namely the endoplasmic reticulum, Golgi apparatus, lysosomes and mitochondria in the COC1/DDP cells. Mitochondrial membrane potential (ΔΨm) was collapsed when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm2 irradiation of LED source. These data demonstrated that LED-activated MPPa significantly deactivated cisplatin-resistant ovarian cell line COC1/DDP cells and enhanced apoptosis and decreased ΔΨm, which suggests LED is an efficient light source for PDT and LED-activated MPPa can be developed as new modality for treating cisplatin-resistant ovarian.

  2. Ovarian Kaleidoscope database: ten years and beyond.

    PubMed

    Hsueh, Aaron J; Rauch, Rami

    2012-06-01

    Ovarian Kaleidoscope database (OKdb) is an online, searchable, public database containing text-based and DNA microarray data to facilitate research by ovarian researchers. Using key words and predetermined categories, users can search ovarian gene information based on gene function, cell type of expression, cellular localization, hormonal regulation, mutant phenotypes, chromosomal location, ligand-receptor relationship, and other criteria, either alone or in combination. For individual genes, users can access more than 10 extensive DNA microarray datasets to interrogate gene expression patterns in a development-specific and cell type-specific manner. All ligand and receptor genes expressed in the ovary are matched to facilitate investigation of paracrine/autocrine signaling. More than 3500 ovarian genes in the database are matched to 185 gene pathways in the Kyoto Encyclopedia of Genes and Genomes to allow for elucidation of gene interactions and relationships. In addition to >400 genes with infertility or subfertility phenotypes when mutated in mice or humans, the OKdb also lists ~50 and ~40 genes associated with polycystic ovarian syndrome and primary ovarian insufficiency, respectively. The expanding OKdb is updated weekly and allows submission of new genes by ovarian researchers to allow instant access to DNA microarray datasets for newly submitted genes. The present database is a virtual community for ovarian researchers and allows users to instantaneously provide their comments for individual gene pages based on an automated Web-discussion system. In the coming years, we will continue to add new features to serve the ovarian research community. PMID:22441797

  3. Human chorionic gonadotrophin in early gestation induces growth of estrogenic ovarian follicles and improves primiparous sow fertility during summer.

    PubMed

    Seyfang, Jemma; Langendijk, P; Chen, T Y; Bouwman, E; Kirkwood, R N

    2016-09-01

    Reduced summer farrowing rates may be due to inadequate corpora luteal (CL) support. Porcine CL become dependent on LH from 12 d of pregnancy and the embryonic estrogen signal for maternal recognition of pregnancy (MRP) is initiated at about 11-12 d after insemination. We hypothesised that injection of the LH analogue human chorionic gonadotropin (hCG) would induce growth of estrogenic follicles and, by mimicking the signal for MRP and stimulating progesterone secretion, increase primiparous sow fertility. In Experiment 1, during a 28 d lactation 53 mixed parity sows were full-fed either throughout lactation (n=16) or until 18 d and then feed restricted during the last 10 d of lactation (n=36). At 12 d after mating restrict-fed sows were injected with 1000IU hCG (n=17) or were not injected (n=19); the full-fed sows acted as non-treated positive controls. Transrectal ovarian ultrasound exams were performed on days 12, 16, 20, 24, and 28; blood samples were obtained on days 12, 14, and 15 for estradiol and progesterone assay. For Experiment 2, during the summer months primiparous sows received 1000IU hCG 12 d after mating (n=28) or were non-injected controls (n=27). Pregnancy status was determined at 28 d and sows allowed to go to term to determine farrowing rates and litter sizes. In Experiment 1, injection of hCG increased (P<0.001) follicle diameter and serum concentrations of estradiol (P<0.01) and progesterone (P<0.05). There were no effects of lactation feeding level on wean-estrus interval, farrowing rate or subsequent litter size. In Experiment 2, hCG injection was associated with a higher pregnancy rate (P<0.05) and farrowing rate (P<0.08). There was no effect on litter size. These data confirm that hCG stimulates growth of estrogenic follicles and CL function, and improves primiparous sow fertility during the summer months. PMID:27397793

  4. Human chorionic gonadotrophin in early gestation induces growth of estrogenic ovarian follicles and improves primiparous sow fertility during summer.

    PubMed

    Seyfang, Jemma; Langendijk, P; Chen, T Y; Bouwman, E; Kirkwood, R N

    2016-09-01

    Reduced summer farrowing rates may be due to inadequate corpora luteal (CL) support. Porcine CL become dependent on LH from 12 d of pregnancy and the embryonic estrogen signal for maternal recognition of pregnancy (MRP) is initiated at about 11-12 d after insemination. We hypothesised that injection of the LH analogue human chorionic gonadotropin (hCG) would induce growth of estrogenic follicles and, by mimicking the signal for MRP and stimulating progesterone secretion, increase primiparous sow fertility. In Experiment 1, during a 28 d lactation 53 mixed parity sows were full-fed either throughout lactation (n=16) or until 18 d and then feed restricted during the last 10 d of lactation (n=36). At 12 d after mating restrict-fed sows were injected with 1000IU hCG (n=17) or were not injected (n=19); the full-fed sows acted as non-treated positive controls. Transrectal ovarian ultrasound exams were performed on days 12, 16, 20, 24, and 28; blood samples were obtained on days 12, 14, and 15 for estradiol and progesterone assay. For Experiment 2, during the summer months primiparous sows received 1000IU hCG 12 d after mating (n=28) or were non-injected controls (n=27). Pregnancy status was determined at 28 d and sows allowed to go to term to determine farrowing rates and litter sizes. In Experiment 1, injection of hCG increased (P<0.001) follicle diameter and serum concentrations of estradiol (P<0.01) and progesterone (P<0.05). There were no effects of lactation feeding level on wean-estrus interval, farrowing rate or subsequent litter size. In Experiment 2, hCG injection was associated with a higher pregnancy rate (P<0.05) and farrowing rate (P<0.08). There was no effect on litter size. These data confirm that hCG stimulates growth of estrogenic follicles and CL function, and improves primiparous sow fertility during the summer months.

  5. Decreased LRIG1 in Human Ovarian Cancer Cell SKOV3 Upregulates MRP-1 and Contributes to the Chemoresistance of VP16.

    PubMed

    Yang, Hua; Yao, Jun; Yin, Jiangpin; Wei, Xuan

    2016-05-01

    The leucine-rich repeats and immunoglobulin-like domains (LRIG) are used as tumor suppressors in clinical applications. Although the LRIG has been identified to manipulate the cell proliferation via various oncogenic receptor tyrosine kinases in diverse cancers, its role in multidrug resistance needs to be further elucidated, especially in human ovarian cancer. We herein established that the etoposide (VP16)-resistant SKOV3 human ovarian cancer cell clones (SKOV3/VP16 cells) and mRNA expression of LRIG1 were significantly reduced by the treatment of VP16 in a concentration-dependent manner. Moreover, downregulated LRIG1 in SKOV3 could enhance the colony formation and resist the inhibition of proliferation by VP16, leading to the elevated expression of Bcl-2 and decreased apoptosis of SKOV3. Interestingly, our results uncovered that the multidrug resistance-associated protein 1 (MRP-1) was upregulated for the chemoresistance of VP16. To overcome the chemoresistance of SKOV3, SKOV3/VP16 was ectopically expressed of LRIG1. We found that the inhibition of VP16 on colony formation and proliferation was remarkably enhanced with increased apoptosis in SKOV3/VP16. Furthermore, the expression of MRP-1 and Bcl-2 was also inhibited, suggesting that the LRIG1could negatively control MRP-1 and the apoptosis to improve the sensitivity of VP16-related chemotherapy. PMID:27183435

  6. The anti-tumour effects of the prodrugs N-l-leucyl-doxorubicin and vinblastine-isoleucinate in human ovarian cancer xenografts.

    PubMed Central

    Boven, E.; Hendriks, H. R.; Erkelens, C. A.; Pinedo, H. M.

    1992-01-01

    N-l-leucyl-doxorubicin and vinblastine-isoleucinate can be considered as relatively non-toxic prodrugs from doxorubicin and vinblastine, respectively. A comparative analysis was carried out of the anti-tumour activity of the four compounds as well as vintriptol in four human ovarian cancer xenografts different in histology, growth rate and chemosensitivity. Injections were given i.v. weekly twice into mice bearing well-established s.c. tumours. At equitoxic doses, the amount of drug administered for N-l-leucyl-doxorubicin and vinblastine-isoleucinate was respectively 3-fold and 2-fold higher than the doses of the parent compound. N-l-leucyl-doxorubicin induced a growth inhibition > 50% in three out of four human ovarian cancer lines. The anti-tumour effects obtained were significantly better (P < 0.01) than in the case of doxorubicin. Vinblastine-isoleucinate studied in two of these lines could induce a growth inhibition of > 50%. This prodrug appeared slightly less effective than vinblastine. Insignificant growth inhibition (< 50%) was obtained by vintriptol. PMID:1457343

  7. Correlation of circular RNA abundance with proliferation – exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues

    PubMed Central

    Bachmayr-Heyda, Anna; Reiner, Agnes T.; Auer, Katharina; Sukhbaatar, Nyamdelger; Aust, Stefanie; Bachleitner-Hofmann, Thomas; Mesteri, Ildiko; Grunt, Thomas W.; Zeillinger, Robert; Pils, Dietmar

    2015-01-01

    Circular RNAs are a recently (re-)discovered abundant RNA species with presumed function as miRNA sponges, thus part of the competing endogenous RNA network. We analysed the expression of circular and linear RNAs and proliferation in matched normal colon mucosa and tumour tissues. We predicted >1,800 circular RNAs and proved the existence of five randomly chosen examples using RT-qPCR. Interestingly, the ratio of circular to linear RNA isoforms was always lower in tumour compared to normal colon samples and even lower in colorectal cancer cell lines. Furthermore, this ratio correlated negatively with the proliferation index. The correlation of global circular RNA abundance (the circRNA index) and proliferation was validated in a non-cancerous proliferative disease, idiopathic pulmonary fibrosis, ovarian cancer cells compared to cultured normal ovarian epithelial cells, and 13 normal human tissues. We are the first to report a global reduction of circular RNA abundance in colorectal cancer cell lines and cancer compared to normal tissues and discovered a negative correlation of global circular RNA abundance and proliferation. This negative correlation seems to be a general principle in human tissues as validated with three different settings. Finally, we present a simple model how circular RNAs could accumulate in non-proliferating cells. PMID:25624062

  8. Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: an ex vivo experiment in human serous ovarian carcinoma.

    PubMed

    Lheureux, Stéphanie; N'Diaye, Monique; Blanc-Fournier, Cécile; Dugué, Audrey Emmanuelle; Clarisse, Bénédicte; Dutoit, Soizic; Giffard, Florence; Abeilard, Edwige; Briand, Mélanie; Labiche, Alexandre; Grellard, Jean-Michel; Crouet, Hubert; Martin, Sandrine; Joly, Florence; Poulain, Laurent

    2015-03-01

    Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737).

  9. [Ovarian tumor markers of presumed benign ovarian tumors].

    PubMed

    Lahlou, N; Brun, J-L

    2013-12-01

    Cancer Antigen 125 (CA125) and Human Epididymis Protein 4 (HE4) are the most studied ovarian tumor markers. Their diagnostic performance for identification of ovarian cancer are superior to CA19-9, CA72-4, and carcinoembryonic antigen, which are no more recommended for the diagnosis of presumed benign ovarian tumor. HE4 (>140 pmol/L) is superior to CA125 (>30 U/mL) in terms of specificity and positive likelihood ratio. CA125 and HE4 can be combined into an algorithm ROMA, or associated to clinical information (composite index), biological data (OVA1) or imaging (Risk for Malignancy Index (RMI), LR2). ROMA algorithm is an exponential equation combining plasmatic concentrations of HE4 and CA125. ROMA is more sensitive and less specific than HE4 in predicting epithelial ovarian cancer. ROMA is more accurate in post-menopausal women. The performance of ROMA is lower than the ultrasound model LR2 in differentiating malignant from benign ovarian tumors, whatever the hormonal status. The composite index combining CA125 with a symptoms index (pain, abdominal distension, bloating, difficulty eating) has a good sensitivity in a screening program, but because of a 12% false positive rate, ultrasound is required before management. The RMI algorithm is based on serum CA125, ultrasound findings (septation, solid zones, metastases, ascite, bilaterality) and menopausal status. RMI is less sensitive, but more specific than ROMA or OVA1 for the classification of ovarian masses. The addition of HE4 to RMI seems to be the most accurate. The subjective evaluation of ovarian cysts by sonography and color Doppler is better than ROMA and RMI algorithms, and not affected by the hormonal status.

  10. Upregulation of p27Kip1 by demethylation sensitizes cisplatin-resistant human ovarian cancer SKOV3 cells.

    PubMed

    Zhao, Yan; Li, Qiaoyan; Wu, Xiaoying; Chen, Puxiang

    2016-08-01

    Ovarian cancer has a poor prognosis due to its chemoresistance, and p27Kip1 (p27) has been implicated in tumor prognosis and drug-resistance. However, the regulatory mechanisms of p27 in drug‑resistance in ovarian cancer remain unknown. The current study successfully established chemoresistant cell lines using paclitaxel (TAX), cisplatin (DDP) and carboplatin (CBP) in SKOV3 ovarian cancer cells. The results indicated that the expression levels of p27 were dramatically downregulated in chemoresistant cells. However, 5-aza-2'-deoxycytidine (5-aza) treatment restored p27 expression in DDP-resistant cells, and increased their sensitivity to DDP. In addition, it was observed that the methylation of DDP‑resistant cells, which was downregulated by 5‑aza treatment, was significantly higher compared with SKOV3 cells. Additionally, the overexpression of p27 arrested the cell cycle in S phase and promoted an apoptotic response to DDP. In conclusion, p27 was involved in chemoresistance of SKOV3 cells. Upregulated p27 expression induced by demethylation may enhance sensitivity to DDP through the regulation of the cell cycle. PMID:27314502

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

    PubMed Central

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

    2008-01-01

    Background 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. Methods 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. Results Cells treated with NCX-4040 (25 μM) 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. Conclusion 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. PMID:18302761

  12. Effect of Procyanidin-rich Extract from Natural Cocoa Powder on Cellular Viability, Cell Cycle Progression, and Chemoresistance in Human Epithelial Ovarian Carcinoma Cell Lines

    PubMed Central

    Taparia, Shruti; Khanna, Aparna

    2016-01-01

    Background: Over the last 400 years, cocoa and chocolate have been described as having potential medicinal value, being consumed as a beverage or eaten as food. Concentration–dependant, antiproliferation, and cytotoxic effects of some of their polyphenolic constituents have been demonstrated against various cancers. Such an effect remains to be demonstrated in ovarian cancer Objective: To investigate the effect of cocoa procyanidins against ovarian cancer in vitro using OAW42 and OVCAR3 cell lines. Materials and Methods: Cocoa procyanidins were extracted and enriched from non alkalized cocoa powder. The polyphenolic content and antioxidant activity were determined. Effect on cell viability was determined after the treatment with ≤1000 μg/mL cocoa procyanidin-rich extract on OAW42 and OVCAR3 and normal human dermal fibroblasts. Similarly, chemosensitization effect was determined by pretreating cancer cell lines with extract followed by doxorubicin hydrochloride treatment. The effect of treatment on cell cycle and P-glycoprotein (P-gp) expression was determined using flow cytometry. Results: The cocoa extract showed high polyphenolic content and antioxidant activity. Treatment with extract caused cytotoxicity and chemosensitization in OAW42 and OVCAR3 cell lines. Normal dermal fibroblasts showed an increase in cell viability post treatment with extract. Treatment with extract affected the cell cycle and an increasing percentage of cells in hypodiploid sub-G1/G0 phase was observed. Treatment of OVCAR3 with the extract caused reduction of P-gp expression. Conclusion: Cocoa procyanidins were found to be selectively cytotoxic against epithelial ovarian cancer, interfered with the normal cell cycle and sensitized cells to subsequent chemotherapeutic treatment. Chemosensitization was found to be associated with P-gp reduction in OVCAR3 cells. SUMMARY Among the naturally occurring flavonoids, procyanidins have been shown to be effective against cancersNon alkalized

  13. Comparison of the therapeutic efficacy of 211At- and 131I-labelled monoclonal antibody MOv18 in nude mice with intraperitoneal growth of human ovarian cancer.

    PubMed

    Andersson, H; Palm, S; Lindegren, S; Bäck, T; Jacobsson, L; Leser, G; Horvath, G

    2001-01-01

    The purpose of the present study was to compare the therapeutic efficacy of the alpha-emitter Astatine-211 with the beta-emitter Iodine-131 bound to the specific monoclonal antibody MOv18. The measurements were performed in an ovarian cancer cell line (NIH:OVCAR 3) growing intraperitoneally in nude mice. Two weeks after the intraperitoneal inoculation of 1 x 10(7) cells of the human ovarian cancer cell line NIH:OVCAR-3 twenty mice were treated intraperitoneally with the specific monoclonal antibody MOv-18 labelled with either 211At (310-400 kBq) or 131I (5100-6200 kBq). The pharmacokinetics and biodistribution of labelled antibody in tumour-free animals were studied and the resulting bone marrow dose was estimated. When the mice were treated with 211At-labelled antibody 9 out of 10 mice were free of macro- and microscopic tumour compared to 3 out of 10 when Iodine-131 was used. The equivalent dose to the bone marrow was 2.4-3.1 Sv from 211At- and 3.4-4.1 Sv from 131I-irradiation. The therapeutic efficacy of 211At-labelled specific antibody is very good and, at approximately equivalent bone marrow doses, better than that of 131I. PMID:11299770

  14. Microscopic Aspects of Autoschizic Cell Death in Human Ovarian Carcinoma (2774) Cells Following Vitamin C, Vitamin K3 or Vitamin C:K3 Treatment

    NASA Astrophysics Data System (ADS)

    Gilloteaux, Jacques; Jamison, James M.; Arnold, David; Taper, Henryk S.; von Gruenigen, Vivian E.; Summers, Jack L.

    2003-08-01

    Human ovarian carcinoma cells (MDAH 2774) were treated with sodium ascorbate (VC), menadione (VK3), or with a VC:VK3 combination for 1 h and then studied using light microscopy (LM) and scanning (SEM) and transmission electron (TEM) microscopy. Plasma membrane damage (blisters and blebs, hairy aspect) results from vitamin C (VC) treatment, while cytoskeletal damage and self-morsellation are caused by vitamin K3 (VK3) treatment. VC:VK3-treated cells exhibit exacerbated injuries characteristic of both VC and VK3 treatment as well as a significant decrease in cell diameters from 20 35 [mu]m for control cells to 7 12 [mu]m for VC:VK3 treatment. Moreover, after a 1-h exposure to the vitamin combination, autoschizis (43%), apoptosis (3%), and oncosis (1.9%) are observed at the percentages indicated. All cellular changes associated with autoschizis observed with SEM were confirmed by LM and TEM observations and are consistent with cell death by autoschizis: decrease in cell size, cytoplasmic self-excisions, degradation of the nucleus and nucleolus without formation of apoptotic bodies and, ultimately, karyorrhexis and karyolysis. These results also suggest that the vitamin combination may find clinical use in the treatment of ovarian cancer.

  15. Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.

    PubMed

    Pulipati, Nageswara R; Jin, Qunyan; Liu, Xin; Sun, Baodong; Pandey, Manoj K; Huber, Jonathan P; Ding, Wei; Mulder, Kathleen M

    2011-08-01

    km23-1 is a dynein light chain that was identified as a TGFβ receptor-interacting protein. To investigate whether km23-1 controls human ovarian carcinoma cell (HOCC) growth, we established a tet-off inducible expression system in SKOV-3 cells in which the expression of km23-1 is induced upon doxycycline removal. We found that forced expression of km23-1 inhibited both anchorage-dependent and anchorage-independent growth of SKOV-3 cells. More importantly, induction of km23-1 expression substantially reduced the tumorigenicity of SKOV-3 cells in a xenograft model in vivo. Fluorescence-activated cell sorting analysis of SKOV-3 and IGROV-1 HOCCs demonstrated that the cells were accumulating at G2/M. Phospho-MEK, phospho-ERK and cyclin B1 were elevated, as was the mitotic index, suggesting that km23-1 suppresses HOCCs growth by inducing a mitotic delay. Immunofluorescence analyses demonstrated that the cells were accumulating at prometaphase/metaphase with increases in multipolar and multinucleated cells. Further, although the mitotic spindle assembly checkpoint protein BubR1 was present at the prometaphase kinetochore in Dox+/- cells, it was inappropriately retained at the metaphase kinetochore in Dox- cells. Thus, the mechanism by which high levels of km23-1 suppress ovarian carcinoma growth in vitro and inhibit ovary tumor formation in vivo appears to involve a BubR1-related mitotic delay.

  16. Bisphenol A and ovarian steroidogenesis.

    PubMed

    Bloom, Michael S; Mok-Lin, Evelyn; Fujimoto, Victor Y

    2016-09-15

    Bisphenol A is widely used as a component in polycarbonate plastics for food and beverage packaging, epoxy linings for canned foods, and dental sealants, among other applications. Experimental literature demonstrates BPA's affinity for estrogen receptors and downstream effects on estrogen-responsive genes. Additional data suggest that BPA reduces endogenous estrogen synthesis, likely by antagonizing ovarian enzyme activities involved in sex-steroid hormone synthesis. More specifically, evidence indicates BPA-mediated disruption of STAR, CYP450scc, and HSD-3β in theca cells and CYP450 aromatase activity in granulosa cells. Yet the results of the few human studies reported to date are equivocal. It also remains in question the extent to which BPA penetrates developing ovarian follicles. Uncertainty as to the relevance of experimental BPA doses and administration routes for common human exposure levels limits extrapolation of experimental results. To more definitively address the potential risk of BPA on human ovarian steroidogenesis, additional experimental studies using biologically active BPA doses likely to reflect those within the ovarian follicle will be necessary, as will additional prospective investigations in human populations with the use of standardized assay methodology. PMID:27543890

  17. A T cell-independent antitumor response in mice with bone marrow cells retrovirally transduced with an antibody/Fc-gamma chain chimeric receptor gene recognizing a human ovarian cancer antigen.

    PubMed

    Wang, G; Chopra, R K; Royal, R E; Yang, J C; Rosenberg, S A; Hwu, P

    1998-02-01

    In order to treat common cancers with immunotherapy, chimeric receptors have been developed that combine the tumor specificity of antibodies with T-cell effector functions. Previously, we demonstrated that T cells transduced with a chimeric receptor gene against human ovarian cancer were able to recognize ovarian cancer cells in vitro and in vivo. We now report that recipients of bone marrow cells transduced with these genes exhibited significant antitumor activity in vivo. Moreover, in vivo depletion of T cells in reconstituted mice did not affect antitumor activity, suggesting that other immune cells expressing the chimeric receptor gene may play an important role in tumor rejection.

  18. The Cockayne syndrome group B DNA repair protein as an anti-cancer target.

    PubMed

    Lu, Y; Mani, S; Kandimalla, E R; Yu, D; Agrawal, S; States, J C; Bregman, D B

    2001-12-01

    Cells from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair (TCR), which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS (of which there are two complementation groups, CSA and CSB) do not demonstrate an elevated incidence of cancer. Recently, we demonstrated that disruption of the CSB gene reduces the spontaneous tumor rate in cancer predisposed Ink4a/ARF-/- mice as well as causing their embryo fibroblasts to proliferate more slowly and be more sensitive to UV-induced apoptosis. In the present study we characterized phosphorothioate backbone antisense oligodeoxynucleotides (AOs) that reduced the levels of CSB mRNA in A2780/CP70 ovarian carcinoma cells. The AOs caused the cells to proliferate more slowly and made them more sensitive to either cisplatin or oxaliplatin. The AOs also enhanced the cytotoxicity of hydrogen peroxide and gamma-radiation, both of which can induce oxidative DNA lesions, which are subject to TCR. The AOs did not potentiate the cytotoxicity of topotecan, which induces DNA strand breaks. Chemically modified () AOs (MBOs) targeting CSB were able to potentiate the anti-tumor effect of cisplatin against A2780/CP70 tumor xenografts formed in nude mice. The MBOs enabled a non-toxic (3 mg/kg) dose of cisplatin to have the same degree of anti-tumor efficacy as a more toxic (5 mg/kg) cisplatin dose. Collectively, these results suggest that the CSB gene product may be viewed as an anti-cancer target. PMID:11713576

  19. PAX2 Expression in Low Malignant Potential Ovarian Tumors and Low-Grade Ovarian Serous Carcinomas

    PubMed Central

    Tung, Celestine S.; Mok, Samuel C.; Tsang, Yvonne T.M.; Zu, Zhifei; Song, Huijuan; Liu, Jinsong; Deavers, Michael; Malpica, Anais; Wolf, Judith K.; Lu, Karen H.; Gershenson, David M.; Wong, Kwong-Kwok

    2009-01-01

    Ovarian tumors of low-malignant potential and low-grade ovarian serous carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from high-grade ovarian serous carcinoma. We performed gene expression profiling on 3 normal human ovarian surface epithelia samples, and 10 low-grade and 10 high-grade ovarian serous carcinomas. Analysis of gene expression profiles of these samples has identified 80 genes up-regulated and 232 genes down-regulated in low-grade ovarian serous carcinomas. PAX2 was found to be one of the most up-regulated genes in low-grade ovarian serous carcinoma. The up-regulation of PAX2 was validated by real-time quantitative RT-PCR, Western blot and immunohistochemical analyses. Real-time RT-PCR demonstrated a statistically significant difference in PAX2 mRNA expression (expressed as fold change in comparison to normal human ovarian surface epithelia) among ovarian tumors of low-malignant potential (1837.38, N=8), low-grade (183.12, N=17), and high-grade (3.72, N=23) carcinoma samples (p=0.015). Western blot analysis revealed strong PAX2 expression in ovarian tumors of low-malignant potential (67%, N=3) and low-grade carcinoma samples (50%, N=10) but no PAX2 protein expression in high-grade carcinomas (0%, N=10). Using immunohistochemistry, tumors of low-malignant potential (59%, N=17) and low-grade carcinoma (63%, N=16) samples expressed significantly stronger nuclear staining than high-grade ovarian carcinoma samples (9.1%, N=263). Furthermore, consistent with previous immunohistochemical findings, PAX2 expression was found to be expressed in the epithelial cells of fallopian tubes but not in normal ovarian surface epithelial cells. Our findings further support the two-tiered hypothesis that tumors of low-malignant potential and low-grade ovarian serous carcinoma are on a continuum and are distinct from high-grade ovarian carcinomas. Additionally, the absence of PAX2 expression in normal

  20. Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes.

    PubMed

    Virant-Klun, Irma; Rozman, Primoz; Cvjeticanin, Branko; Vrtacnik-Bokal, Eda; Novakovic, Srdjan; Rülicke, Thomas; Dovc, Peter; Meden-Vrtovec, Helena

    2009-01-01

    Little is known about parthenogenesis in the human ovary. What is known is related to patients with teratoma in their medical history. Ovarian surface epithelium (OSE) was often proposed as a source of ovarian stem cells with an embryonic character in the past, and was also termed "germinal epithelium." The aim of this study was to isolate putative stem cells from OSE scrapings, to set up an OSE cell culture, to follow the in vitro oogenesis and possible formation of parthenogenetic embryos in 21 postmenopausal women with no naturally present follicles and oocytes. Small round cells with a bubble-like structure and with a diameter from 2 to 4 microm were isolated from the material obtained by OSE scrapings in all women. They expressed early embryonic developmental markers such as stage-specific embryonic antigen-4 (SSEA-4) surface antigen and Oct-4, Nanog, Sox-2, and c-kit transcription factors. These cells were separated by density gradient centrifugation and grown in vitro, where they proliferated and formed embryoid body-like structures. Their markers of pluripotency such as telomerase activity were decreased during in vitro culture and they did not form teratoma after the injection into SCID mice. Some of them grew intensively and reached a diameter of approximately 20 microm after 5-7 days of culture. In the OSE cell culture, oocyte-like cells developed among them, which reached a diameter up to 95 mum, and expressed Oct-4, c-kit, VASA, and ZP2 transcription markers after 20 days of culture. Some of them expressed a zona pellucida-like structure and rarely germinal vesicle- and polar body-like structures. At the same time, parthenogenetic blastocyst-like structures developed, which expressed transcription markers Oct-4, Sox-2, and Nanog and were normal for chromosomes X, Y, 13, 16, 18, 21, and 22. In conclusion, the discovered cells expressed embryonic stem cell markers, gave rise to embryoid body-, oocyte-, and blastocyst-like structures, and might be

  1. Environmentally induced epigenetic transgenerational inheritance of ovarian disease.

    PubMed

    Nilsson, Eric; Larsen, Ginger; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Savenkova, Marina I; Skinner, Michael K

    2012-01-01

    The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology.

  2. Ovarian aging and premature ovarian failure

    PubMed Central

    Şükür, Yavuz Emre; Kıvançlı, İçten Balık; Özmen, Batuhan

    2014-01-01

    Physiological reproductive aging occurs as a result of a decrease in the number and quality of oocytes in ovarian cortex follicles. Although the reason for the decrease in the quality of the pool and follicular oocytes is not fully understood, endocrine, paracrine, genetic, and metabolic factors are thought to be effective. Nowadays, in order to understand the mechanisms of ovarian aging, genomic research has gained importance. The effect of co-factors, such as telomerase and ceramide, in the ovarian aging process is only getting ascertained with new research studies. The most important tests in the assessment of ovarian aging are antral follicle count and anti-Mullerian hormone. PMID:25317048

  3. A covalently dimerized recombinant human bone morphogenetic protein-15 variant identifies bone morphogenetic protein receptor type 1B as a key cell surface receptor on ovarian granulosa cells.

    PubMed

    Pulkki, Minna M; Mottershead, David G; Pasternack, Arja H; Muggalla, Pranuthi; Ludlow, Helen; van Dinther, Maarten; Myllymaa, Samu; Koli, Katri; ten Dijke, Peter; Laitinen, Mika; Ritvos, Olli

    2012-03-01

    Genetic studies have identified bone morphogenetic protein-15 (BMP15) as an essential regulator of female fertility in humans and in sheep. Oocyte-derived BMP15 is a noncovalently linked dimeric growth factor mediating its effects to ovarian somatic cells in a paracrine manner. Although receptor ectodomains capable of binding BMP15 have previously been reported, no cell surface receptor complex involved in BMP15 signaling has previously been characterized. Here we have expressed and purified recombinant human BMP15 noncovalent and covalent dimer variants. The biological effects of these BMP15 variants were assessed in cultured human granulosa-luteal cells or COV434 granulosa cell tumor cells using BMP-responsive transcriptional reporter assays and an inhibin B ELISA. Biochemical characterization of ligand-receptor interactions was performed with affinity-labeling experiments using [(125)I]iodinated BMP15 variants. Both ligand variants were shown to form homodimers and to stimulate Smad1/5/8 signaling and inhibin B production in human granulosa cells in a similar manner. [(125)I]Iodination of both ligands was achieved, but only the covalent dimer variant retained receptor binding capacity. The [(125)I]BMP15(S356C) variant bound preferentially to endogenous BMP receptor 1B (BMPR1B) and BMPR2 receptors on COV434 cells. Binding experiments in COS cells with overexpression of these receptors confirmed that the [(125)I]BMP15(S356C) variant binds to BMPR1B and BMPR2 forming the BMP15 signaling complex. The results provide the first direct evidence in any species on the identification of specific cell surface receptors for a member of the GDF9/BMP15 subfamily of oocyte growth factors. The fact that BMP15 uses preferentially BMPR1B as its type I receptor suggests an important role for the BMPR1B receptor in human female fertility. The result is well in line with the demonstration of ovarian failure in a recently reported human subject with a homozygous BMPR1B loss

  4. Symptoms of Ovarian Cancer

    MedlinePlus

    ... Informed Cancer Home What Are the Symptoms of Ovarian Cancer? Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Gynecologic cancer symptoms diaries Ovarian cancer may cause one or more of these signs ...

  5. Live birth after ovarian tissue transplant

    NASA Astrophysics Data System (ADS)

    Lee, D. M.; Yeoman, R. R.; Battaglia, D. E.; Stouffer, R. L.; Zelinski-Wooten, M. B.; Fanton, J. W.; Wolf, D. P.

    2004-03-01

    Radiation and high-dose chemotherapy may render women with cancer prematurely sterile, a side-effect that would be avoided if ovarian tissue that had been removed before treatment could be made to function afterwards. Live offspring have been produced from transplanted ovarian tissue in mice and sheep but not in monkeys or humans, although sex steroid hormones are still secreted. Here we describe the successful transplantation of fresh ovarian tissue to a different site in a monkey, which has led to the birth of a healthy female after oocyte production, fertilization and transfer to a surrogate mother. The ectopically grafted tissue functions without surgical connection to major blood vessels and sets the stage for the transplantation of cryopreserved ovarian tissue in humans.

  6. Oxidative modification induced by photodynamic therapy with Photofrin®II and 2-methoxyestradiol in human ovarian clear carcinoma (OvBH-1) and human breast adenocarcinoma (MCF-7) cells.

    PubMed

    Saczko, Jolanta; Choromańska, Anna; Rembiałkowska, Nina; Dubińska-Magiera, Magda; Bednarz-Misa, Iwona; Bar, Julia; Marcinkowska, Anna; Kulbacka, Julita

    2015-04-01

    Ovarian cancer is among the most lethal cancers in women. The successful anticancer treatment depends on the effectiveness of cytotoxic effect of applied therapeutic procedures either alone or in combination with other treatments. Photodynamic therapy (PDT) is a relatively new method of anticancer therapy. Its dominant mechanism of action is the over-production of reactive oxygen species induced by oxidative stress in malignant cells, which attack lipid membranes, proteins and nucleic acids. One of the important mechanisms is induction of unfolded protein response, ubiquitin-proteasome pathway of protein degradation. The aim of this study was to evaluate the cytotoxic effect of various protective enzymes in ovarian carcinoma clear cell line in comparison to the model breast cell line after photodynamic reaction and photodynamic reaction with 2-methoxyestradiol (2-Me). Human malignant ovarian cell line (OvBH-1) was used and human breast adenocarcinoma cells (MCF-7) were used as a control. Photodynamic reaction (PDR) with Photofrin(®)II and Ph(®)II with 2-Me was performed. The expression of protective proteins by immunocytochemistry (HSP70 and iNOS) and western blot (Hsp27 and Hsp70) methods was evaluated directly, 3 and 6 h after PDR. The changes in cells' cytoskeleton were evaluated using immunofluorescence by confocal microscopy. The expression of iNOS was observed for both experiments with differential intensity and quantity. A higher expression of Hsp70 in MCF-7 cells was observed than in OvBh-1 cells. The reorganization of cytoskeleton and nucleus was observed after 3 and 6 h after exposition to light.

  7. The Aminosteroid Derivative RM-133 Shows In Vitro and In Vivo Antitumor Activity in Human Ovarian and Pancreatic Cancers

    PubMed Central

    Kenmogne, Lucie Carolle; Ayan, Diana; Roy, Jenny; Maltais, René; Poirier, Donald

    2015-01-01

    Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new drugs acting via a different mechanism of action represents a clear priority. Herein, we are reporting for the first time that the aminosteroid derivative RM-133, developed in our laboratory, displays promising activity on two models of aggressive cancers, namely ovarian (OVCAR-3) and pancreatic (PANC-1) cancers. The IC50 value of RM-133 was 0.8 μM and 0.3 μM for OVCAR-3 and PANC-1 cell lines in culture, respectively. Based on pharmacokinetic studies on RM-133 using 11 different vehicles, we selected two main vehicles: aqueous 0.4% methylcellulose:ethanol (92:8) and sunflower oil:ethanol (92:8) for in vivo studies. Using subcutaneous injection of RM-133 with the methylcellulose-based vehicle, growth of PANC-1 tumors xenografted to nude mice was inhibited by 63%. Quite interestingly, RM-133 injected subcutaneously with the methylcellulose-based or sunflower-based vehicles reduced OVCAR-3 xenograft growth by 122% and 100%, respectively. After the end of RM-133 treatment using the methylcellulose-based vehicle, OVCAR-3 tumor growth inhibition was maintained for ≥ 1 week. RM-133 was also well tolerated in the whole animal, no apparent sign of toxicity having been detected in the xenograft studies. PMID:26660672

  8. Radiation survival parameters of antineoplastic drug-sensitive and -resistant human ovarian cancer cell lines and their modification by buthionine sulfoximine

    SciTech Connect

    Louie, K.G.; Behrens, B.C.; Kinsella, T.J.; Hamilton, T.C.; Grotzinger, K.R.; McKoy, W.M.; Winker, M.A.; Ozols, R.F.

    1985-05-01

    The optimum integration of chemotherapy and irradiation is of potential clinical significance in the treatment of ovarian cancer. A series of human ovarian cancer cell lines have been developed in which dose-response relationships to standard anticancer drugs have been determined, and the patterns of cross-resistance between these drugs and irradiation have been established. By stepwise incubation with drugs, sublines of A2780, a drug-sensitive cell line, have been made 100-fold, 10-fold, and 10-fold more resistant to Adriamycin (2780AD), melphalan (2780ME), and cisplatin (2780CP). Two additional cell lines, NIH:OVCAR-3nu(Ag+) and NIH:OVCAR-4(Ag+), were established from drug-refractory patients. 2780ME, 2780CP, OVCAR-3nu(Ag+), and OVCAR-4(Ag+) are all cross-resistant to irradiation, with DOS of 146, 187, 143, and 203, respectively. However, 2780AD remains sensitive to radiation, with a DO of 111, which is similar to that of A2780 (101). Glutathione (GSH) levels are elevated in 2780ME, 2780CP, OVCAR-3nu(Ag+), and OVCAR-4(Ag+) to 4.58, 6.13, 12.10, and 15.14 nmol/10(6) cells as compared to A2780, with 1.89 nmol/10(6) cells. However, the GSH level in 2780AD is only minimally higher than that in A2780 (2.94 nmol/10(6) cells). Buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly increases the radiation sensitivity of 2780ME (changing the DO from 143 to 95) and 2780CP to a lesser extent, suggesting that intracellular GSH levels may play an important role in the radiation response of certain neoplastic cells.

  9. Monofunctional Platinum-containing Pyridine-based Ligand Acts Synergistically in Combination with the Phytochemicals Curcumin and Quercetin in Human Ovarian Tumour Models.

    PubMed

    Arzuman, Laila; Beale, Philip; Yu, Jun Q; Huq, Fazlul

    2015-05-01

    With the idea that platinum compounds that bind with DNA differently than cisplatin may be better-able to overcome platinum resistance in ovarian tumor, the monofunctional platinum complex tris(imidazo(1,2-α)pyridine) chloroplatinum(II) chloride (coded as LH6) has been synthesized and investigated for its activity, alone and in combination with the phytochemicals curcumin and quercetin, against human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cancer cell lines. LH6 is found to be more active than cisplatin against the resistant cell lines and its bolus combinations with curcumin and quercetin are found to produce more pronounced cell kill. Whereas platinum accumulation from cisplatin is found to increase almost linearly with time, that from LH6 reaches a maximum at 4 h and is somewhat lowered at 24 h. It is possible that the presence of bulky hydrophobic imidazo (1,2-α-pyridine) ligand in LH6 facilitates its rapid uptake through the cytoplasmic membrane. Lower platinum accumulation at 24 h than at 4 h for LH6 can be seen to imply that efflux processes may be more dominant as the period of incubation is increased. When platinum-DNA binding levels at 24 h are compared, cisplatin is found to be associated with the higher level in the parent A2780 cell line and LH6 in the resistant A2780(cisR) cell line, in line with greater activity of cisplatin in the parent cell line and that of LH6 in the resistant cell line. If the observed in vitro activity of LH6 is confirmed in vivo, it can be seen to have the potential for development as novel platinum based anticancer drug.

  10. Decreased expression of H3K27me3 in human ovarian carcinomas correlates with more aggressive tumor behavior and poor patient survival.

    PubMed

    He, W P; Li, Q; Zhou, J; H, Z S; Kung, H F; Guan, X Y; Xie, D; Yang, G F

    2015-01-01

    It has been confirmed that trimethylation of lysine 27 on histone H3 (H3K27me3) plays an important role in epigenetic process of tumorigenesis. However, the status of H3K27me3 in ovarian cancer and its impact on patients' clinicopathologic characteristics and prognosis are unclear. In the present study, the immunohistochemistry (IHC) was utilized to detect protein expression of H3K27me3 in 12 normal ovaries, 26 ovarian cystadenomas, 31 borderline ovarian tumors and 168 ovarian carcinomas by tissue microarray. The association between H3K27me3 expression with clinicopathologic features and patient prognosis were also evaluated using various statistical models. The expression of H3K27me3 was decreased in 2 of 12 (16.7%) cases of the normal ovaries, 8 of 26 (30.8%) cases of cystadenomas, 12 of 31 (38.7%) cases of borderline ovarian tumors, and 93 of 168 (55.4%) cases of primary ovarian carcinomas, respectively (P<0.05). Further correlation analysis suggested that decreased expression of H3K27me3 in ovarian carcinomas was significantly correlated with more advanced pM and FIGO stages (P<0.05). In addition, a significant association between decreased expression of H3K27me3 and shortened patient survival (mean 66 months versus 101 months, p=0.019) was demonstrated by univariate survival analysis of the ovarian carcinoma cohorts. Importantly, H3K27me3 expression provided a significant independent prognostic factor in multivariate analysis (p=0.028). These findings confirmed that decreased expression of H3K27me3 in primary ovarian cancer might be correlated with the acquisition of an invasive and/or aggressive phenotype of tumor, and might serve as an independent biomarker for poor prognosis in patients with ovarian carcinoma.

  11. Predictive and therapeutic markers in ovarian cancer

    DOEpatents

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  12. Theaflavin-3, 3′-digallate decreases human ovarian carcinoma OVCAR-3 cell-induced angiogenesis via Akt and Notch-1 pathways, not via MAPK pathways

    PubMed Central

    GAO, YING; RANKIN, GARY O.; TU, YOUYING; CHEN, YI CHARLIE

    2016-01-01

    Theaflavin-3, 3′-digallate (TF3) is a black tea poly-phenol produced from polymerization and oxidization of the green tea ployphenols epicatechin gallate and (−)-epigallocatechin-3-gallate (EGCG) during fermentation of fresh tea leaves. TF3 has been reported to have anticancer properties. However, the effect of TF3 on tumor angiogenesis and the underlying mechanisms are not clear. In the present study, TF3 was verified to inhibit tumor angiogenesis. Compared with EGCG, TF3 was more potent. TF3 inhibited human ovarian carcinoma OVCAR-3 cell-induced angiogenesis in human umbilical vein endothelial cell model and in chick chorioallantoic membrane model. TF3 reduced tumor angiogenesis by downregulating HIF-1α and VEGF. One of the mechanisms was TF3 inactivated Akt/mTOR/p70S6K/4E-BP1 pathway and Akt/c-Myc pathway. Besides, TF3 suppressed the cleavage of Notch-1, subsequently decreased the expression of c-Myc, HIF-1α and VEGF, and finally the impaired cancer cells induced angiogenesis. Nevertheless, TF3 did not have any influence on the MAPK pathways. Taken together, these findings suggest that TF3 might serve as a potential anti-angiogenic agent for cancer treatment. PMID:26648098

  13. Ormeloxifene efficiently inhibits ovarian cancer growth

    PubMed Central

    Maher, Diane M.; Khan, Sheema; Nordquist, Jordan; Ebeling, Mara C.; Bauer, Nichole A.; Kopel, Lucas; Singh, Man Mohan; Halaweish, Fathi; Bell, Maria C.; Jaggi, Meena; Chauhan, Subhash C.

    2014-01-01

    Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer. PMID:25306892

  14. Myricetin induces apoptosis via endoplasmic reticulum stress and DNA double-strand breaks in human ovarian cancer cells

    PubMed Central

    XU, YE; XIE, QI; WU, SHAOHUA; YI, DAN; YU, YANG; LIU, SHIBING; LI, SONGYAN; LI, ZHIXIN

    2016-01-01

    The mechanisms underlying myricetin-induced cancer cell apoptosis remain to be elucidated. Certain previous studies have shown that myricetin induces apoptosis through the mitochondrial pathway. Apoptosis, however, can also be induced by other classical pathways, including endoplasmic reticulum (ER) stress and DNA double-strand breaks (DSBs). The aim of the present study was to assess whether these two apoptotic pathways are involved in myricetin-induced cell death in SKOV3 ovarian cancer cells. The results revealed that treatment with myricetin inhibited viability of SKOV3 cells in a dose-dependent manner. Myricetin induced nuclear chromatin condensation and fragmentation, and also upregulated the protein levels of active caspase 3 in a time-dependent manner. In addition, myricetin upregulated ER stress-associated proteins, glucose-regulated protein-78 and C/EBP homologous protein in SKOV3 cells. Phosphorylation of H2AX, a marker of DNA DSBs, was revealed to be upregulated in myricetin-treated cells. The data indicated that myricetin induces DNA DSBs and ER stress, which leads to apoptosis in SKOV3 cells. PMID:26782830

  15. Elevated blood plasma concentrations of active ghrelin and obestatin in benign ovarian neoplasms and ovarian cancers.

    PubMed

    Markowska, A; Ziółkowska, A; Jaszczyńska-Nowinka, K; Madry, R; Malendowicz, L K

    2009-01-01

    Both ghrelin and obestatin are derived from preproghrelin by post-translational processing. The two peptides are secreted into the blood but circulating levels of these peptides have not been assessed in women with ovarian tumours. Therefore, the purpose of this study was to evaluate peripheral blood concentrations of active and total ghrelin and obestatin in patients with benign ovarian tumours and those with ovarian cancer. The studies were conducted on 22 patients operated due to benign ovarian tumours, and 31 patients operated due to ovarian cancer. A control group consisted of 32 women, 24 to 65 years of age. Both in women with benign ovarian tumours and those with ovarian cancer blood concentrations of active ghrelin and obestatin were higher than in the control group (active ghrelin: 90 +/- 4, 84 +/- 4 and 56 +/- 9 pg/ml, respectively, obestatin: 660 +/- 36; 630 +/- 30 and 538 +/- 31 ng/ml (x +/- SE), respectively). In contrast, total ghrelin concentrations in blood were similar in the studied groups. The alterations resulted in increased values of active to total ghrelin concentration ratio in the peripheral blood of patients with benign ovarian tumours or with ovarian cancer (0.79 +/- 0.02 and 0.93 +/- 0.05, respectively vs 0.58 +/- 0.02 in the control group). Due to the absence of any convincing proof for the presence of a functional GHS-R-1a receptor for ghrelin in human ovaries it did not seem probable that the observed elevated levels of active ghrelin and obestatin were directly linked to development of ovarian tumours.

  16. 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

  17. Human ovarian cancer multicellular spheroids: a model for testing antiproliferation activity of Devil's club (Oplopanax horridus) and anticancer agents.

    PubMed

    Tai, Joseph; Cheung, Susan S C; Hasman, David

    2014-06-01

    This study was conducted to employ an ovarian cancer Ovcar 10 three-dimensional model to assess the antiproliferation activity of the medicinal plant Devil's club, Oplopanax horridus, and its active compound, alone and in combination, with chemotherapeutic agents compared to Ovcar 10 two-dimensional cells grown as monolayer cells. Ovcar 10 three-dimensional spheroids were prepared with a rotary cell culture system. Cell counting kit-8 assessed the antiproliferation activity. Apoptosis-related gene expression in three-dimensional spheroids and two- dimensional cells was analyzed with an apoptosis antibody array. Flow cytometry was used to analyze the cell cycle. Ovcar 10 cells formed compact three-dimensional spheroids after 5 days of culture in a rotary culture system. Ovcar 10 three-dimensional spheroids were significantly more resistant to killing by Devil's club extract, its active compound alone, gemcitabine, and paclitaxel, but not cisplatin compared to two-dimensional cells, with IC50 levels closer to that observed in vivo. Devil's club extract and its active compound alone significantly enhanced the antiproliferation activity of cisplatin and gemcitabine at some concentrations, but did not affect the activity of paclitaxel. A number of apoptosis-related genes were differentially expressed in three-dimensional spheroids, two-dimensional cells, and cells treated with Devil's club extract compared to untreated controls. In three-dimensional spheroids, the proportion of cells in the G2/M phase was slightly increased and the S phase was slightly decreased compared to two-dimensional cells. Ovcar 10 cells in three-dimensional spheroids altered the expression of multiple apoptosis-related genes, which may have contributed to the increased resistance of the cells to some drugs. PMID:24922275

  18. Vanishing ovarian mass: Sarcoidosis.

    PubMed

    Turkay, Rustu; Bakir, Baris; Golabi, Uygar Cenik; Topuz, Samet; Ilhan, Huseyin Ridvan

    2012-01-01

    A woman was referred to our hospital with the working diagnosis of ovarian malignancy. While she was undergoing both clinical and radiological evaluation and monitoring, a decrease in the size of the ovarian mass was noted. After further evaluation via laboratory findings and tissue biopsy, we arrived at a final diagnosis of sarcoidosis, which is very unusual in the ovaries. Our case places emphasis on the importance of considering rare entities, such as ovarian sarcoidosis, and the importance of radiologic changes in solid ovarian mass dimensions over time.

  19. Plasma, tumor and tissue pharmacokinetics of Docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft

    PubMed Central

    Chu, Kevin S.; Hasan, Warefta; Rawal, Sumit; Walsh, Mark D.; Enlow, Elizabeth M.; Luft, J. Christopher; Bridges, Arlene S.; Kuijer, Jennifer L.; Napier, Mary E.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently lead to increased tumor exposure of Docetaxel from 0-168 hours (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. PMID:23219874

  20. Ovarian hyperstimulation syndrome

    PubMed Central

    Kumar, Pratap; Sait, Sameer Farouk; Sharma, Alok; Kumar, Mukesh

    2011-01-01

    Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology. The syndrome is characterized by cystic enlargement of the ovaries and a fluid shift from the intravascular to the third space due to increased capillary permeability and ovarian neoangiogenesis. Its occurrence is dependent on the administration of human chorionic gonadotrophin (hCG). β-hCG and its analogs, estrogen, estradiol, prolactin, histamine and prostaglandins have all been implicated in OHSS but now it is increasingly better understood that the vasoactivesubstances such as interleukins, tumor necrosis factor-α, endothelin-1, and vascular endothelial growth factor (VEGF) secreted by the ovaries have been implicated in increasing vascular permeability. Enlargement of the ovaries causes abdominal pain, nausea and vomiting. Leakage of fluid from follicles, increased capillary permeability leading to third spacing (due to the release of vasoactive substances), or frank rupture of follicles can all cause ascites. Due to leakage of fluid through the impaired blood vessels both within and outside the ovary there is massive fluid-shift from the intra-vescular bed to the third compartment results in intravascular hypovolemia with concomitant development of edema, ascites, hydrothorax and/or hydropericardium. Low-dose gonadotrophin protocols have been implemented to reduce the risks of fertility treatment in polycystic ovary syndrome patients. Prophylactic albumin administration may interrupt the development of OHSS by increasing the plasma oncotic pressure and binding mediators of ovarian origin. OHSS is significantly lower in an antagonist protocol than in an agonist protocol. Cabergoline inhibits partially the VEGF receptor 2 phosphorylation levels and associated vascular permeability without affecting luteal angiogenesis reduces the ‘early’ (within the first 9 days after hCG) onset of OHSS. To prevent thrombosis, subcutaneous heparin 5000-7500 U/d is

  1. Effectiveness of a recombinant human follicle stimulating hormone on the ovarian follicles, peripheral progesterone, estradiol-17β, and pregnancy rate of dairy cows

    PubMed Central

    Ali, Mohamed; Moustafa M., Zeitoun

    2016-01-01

    Aims: This study aimed at elucidating the effects of recombinant human follicle stimulating hormone (r-hFSH) on the ovarian follicular dynamics, progesterone, estradiol-17β profiles, and pregnancy of dairy cows. Materials and Methods: Three groups (G, n=5 cows) of multiparous dairy cows were used. G1 (C) control cows were given controlled internal drug release (CIDR) and prostaglandin F2α; G2 (L) cows were given low dose (525 IU and G3 (H) cows were given high dose (1800 IU) of r-hFSH on twice daily basis at the last 3 days before CIDR removal. All cows were ultrasonically scanned for follicular growth and dynamics, and blood samples were collected every other day for two consecutive estrus cycles for the determination of estradiol-17β and progesterone. Results: Estrus was observed in all C and L but not in H cows. Dominant follicle was bigger in L compared to C and H cows. Dominant follicle in C (16.00±2.5 mm) and L cows (17.40±2.3 mm) disappeared at 72 h after CIDR removal. However, in H cows, no ovulation has occurred during 7 days post-CIDR removal. Progesterone was not different (p>0.10) among groups, whereas estradiol-17β revealed significant (p<0.01) reduction in H (15.96±2.5 pg/ml) cows compared to C (112.26±26.1 pg/ml) and L (97.49±15.9 pg/ml) cows. Pregnancy rate was higher in L cows (60%) compared with C cows (20%). However, H cows were not artificially inseminated due to non-ovulation. Only a cow of C group has calved one calf, however, 2 of the L cows gave birth of twins and a cow gave single calf. Conclusion: Administration of a low dose (525 IU) of r-hFSH resulted in an optimal size of dominant follicle, normal values of progesterone and estradiol-17β, and 40% twinning rate, howeverusing 1800 IU of r-hFSH, have adverse effects on ovarian follicular dynamics and hormonal profiles with non-pregnancy of dairy cows raised under hot climate. PMID:27536029

  2. 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

  3. Expression of organic cation transporter SLC22A16 in human epithelial ovarian cancer: a possible role of the adriamycin importer.

    PubMed

    Ota, Kyoko; Ito, Kiyoshi; Akahira, Jun-ichi; Sato, Naoko; Onogawa, Tohru; Moriya, Takuya; Unno, Michiaki; Abe, Takaaki; Niikura, Hitoshi; Takano, Tadao; Yaegashi, Nobuo

    2007-07-01

    The SLC22A16 is one of the newly isolated organic cation transporters, which is responsible for uptake and transport of adriamycin into cells. Adriamycin is considered to be an active agent for ovarian cancer. Recently, the benefit of adding adriamycin to the current standard regimen, paclitaxel and platinum, is evaluated to improve the outcome of patients with ovarian cancer. Therefore, we examined the expression of SLC22A16 in ovarian cancers. Twelve ovarian carcinoma cell lines were used for immunoblotting and reverse transcription-polymerase chain reaction to confirm the expression of SLC22A16 mRNA and protein. Five normal ovaries, 12 ovarian adenomas, and 94 ovarian cancer cases were obtained from patients after surgical therapy. The specimens were used for immunohistochemistry. The median value of relative SLC22A16 gene expression in cell lines derived from clear-cell adenocarcinoma was significantly higher than that in cell lines from other histologies (P < 0.001). Expression of SLC22A16 protein was also detected in cell lines derived from clear-cell adenocarcinoma. The SLC22A16 immunoreactivity was detected in 15 (16%) of 94 epithelial ovarian cancer, 1 (8.3%) of 12 benign adenomas, but 0 (0%) of 5 normal ovary cases. In ovarian cancer tissues, SLC22A16 immunoreactivity was detected in 2 (5%) of 38 serous adenocarcinoma, 1 (6.7%) of 15 endometrioid adenocarcinoma, 0 (0%) of 14 mucinous adenocarcinoma, and 12 (46.2%) of 26 clear-cell adenocarcinoma (P < 0.0001, clear-cell vs other histologies). In conclusion, SLC22A16 was abundantly expressed in clear-cell adenocarcinoma. Our results suggest that adriamycin-related chemicals that are taken up via SLC22A16 may have the potential to be effective against clear-cell adenocarcinoma.

  4. Ovarian Kaleidoscope Database: Ten Years and Beyond1

    PubMed Central

    Hsueh, Aaron J.; Rauch, Rami

    2012-01-01

    ABSTRACT Ovarian Kaleidoscope database (OKdb) is an online, searchable, public database containing text-based and DNA microarray data to facilitate research by ovarian researchers. Using key words and predetermined categories, users can search ovarian gene information based on gene function, cell type of expression, cellular localization, hormonal regulation, mutant phenotypes, chromosomal location, ligand-receptor relationship, and other criteria, either alone or in combination. For individual genes, users can access more than 10 extensive DNA microarray datasets to interrogate gene expression patterns in a development-specific and cell type-specific manner. All ligand and receptor genes expressed in the ovary are matched to facilitate investigation of paracrine/autocrine signaling. More than 3500 ovarian genes in the database are matched to 185 gene pathways in the Kyoto Encyclopedia of Genes and Genomes to allow for elucidation of gene interactions and relationships. In addition to >400 genes with infertility or subfertility phenotypes when mutated in mice or humans, the OKdb also lists ∼50 and ∼40 genes associated with polycystic ovarian syndrome and primary ovarian insufficiency, respectively. The expanding OKdb is updated weekly and allows submission of new genes by ovarian researchers to allow instant access to DNA microarray datasets for newly submitted genes. The present database is a virtual community for ovarian researchers and allows users to instantaneously provide their comments for individual gene pages based on an automated Web-discussion system. In the coming years, we will continue to add new features to serve the ovarian research community. PMID:22441797

  5. Real-Time Imaging of Resident T Cells in Human Lung and Ovarian Carcinomas Reveals How Different Tumor Microenvironments Control T Lymphocyte Migration.

    PubMed

    Bougherara, Houcine; Mansuet-Lupo, Audrey; Alifano, Marco; Ngô, Charlotte; Damotte, Diane; Le Frère-Belda, Marie-Aude; Donnadieu, Emmanuel; Peranzoni, Elisa

    2015-01-01

    T cells play a key role in the battle against cancer. To perform their antitumor activities, T cells need to adequately respond to tumor antigens by establishing contacts with either malignant cells or antigen-presenting cells. These latter functions rely on a series of migratory steps that go from entry of T cells into the tumor followed by their locomotion in the tumor stroma. Our knowledge of how T cells migrate within tumors mainly comes from experiments performed in mouse models. Whereas such systems have greatly advanced our understanding, they do not always faithfully recapitulate the disease observed in cancer patients. We previously described a technique based on tissue slices that enables to track with real-time imaging microscopy the motile behavior of fluorescent T cells plated onto fresh sections of human lung tumors. We have now refined this approach to monitor the locomotion of resident tumor-infiltrating CD8 T cells labeled with fluorescently coupled antibodies. Using this approach, our findings reveal that CD8 T cells accumulate in the stroma of ovarian and lung carcinomas but move slowly in this compartment. Conversely, even though less populated, tumors islets were found to be zones of faster migration for resident CD8 T cells. We also confirm the key role played by collagen fibers, which, by their orientation, spacing and density, control the distribution and migration of resident CD8 T cells within the tumor stroma. We have subsequently demonstrated that, under some physical tissue constraints, CD8 T cells exhibited a mode of migration characterized by alternate forward and backward movements. In sum, using an ex vivo assay to track CD8 T cells in fresh human tumor tissues, we have identified the extracellular matrix as a major stromal component in influencing T cell migration, thereby impacting the control of tumor growth. This approach will aid in the development and testing of novel immunotherapy strategies to promote T cell migration in

  6. Monitor Therapeutic Response of Human Ovarian Cancer to 17-DMAG by Non-invasive PET imaging with 64Cu-DOTA-Trastuzumab

    PubMed Central

    Niu, Gang; Li, Zibo; Cao, Qizhen; Chen, Xiaoyuan

    2012-01-01

    Purposes 17-DMAG, a heat shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to non-invasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice. Methods The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression of SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using 64Cu-DOTA-trastuzumab and 18F-FDG. Biodistribution studies, immunofluorescence staining were performed to validate the microPET results. Results SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose dependent manner, with an IC50 value of 68.7 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that 64Cu-DOTA-trastuzumab had prominent tumor activity accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment. Conclusion The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using 64Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment. PMID:19440708

  7. Mechanism of cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cells in vitro and modulation of the drug activity by folic or folinic acid.

    PubMed Central

    Erba, E.; Sen, S.; Sessa, C.; Vikhanskaya, F. L.; D'Incalci, M.

    1994-01-01

    Inhibition of clonogenic potential by the glycinamideribonucleosyl transformylase inhibitor 5,10-dideazatetrahydrofolic acid (DDATHF, Lometrexol) was evaluated in vitro in a human ovarian carcinoma cell line, SW626. Drug-induced inhibition of clonogenic potential is a function of the dose and time of exposure and is independent of the formation of DNA single-strand breaks or de novo synthesis of protein. Simultaneous treatment with 100 microM hypoxanthine completely prevented the inhibition of clonogenic potential caused by 0.5 microM DDATHF. DDATHF blocked cells in the early-middle S-phases of the cell cycle, and there was a corresponding marked reduction in the rate of DNA synthesis after drug withdrawal. The cytotoxic potential of DDATHF was modulated by the folic acid concentration present in the medium. In a medium containing 0.22 microM folic acid, DDATHF cytotoxicity was at least 100 times that in a regular medium containing 2.22 microM folic acid, levels which, however, are about 100 times those found in human plasma. DDATHF cytotoxicity differed moderately when folic acid concentrations varied between 0.22 and 0 microM, suggesting that folic acid does not necessarily antagonise DDATHF anti-tumour activity. Folinic acid at a concentration as low as 0.1 microM can completely rescue cells when given simultaneously with 0.5 microM DDATHF. When folinic acid was given 24 h after DDATHF, a reversal of cytotoxicity was observed at 0.5 and 1 microM, but to a much lesser extent than simultaneous treatment. When folinic acid was added after 48 or 72 h of DDATHF washout, even at a high concentration and for a long time, no reduction in DDATHF cytotoxicity was found. In conclusion, the study highlights the modulation of DDATHF cytotoxicity by folic acid or by folinic acid and provides further rationale for in vivo clinical investigation with these combinations. PMID:8297715

  8. Ovarian Cancer Fact Sheet

    MedlinePlus

    ... States, ovarian cancer is the eighth most common cancer and the fifth leading cause of cancer death. Around one in every 60 ... States, ovarian cancer is the eighth most common cancer and the fifth leading cause of cancer death. Are some women more at ...

  9. Ovarian Cancer Stage IV

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IV Add to My Pictures View /Download : ... 1200x1335 View Download Large: 2400x2670 View Download Title: Ovarian Cancer Stage IV Description: Drawing of stage IV shows ...

  10. Ovarian Cancer Stage IIIC

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IIIC Add to My Pictures View /Download : ... 1530x1350 View Download Large: 3060x2700 View Download Title: Ovarian Cancer Stage IIIC Description: Drawing of stage IIIC shows ...

  11. Ovarian Cancer Stage II

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage II Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage II Description: Three-panel drawing of stage ...

  12. Ovarian Cancer Stage I

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage I Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage I Description: Three-panel drawing of stage ...

  13. Polycystic ovarian disease: animal models.

    PubMed

    Mahajan, D K

    1988-12-01

    The reproductive systems of human beings and other vertebrates are grossly similar. In the ovary particularly, the biochemical and physiologic processes are identical not only in the formation of germ cells, the development of primordial follicles and their subsequent growth to Graafian follicles, and eventual ovulation but also in anatomic structure. In a noncarcinogenic human ovary, hypersecretion of androgen causes PCOD. Such hypersecretion may result from a nonpulsatile, constant elevated level of circulating LH or a disturbance in the action of neurotransmitters in the hypothalamus. In studying the pathophysiology of PCOD in humans, one must be aware of the limitations for manipulating the hypothalamic-pituitary axis. Although the rat is a polytocous rodent, the female has a regular ovarian cyclicity of 4 or 5 days, with distinct proestrus, estrus, and diestrus phases. Inasmuch as PCOD can be experimentally produced in the rat, that species is a good model for studying the pathophysiology of human PCOD. These PCOD models and their validity have been described: (1) estradiol-valerate, (2) DHA, (3) constant-light (LL), and (4) neonatally androgenized. Among these, the LL model is noninvasive and seems superior to the others for study of the pathophysiology of PCOD. The production of the polycystic ovarian condition in the rat by the injection of estrogens or androgens in neonate animals, or estradiol or DHA in adult rats, or the administration of antigonadotropins to these animals all cause a sudden appearance of the persistent estrus state by disturbing the metabolic and physiologic processes, whereas exposure of the adult rat to LL causes polycystic ovaries gradually, similar to what is seen in human idiopathic PCOD. After about 50 days of LL, the rat becomes anovulatory and the ovaries contain thickened tunica albuginea and many atretic follicles, and the tertiary follicles are considerably distended and cystic. The granulosa and theca cells appear normal

  14. Reproductive responses of dairy cows with ovarian cysts to simultaneous human chorionic gonadotropin or gonadotropin-releasing hormone and cloprostenol compared to gonadotropin-releasing hormone alone treatment

    PubMed Central

    Taktaz, T.; Kafi, M.; Mokhtari, Adel; Heidari, M.

    2015-01-01

    Aim: Bovine ovarian cysts are a common cause of economic loss in modern dairy herds. The objective of the present study was to evaluate the reproductive responses to three protocols using hCG, GnRH and cloprostenol when the definite diagnosis of the type of ovarian cyst is/is not possible in dairy cows. Materials and Methods: A total of 144 lactating dairy cows with ovarian cysts were divided into three groups. At diagnosis (Day 0), cows in Group 1 (the conventional method, n=47) were injected with 0.02 mg of a GnRH analogue i.m. (Buserelin); cows in Group 2 (n=47) were intramuscularly treated with 0.02 mg Buserelin plus 500 µg cloprostenol; and cows in Group 3 (n=50) were intramuscularly treated with 1500 IU hCG plus 500 µg cloprostenol. All cows received 500 µg cloprostenol intramuscularly on Day 10. Results: No statistically significant differences were found in the recovery time, interval to conception, conception rate at first AI, and pregnancy rates by Days 70 and 100 after treatment among the three groups. Conclusions: Simultaneous treatment of ovarian cysts with hCG or GnRH and cloprostenol appeared to have no advantage over the conventional method, GnRH alone, in dairy cows. Furthermore, hCG and GnRH have an equal therapeutic effect in cows with ovarian cysts. PMID:27047149

  15. Effects of supra-physiological changes in human ovarian hormone levels on maximum force production of the first dorsal interosseus muscle.

    PubMed

    Elliott, Kirsty Jayne; Cable, Nigel Timothy; Reilly, Thomas; Sefton, Victoria; Kingsland, Charles; Diver, Michael

    2005-03-01

    The purpose of this study was to investigate the effects of supra-physiological changes in ovarian hormone levels on maximum force production in two conditions, one physiological (pregnancy) and one pseudo-physiological (in vitro fertilization (IVF) treatment). Forty IVF patients were tested at four distinct stages of treatment and 35 women were tested during each trimester of pregnancy and following parturition. Maximum voluntary isometric force per unit cross-sectional area of the first dorsal interosseus muscle was measured. Plasma concentrations of total and bioavailable oestradiol and testosterone were measured, in addition to the total concentrations of progesterone and human chorionic gonadotropin. Despite significant changes in the concentrations of total progesterone, 17beta-oestradiol, bioavailable oestradiol and testosterone between phases, strength did not change significantly throughout IVF treatment (1.30+/-0.29, 1.16+/-0.38, 1.20+/-0.29 and 1.26+/-0.34 N mm-2, respectively, in the 4 phases of IVF treatment). Force production was significantly higher during the second trimester of pregnancy than following childbirth (1.33+/-0.20 N mm-2 at week 12 of pregnancy, 1.51+/-0.42 N mm-2 at week 20, 1.15+/-0.26 N mm-2 at week 36 and 0.94+/-0.31 N mm-2 at week 6 postnatal) but was not significantly correlated with any of the hormones measured. These data suggest that extreme changes in the concentrations of reproductive hormones do not affect the maximum force-generating capacity of young women.

  16. In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer

    PubMed Central

    Aird, R E; Cummings, J; Ritchie, A A; Muir, M; Morris, R E; Chen, H; Sadler, P J; Jodrell, D I

    2002-01-01

    Ruthenium complexes offer the potential of reduced toxicity, a novel mechanism of action, non-cross resistance and a different spectrum of activity compared to platinum containing compounds. Thirteen novel ruthenium(II) organometallic arene complexes have been evaluated for activity (in vitro and in vivo) in models of human ovarian cancer, and cross-resistance profiles established in cisplatin and multi-drug-resistant variants. A broad range of IC50 values was obtained (0.5 to >100 μM) in A2780 parental cells with two compounds (RM175 and HC29) equipotent to carboplatin (6 μM), and the most active compound (HC11) equipotent to cisplatin (0.6 μM). Stable bi-dentate chelating ligands (ethylenediamine), a more hydrophobic arene ligand (tetrahydroanthracene) and a single ligand exchange centre (chloride) were associated with increased activity. None of the six active ruthenium(II) compounds were cross-resistant in the A2780cis cell line, demonstrated to be 10-fold resistant to cisplatin/carboplatin by a mechanism involving, at least in part, silencing of MLH1 protein expression via methylation. Varying degrees of cross-resistance were observed in the P-170 glycoprotein overexpressing multi-drug-resistant cell line 2780AD that could be reversed by co-treatment with verapamil. In vivo activity was established with RM175 in the A2780 xenograft together with non-cross-resistance in the A2780cis xenograft and a lack of activity in the 2780AD xenograft. High activity coupled to non cross-resistance in cisplatin resistant models merit further development of this novel group of anticancer compounds. British Journal of Cancer (2002) 86, 1652–1657. DOI: 10.1038/sj/bjc/6600290 www.bjcancer.com © 2002 Cancer Research UK PMID:12085218

  17. Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer.

    PubMed

    Mariya, Tasuku; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Asano, Takuya; Kuroda, Takafumi; Yasuda, Kazuyo; Mizuuchi, Masahito; Sonoda, Tomoko; Saito, Tsuyoshi; Sato, Noriyuki

    2014-12-01

    Epithelial ovarian cancer (EOC) is one of the most deadly carcinomas in females. Immune systems can recognize EOCs; however, a defect of human leukocyte antigen (HLA) class I expression is known to be a major mechanism for escape from immune systems, resulting in poor prognosis. The purpose of this study is to identify novel correlations between immunologic responses and other clinical factors. We investigated the expression of immunologic components in 122 cases of EOCs for which surgical operations were performed between 2001 and 2011. We immunohistochemically stained EOC specimens using an anti-pan HLA class I monoclonal antibody (EMR8-5) and anti-CD3, -CD4, and -CD8 antibodies, and we analyzed correlations between immunologic parameters and clinical factors. In multivariate analysis that used the Cox proportional hazards model, independent prognostic factors for overall survival in advanced EOCs included low expression level of HLA class I [risk ratio (RR), 1.97; 95% confidence interval (CI), 1.01-3.83; P = 0.046] and loss of intraepithelial cytotoxic T lymphocyte (CTL) infiltration (RR, 2.11; 95% CI, 1.06-4.20; P = 0.033). Interestingly, almost all platinum-resistant cases showed a significantly low rate of intraepithelial CTL infiltration in the χ(2) test (positive vs. negative: 9.0% vs. 97.7%; P < 0.001). Results from a logistic regression model revealed that low CTL infiltration rate was an independent factor of platinum resistance in multivariate analysis (OR, 3.77; 95% CI, 1.08-13.12; P = 0.037). Platinum-resistant EOCs show poor immunologic responses. The immune escape system of EOCs may be one of the mechanisms of platinum resistance.

  18. Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor α and β for improved detection of estrogenic/antiestrogenic chemicals.

    PubMed

    Brennan, Jennifer C; Bassal, Arzoo; He, Guochun; Denison, Michael S

    2016-01-01

    Estrogenic endocrine-disrupting chemicals are found in environmental and biological samples, commercial and consumer products, food, and numerous other sources. Given their ubiquitous nature and potential for adverse effects, a critical need exists for rapidly detecting these chemicals. The authors developed an estrogen-responsive recombinant human ovarian (BG1Luc4E2) cell line recently accepted by the US Environmental Protection Agency (USEPA) and Organisation for Economic Co-operation and Development (OECD) as a bioanalytical method to detect estrogen receptor (ER) agonists/antagonists. Unfortunately, these cells appear to contain only 1 of the 2 known ER isoforms, ERα but not ERβ, and the differential ligand selectivity of these ERs indicates that the currently accepted screening method only detects a subset of total estrogenic chemicals. To improve the estrogen screening bioassay, BG1Luc4E2 cells were stably transfected with an ERβ expression plasmid and positive clones identified using ERβ-selective ligands (genistein and Br-ERβ-041). A highly responsive clone (BG1LucERβc9) was identified that exhibited greater sensitivity and responsiveness to ERβ-selective ligands than BG1Luc4E2 cells, and quantitative reverse-transcription polymerase chain reaction confirmed the presence of ERβ expression in these cells. Screening of pesticides and industrial chemicals identified chemicals that preferentially stimulated ERβ-dependent reporter gene expression. Together, these results not only demonstrate the utility of this dual-ER recombinant cell line for detecting a broader range of estrogenic chemicals than the current BG1Luc4E2 cell line, but screening with both cell lines allows identification of ERα- and ERβ-selective chemicals. PMID:26139245

  19. Sheep stromal-epithelial cell interactions and ovarian tumor progression.

    PubMed

    Wang-Johanning, Feng; Huang, Miao; Liu, Jinsong; Rycaj, Kiera; Plummer, Joshua B; Barnhart, Kirstin F; Satterfield, William C; Johanning, Gary L

    2007-11-15

    Previous studies suggest that underlying ovarian stromal cues may regulate the ovarian surface epithelium. However, little is known about the interaction between ovarian stromal cells (OSC) and ovarian surface epithelial cells (OSE) under normal physiologic and pathologic conditions, largely because of the lack of a suitable model. In the current study, the OSC obtained from a sheep were immortalized with SV-40 T/t antigen (designated IOSC) and telomerase reverse transcriptase (designated IOSCH), followed by transfection with the oncogenic allele of the human H-Ras oncogene (designated IOSChR). IOSC cells transfected with H-Ras before immortalization with telomerase were designated IOSCRH. These sheep OSCs were used in both in vitro and in vivo model systems to evaluate mechanisms by which OSCs influence ovarian tumor progression. Normal sheep OSCs were found to inhibit the growth of SKOV3 and OVCAR3 human ovarian cancer cells, but not normal sheep OSE and human OSE cells (hOSE137 cells). In contrast, IOSChR and IOSCRH cells stimulated the growth of normal sheep and human OSE cells, as well as cancer cells. These findings were confirmed by in vivo studies. Our data provide compelling support for the importance of stromal-epithelial cell interactions during tumor progression, and show for the first time that immortalized and transformed OSCs promote growth of ovarian epithelial tumors.

  20. 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

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

    ClinicalTrials.gov

    2016-07-08

    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

  2. Ovarian tissue characterization using bulk optical properties

    NASA Astrophysics Data System (ADS)

    Tavakoli, B.; Xu, Y.; Zhu, Q.

    2013-03-01

    Ovarian cancer, the deadliest of all gynecologic cancers, is not often found in its early stages due to few symptoms and no reliable screening test. Optical imaging has a great potential to improve the ovarian cancer detection and diagnosis. In this study we have characterized the bulk optical properties of 26 ex-vivo human ovaries using a Diffuse Optical Tomography system. The quantitative values indicated that, in the postmenopausal group, malignant ovaries showed significantly lower scattering coefficient than normal ones. The scattering parameter is largely related to the collagen content that has shown a strong correlation with the cancer development.

  3. Can Ovarian Cancer Be Found Early?

    MedlinePlus

    ... Topic Signs and symptoms of ovarian cancer Can ovarian cancer be found early? About 20% of ovarian cancers ... cancer in its earliest stage. Ways to find ovarian cancer early Regular women's health exams During a pelvic ...

  4. Facile Synthesis of cis-Dichloro-(1,4,7-Triazacyclononane) Platinum(II) and its Screening Against Human Ovarian Cancer (SK-OV-3) and Leukemia (K-562) Cell Lines

    PubMed Central

    Murnaghan, Aleisha M.

    2002-01-01

    A simple method for the preparation of cis-dichloro(1,4,7-triazacyclononane)platinum(II), cis-Pt(tacn)Cl2 is presented, together with the results of screening the compound against the K-562 (leukemia) and SK-OV-3 (ovarian) human cancer cell lines. While the compound shows no activity against K-562 cells, there is evidence for some cytotoxicity against SK-OV-3. The compound is much less effective than cisplatin, and its limited solubility restricts the useable concentration range. PMID:18475426

  5. Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model

    PubMed Central

    Chang, De-Kuan; Peterson, Eric; Sun, Jiusong; Goudie, Calum; Drapkin, Ronny I.; Liu, Joyce F.; Matulonis, Ursula; Zhu, Quan; Marasco, Wayne A.

    2016-01-01

    ABSTRACT Recent studies have demonstrated that regulatory T cells (Tregs) are recruited to tumor sites where they can suppress antitumor immunity. The chemokine receptor CCR4 is expressed at high levels on functional CD4+CD25+FoxP3+ Tregs and production of the CCR4 ligand CCL22 by tumor cells and tumor-associated macrophages is associated with Treg recruitment to the tumor site. Here, we tested IgG1 and IgG4 isotypes of human anti-CCR4 mAb2-3 for their in vitro activity and in vivo capacity in a NSG mouse model bearing CCL22-secreting ovarian cancer (OvCA) xenograft to modulate Tregs and restore antitumor activity. Both mAb2-3 isotypes blocked in vitro chemoattraction of Tregs to CCL22-secreting OvCA cells. However, they differed in their in vivo mode of action with IgG1 causing Treg depletion and IgG4 blocking migration to the tumors. Primary T cells that were primed with OvCA-pulsed dendritic cells (DCs) demonstrated INFγ secretion that could be enhanced through Treg depletion by mAb2-3. Humanized mice reconstructed with allogeneic tumor-primed T cells (TP-T) were used to evaluate the restoration of OvCA immunity by depletion or blockade of Tregs with mAb2-3. We observed that IgG1 was more potent than IgG4 in inhibiting tumor growth. Mechanism studies demonstrated that mAb2-3 treatment lead to inhibition of IL-2 binding to its receptor. Further studies showed that mAb2-3 induced CD25 shedding (sCD25) from Tregs which lead to a decrease in IL-2-dependent survival. Together, the results demonstrate that mAb2-3 is an agonist antibody that can restore anti-OvCA immunity through modulation of Treg activity. PMID:27141347

  6. Preclinical evaluation of light-activatable, bispecific anti-human CD3 antibody conjugates as anti-ovarian cancer therapeutics

    PubMed Central

    Dessi, John

    2009-01-01

    The administration of anti-CD3 antibodies, either unmodified or in bispecific formats, has been shown to kill tumors. However, their activity needs to be carefully controlled. We have approached this problem by inhibiting their anti-CD3 activity until it is required. Folated anti-human CD3 antibody bispecific conjugates were therefore synthesised in which the folate portion of the conjugates remained free to bind to folate receptor (FR) expressing cancer cells, whilst their anti-CD3 activity was reversibly inhibited. On irradiation with UV-A light, the T-cell binding activity of the anti-CD3 antibody can be restored only when and where it is required, i.e., adjacent to a tumor. Conjugate bound to FR expressed on normal tissues in other parts of the body remains inactive. This report describes the preclinical in vivo testing of these conjugates in transgenic mice whose T-cells express human CD3 molecules. When the ‘cloaked’ conjugates were reactivated in the region of the primary tumor, both primary tumor growth and liver metastasis were markedly reduced. That the deliberate targeting of T-cell activity locally to the primary tumor also resulted in reduced distant metastatic growth was a key finding. Light-activatable bispecific antibody conjugates similar to those described here offer a means to control T-cell targeting with a much higher degree of specificity to tumors because they minimize potentially dangerous and unwanted side effects in non-illuminated areas. The addition of light-specific targeting to the inherent tumor specific targeting of therapeutic antibody conjugates could result in the development of safer treatments for patients. PMID:20068406

  7. Hemoglobin: a gas transport molecule that is hormonally regulated in the ovarian follicle in mice and humans.

    PubMed

    Brown, Hannah M; Anastasi, Marie R; Frank, Laura A; Kind, Karen L; Richani, Dulama; Robker, Rebecca L; Russell, Darryl L; Gilchrist, Robert B; Thompson, Jeremy G

    2015-01-01

    An increasing number of nonerythroid tissues are found to express hemoglobin mRNA and protein. Hemoglobin is a well-described gas transport molecule, especially for O2, but also for NO, CO2, and CO, and also acts as a reactive oxygen species scavenger. We previously found Hba-a1 and Hbb mRNA and protein at high levels within mouse periovulatory cumulus cells, but not in cumulus following in vitro maturation. This led us to investigate the temporal and spatial regulation in follicular cells during the periovulatory period. Cumulus-oocyte complexes were collected from equine chorionic gonadotropin/human chorionic gonadotropin-treated peripubertal SV129 female mice and collected and analyzed for gene expression and protein localization at a variety of time points over the periovulatory period. A further cohort matured in vitro with different forms of hemoglobin (ferro- and ferrihemoglobin) under different O2 atmospheric conditions (2%, 5%, and 20% O2) were subsequently fertilized in vitro and cultured to the blastocyst stage. Murine mRNA transcripts for hemoglobin were regulated by stimulation of the ovulatory cascade, in both granulosa and cumulus cells, and expression of HBA1 and HBB was highly significant in human granulosa and cumulus, but erythrocyte cell marker genes were not. Several other genes involved in hemoglobin function were similarly luteinizing hormone-regulated, including genes for heme biosynthesis. Immunohistochemistry revealed a changing localization pattern of HBA-A1 protein in murine cumulus cells and oocytes following the ovulatory signal. Significantly, no positive staining for HBA-A1 protein was observed within in vitro-matured oocytes, but, if coincubated with ferro- or ferrihemoglobin, cytoplasmic HBA-A1 was observed, similar to in vivo-derived oocytes. Addition of ferro-, but not ferrihemoglobin, had a small, positive effect on blastocyst yield, but only under either 2% or 20% O2 gas atmosphere. The identification of hemoglobin within

  8. The pro-social neurohormone oxytocin reverses the actions of the stress hormone cortisol in human ovarian carcinoma cells in vitro.

    PubMed

    Mankarious, Amanda; Dave, Foram; Pados, George; Tsolakidis, Dimitris; Gidron, Yori; Pang, Yefei; Thomas, Peter; Hall, Marcia; Karteris, Emmanouil

    2016-05-01

    The journey patients with ovarian cancer travel from non-specific symptoms causing delayed diagnosis through surgery and chemotherapy, culminating in a 5-year survival rate of 43%, must have a profound and detrimental psychological impact on patients. Emerging studies link higher levels of oxytocin (OT) and increased social support, an independent prognostic factor in cancer, with a moderating effect on stress. In contrast, there is a known association of tumour cell proliferation with elevated cortisol (stress hormone) levels. We hypothesise therefore that there is cross-talk between cortisol and oxytocin at a molecular level. Three ovarian cancer cell lines, used as in vitro models, were treated with cortisol at concentrations mimicking physiological stress in vivo in the presence or absence of OT. OT reduced cell proliferation and migration, induced apoptosis and autophagy for all three cell lines, partially reversing the effects of cortisol. Quantitative RT-PCR of tissue taken from ovarian cancer patients revealed that the glucocorticoid receptor (splice variant GR-P) and OT receptor (OTR) were significantly upregulated compared to controls. Tissue microarray revealed that the expression of GRα was lower in the ovarian cancer samples compared to normal tissue. OT is also shown to drive alternative splicing of the GR gene and cortisol-induced OTR expression. OT was able to transactivate GR in the presence of cortisol, thus providing further evidence of cross-talk in vitro. These data provide explanations for why social support might help distressed ovarian cancer patients and help define novel hypotheses regarding potential therapeutic interventions in socially isolated patients. PMID:26935408

  9. Low expression of the X-linked ribosomal protein S4 in human serous epithelial ovarian cancer is associated with a poor prognosis

    PubMed Central

    2013-01-01

    Background The X-linked ribosomal protein S4 (RPS4X), which is involved in cellular translation and proliferation, has previously been identified as a partner of the overexpressed multifunctional protein YB-1 in several breast cancer cells. Depletion of RPS4X results in consistent resistance to cisplatin in such cell lines. Methods As platinum-based chemotherapy is a standard first line therapy used to treat patients with ovarian cancer, we evaluated the prognostic value of RPS4X and YB-1 at the protein level in specimen from 192 high-grade serous epithelial ovarian cancer patients. Results Immunohistochemistry studies indicated that high expression of RPS4X was associated with a lower risk of death and later disease progression (HR = 0.713, P = 0.001 and HR = 0.761, P = 0.001, respectively) as compared to low expression of RPS4X. In contrast, YB-1 was not significantly associated with either recurrence or survival time in this cohort. Finally, the depletion of RPS4X with different siRNAs in two different ovarian cancer cell lines reduced their proliferative growth rate but more importantly increased their resistance to cisplatin. Conclusion Altogether, these results suggest that the levels of RPS4X could be a good indicator for resistance to platinum-based therapy and a prognostic marker for ovarian cancer. Our study also showed that RPS4X is an independent prognostic factor in patients with serous epithelial ovarian cancer. PMID:23800275

  10. The pro-social neurohormone oxytocin reverses the actions of the stress hormone cortisol in human ovarian carcinoma cells in vitro

    PubMed Central

    MANKARIOUS, AMANDA; DAVE, FORAM; PADOS, GEORGE; TSOLAKIDIS, DIMITRIS; GIDRON, YORI; PANG, YEFEI; THOMAS, PETER; HALL, MARCIA; KARTERIS, EMMANOUIL

    2016-01-01

    The journey patients with ovarian cancer travel from non-specific symptoms causing delayed diagnosis through surgery and chemotherapy, culminating in a 5-year survival rate of 43%, must have a profound and detrimental psychological impact on patients. Emerging studies link higher levels of oxytocin (OT) and increased social support, an independent prognostic factor in cancer, with a moderating effect on stress. In contrast, there is a known association of tumour cell proliferation with elevated cortisol (stress hormone) levels. We hypothesise therefore that there is cross-talk between cortisol and oxytocin at a molecular level. Three ovarian cancer cell lines, used as in vitro models, were treated with cortisol at concentrations mimicking physiological stress in vivo in the presence or absence of OT. OT reduced cell proliferation and migration, induced apoptosis and autophagy for all three cell lines, partially reversing the effects of cortisol. Quantitative RT-PCR of tissue taken from ovarian cancer patients revealed that the glucocorticoid receptor (splice variant GR-P) and OT receptor (OTR) were significantly upregulated compared to controls. Tissue microarray revealed that the expression of GRα was lower in the ovarian cancer samples compared to normal tissue. OT is also shown to drive alternative splicing of the GR gene and cortisol-induced OTR expression. OT was able to transactivate GR in the presence of cortisol, thus providing further evidence of cross-talk in vitro. These data provide explanations for why social support might help distressed ovarian cancer patients and help define novel hypotheses regarding potential therapeutic interventions in socially isolated patients. PMID:26935408

  11. Upregulation of steroidogenic enzymes and ovarian 17beta-estradiol in human granulosa-lutein cells by Cordyceps sinensis mycelium.

    PubMed

    Huang, Bu-Miin; Hsiao, Kuei-Yang; Chuang, Pei-Chin; Wu, Meng-Hsing; Pan, Hsien-An; Tsai, Shaw-Jenq

    2004-05-01

    There is increasing evidence that 17beta-estradiol (E2) directly influences the quality of maturing oocytes and thus the outcome of assisted reproduction treatment. Although Cordyceps sinensis (CS) mycelium, a Chinese herbal medicine, is believed to enhance libido and fertility in both sexes, the mechanism of its effect in women has not been determined. The aim of the present study was to evaluate the effects of CS on steroidogenic enzyme expression and E2 biosynthesis in human granulosa-lutein cells (GLC). We found that CS induced E2 production by GLC in a dose- and time-dependent manner and that a 3-h treatment with CS induced increased levels of mRNAs coding for the P450 side chain cleavage enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and aromatase. Western blot analysis demonstrated that, after treatment with CS for 3 h, protein levels of steroidogenic acute regulatory protein (StAR) and aromatase were upregulated while P450scc and 3beta-HSD levels showed no substantial change. New protein synthesis was required for CS-induced E2 production because it was abrogated by cycloheximide pretreatment. Addition of 22(R)-hydroxycholesterol, thus bypassing the need for StAR protein, did not induce as much E2 production as CS treatment, indicating that upregulation of StAR protein was not the only factor contributing to CS-induced steroidogenesis. Cotreatment of GLCs with CS and aminoglutethimide, an aromatase inhibitor, completely abolished CS-induced E2 production. In conclusion, treatment of GLCs with CS results in increased E2 production due, at least in part, to increased StAR and aromatase expression. These data may help in the development of treatment regimens to improve the success rate of in vitro fertilization. PMID:14711788

  12. Ovarian and Adrenal Androgens and Their Link to High Human Chorionic Gonadotropin Levels: A Prospective Controlled Study

    PubMed Central

    Rodríguez-Gutiérrez, René; Villarreal-Pérez, Jesús Zacarías; Morales-Martinez, Felipe Arturo; Rodríguez-Guajardo, René; González-Saldivar, Gloria; Mancillas-Adame, Leonardo G.; Alvarez-Villalobos, Neri Alejandro; Lavalle-Gonzalez, Fernando Javier; González-González, José Gerardo

    2014-01-01

    Background. Although the association between human chorionic gonadotropin (hCG) and hyperandrogenism was identified more than 40 years ago, relevant questions remain unanswered. Design and Methods. We conducted a prospective, longitudinal, and controlled study in 23 women with a diagnosis of a complete hydatidiform mole (HM). Results. All participants completed the study. Before HM evacuation mean hCG was markedly higher in the cases than in the control group (P ≤ 0.001). Free testosterone (T) and dehydroepiandrosterone sulfate (DHEA-S) were found to be higher in the cases (2.78 ± 1.24 pg/mL and 231.50 ± 127.20 μ/dL) when compared to the control group (1.50 ± 0.75 pg/mL and 133.59 ± 60.69 μ/dL) (P = 0.0001 and 0.001), respectively. There was a strong correlation between hCG and free T/total T/DHEA-S concentrations (r = 0.78; P ≤ 0.001, r = 0.74;  P ≤ 0.001, and r = 0.71;  P ≤ 0.001), respectively. In the cases group 48 hours after HM evacuation, hCG levels were found to be significantly lower when compared to initial levels (P = 0.001) and free T and DHEA-S declined significantly (P = 0.0002 and 0.009). Conclusion. Before uterus evacuation, hCG, free T, and DHEA-S levels were significantly higher when compared with controls finding a strong correlation between hCG and free T/DHEA-S levels. Forty-eight hours after HM treatment hCG levels declined and the difference was lost. A novel finding of our study is that in cases, besides free T, DHEA-S was also found to be significantly higher and both the ovaries and adrenal glands appear to be the sites of this androgen overproduction. PMID:25505909

  13. Ovarian and adrenal androgens and their link to high human chorionic gonadotropin levels: a prospective controlled study.

    PubMed

    Rodríguez-Gutiérrez, René; Villarreal-Pérez, Jesús Zacarías; Morales-Martinez, Felipe Arturo; Rodríguez-Guajardo, René; González-Saldivar, Gloria; Mancillas-Adame, Leonardo G; Alvarez-Villalobos, Neri Alejandro; Lavalle-Gonzalez, Fernando Javier; González-González, José Gerardo

    2014-01-01

    Background. Although the association between human chorionic gonadotropin (hCG) and hyperandrogenism was identified more than 40 years ago, relevant questions remain unanswered. Design and Methods. We conducted a prospective, longitudinal, and controlled study in 23 women with a diagnosis of a complete hydatidiform mole (HM). Results. All participants completed the study. Before HM evacuation mean hCG was markedly higher in the cases than in the control group (P ≤ 0.001). Free testosterone (T) and dehydroepiandrosterone sulfate (DHEA-S) were found to be higher in the cases (2.78 ± 1.24 pg/mL and 231.50 ± 127.20 μ/dL) when compared to the control group (1.50 ± 0.75 pg/mL and 133.59 ± 60.69 μ/dL) (P = 0.0001 and 0.001), respectively. There was a strong correlation between hCG and free T/total T/DHEA-S concentrations (r = 0.78; P ≤ 0.001, r = 0.74;  P ≤ 0.001, and r = 0.71;  P ≤ 0.001), respectively. In the cases group 48 hours after HM evacuation, hCG levels were found to be significantly lower when compared to initial levels (P = 0.001) and free T and DHEA-S declined significantly (P = 0.0002 and 0.009). Conclusion. Before uterus evacuation, hCG, free T, and DHEA-S levels were significantly higher when compared with controls finding a strong correlation between hCG and free T/DHEA-S levels. Forty-eight hours after HM treatment hCG levels declined and the difference was lost. A novel finding of our study is that in cases, besides free T, DHEA-S was also found to be significantly higher and both the ovaries and adrenal glands appear to be the sites of this androgen overproduction.

  14. Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.

    PubMed

    Hover, Laura D; Young, Christian D; Bhola, Neil E; Wilson, Andrew J; Khabele, Dineo; Hong, Charles C; Moses, Harold L; Owens, Philip

    2015-11-01

    The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.

  15. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells

    PubMed Central

    Kalayda, Ganna V; Wagner, Christina H; Buß, Irina; Reedijk, Jan; Jaehde, Ulrich

    2008-01-01

    Background Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Methods Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of < 0.05 were considered significant. Results In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Conclusion Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant

  16. Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers

    PubMed Central

    Herter, Sylvia; Piper, Derek E.; Aaron, Wade; Gabriele, Timothy; Cutler, Gene; Cao, Ping; Bhatt, Ami S.; Choe, Youngchool; Craik, Charles S.; Walker, Nigel; Meininger, David; Hoey, Timothy; Austin, Richard J.

    2005-01-01

    Hepsin is a membrane-anchored, trypsin-like serine protease with prominent expression in the human liver and tumours of the prostate and ovaries. To better understand the biological functions of hepsin, we identified macromolecular substrates employing a tetrapeptide PS-SCL (positional scanning-synthetic combinatorial library) screen that rapidly determines the P1–P4 substrate specificity. Hepsin exhibited strong preference at the P1 position for arginine over lysine, and favoured threonine, leucine or asparagine at the P2, glutamine or lysine at the P3, and proline or lysine at the P4 position. The relative activity of hepsin toward individual AMC (7-amino-4-methylcoumarin)-tetrapeptides was generally consistent with the overall peptide profiling results derived from the PC-SCL screen. The most active tetrapeptide substrate Ac (acetyl)-KQLR-AMC matched with the activation cleavage site of the hepatocyte growth factor precursor sc-HGF (single-chain HGF), KQLR↓VVNG (where ↓ denotes the cleavage site), as identified by a database analysis of trypsin-like precursors. X-ray crystallographic studies with KQLR chloromethylketone showed that the KQLR peptide fits well into the substrate-binding cleft of hepsin. This hepsin-processed HGF induced c-Met receptor tyrosine phosphorylation in SKOV-3 ovarian cancer cells, indicating that the hepsin-cleaved HGF is biologically active. Activation cleavage site mutants of sc-HGF with predicted non-preferred sequences, DPGR↓VVNG or KQLQ↓VVNG, were not processed, illustrating that the P4–P1 residues can be important determinants for substrate specificity. In addition to finding macromolecular hepsin substrates, the extracellular inhibitors of the HGF activator, HAI-1 and HAI-2, were potent inhibitors of hepsin activity (IC50 4±0.2 nM and 12±0.5 nM respectively). Together, our findings suggest that the HGF precursor is a potential in vivo substrate for hepsin in tumours, where hepsin expression is dysregulated and may

  17. Xenobiotic Effects on Ovarian Preantral Follicles1

    PubMed Central

    Mark-Kappeler, Connie J.; Hoyer, Patricia B.; Devine, Patrick J.

    2011-01-01

    Women are born with a finite population of ovarian follicles, which are slowly depleted during their reproductive years until reproductive failure (menopause) occurs. The rate of loss of primordial follicles is determined by genetic and environmental influences, but certain toxic exposures can accelerate this process. Ionizing radiation reduces preantral follicle numbers in rodents and humans in a dose-dependent manner. Cigarette smoking is linked to menopause occurring 1–4 yr earlier than with nonsmokers, and components of smoke, polycyclic aromatic hydrocarbons, can cause follicle depletion in rodents or in ovaries in vitro. Chemotherapeutic agents, such as alkylating drugs and cisplatin, also cause loss of preantral ovarian follicles. Effects depend on dose, type, and reactivity of the drug, and the age of the individual. Evidence suggests DNA damage may underlie follicle loss induced by one common alkylating drug, cyclophosphamide. Occupational exposures have also been linked to ovarian damage. In an industrial setting, 2-bromopropane caused infertility in men and women, and it can induce ovarian follicle depletion in rats. Solvents, such as butadiene, 4-vinylcyclohexene, and their diepoxides, can also cause specific preantral follicle depletion. The mechanism(s) underlying effects of the latter compound may involve alterations in apoptosis, survival factors such as KIT/Kit Ligand, and/or the cellular signaling that maintains primordial follicle dormancy. Estrogenic endocrine disruptors may alter follicle formation/development and impair fertility or normal development of offspring. Thus, specific exposures are known or suspected of detrimentally impacting preantral ovarian follicles, leading to early ovarian failure. PMID:21697514

  18. Overexpression of TAZ promotes cell proliferation, migration and epithelial-mesenchymal transition in ovarian cancer

    PubMed Central

    Chen, Guangyuan; Xie, Jiabin; Huang, Ping; Yang, Zhihong

    2016-01-01

    The Hippo pathway is dysregulated in multiple types of human cancer, including ovarian cancer. Nuclear expression of yes-associated protein 1 (YAP1), a downstream transcription coactivator of the Hippo pathway, has been demonstrated to promote tumorigenesis in ovarian cancer and may serve as a poor prognostic indicator. However, transcriptional coactivator with PDZ binding motif (TAZ), a downstream target of the Hippo pathway and paralog of YAP in mammalian cells, has not been fully investigated in ovarian cancer. The present study aimed to investigate the dysregulation and biological function of TAZ in ovarian cancer. Reverse transcription-quantitative polymerase chain reaction and western blotting revealed that TAZ mRNA and protein levels, respectively, were upregulated in ovarian cancer, and a meta-analysis of ovarian cancer microarray datasets identified that increased expression of TAZ mRNA is correlated with poor prognosis in patients with ovarian cancer. In addition, TAZ-knockdown in ovarian cancer cells demonstrated that TAZ regulates the migration, proliferation and epithelial-mesenchymal transition of ovarian cancer cells. Furthermore, pharmacological disruption of the YAP/TAZ/TEA domain protein complex resulted in a decrease in ovarian cancer cell migration, proliferation and vimentin expression. The results of the present study indicate that the overexpression of TAZ is important in the development and progression of ovarian cancer, and may function as a potential drug target for treatment of this disease entity. PMID:27588129

  19. [Ovarian surface epithelium and its histogenic relation to ovarian cancer].

    PubMed

    Dietl, J; Buchholz, F; Stoll, P

    1986-09-01

    Approximately 80 to 90 per cent of adult ovarian cancers are assumed to originate from ovarian surface cells. A series of morphological and biochemical studies has been recently conducted to test this. The ovarian surface epithelium shows permanent morphological changes such as crypts, inclusion cysts, villous processes and different forms of müllerian epithelium. The unique nature of ovarian surface changes and their abrupt disappearance in immediately adjacent mesothelia suggest that local factors may play an important part in modifying the growth and morphogenesis of the epithelium of the ovarian surface. Whether these endogenous and/or exogenous factors may also induce surface neoplasia is a moot point.

  20. Inhibition of the long non-coding RNA MALAT1 suppresses tumorigenicity and induces apoptosis in the human ovarian cancer SKOV3 cell line

    PubMed Central

    LIU, SHIPING; JIANG, XUAN; LI, WEIHUA; CAO, DONGYAN; SHEN, KENG; YANG, JIAXIN

    2016-01-01

    Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a 8,000 nucleotide-long, spliced non-coding RNA, which has been reported to be deregulated in several tumors. However, to the best of our knowledge, the role of MALAT1 in ovarian cancer has not been previously investigated. The aim of the present study was to investigate the effect of MALAT1 inhibition on the tumorigenity of SKOV3 cells. First, stable MALAT1-knockdown ovarian cancer cells and control cells were established using lentivirus-mediated artificial micro RNA interference in order to investigate the effect of MALAT1 inhibition on cell viability, clonability, migration, invasion and apoptosis in vitro. In addition, the effect of MALAT1 on cell growth in nude mice was assessed. To identify the possible targets of MALAT1, total RNA was extracted from MALAT1-knockdown cells and control cells and a microarray analysis was performed. The results showed that MALAT1 inhibition significantly suppressed tumorigenity in vitro and in vivo (P<0.01). Compared with the control cells, 921 genes in the MALAT1-knockdown cells were deregulated by at least two-fold. The results of the reverse transcription-quantitative polymerase chain reaction showed that 19 of the 20 genes selected for validation confirmed the deregulation indicated by the microarray analysis. The findings define a major oncogenic role for MALAT1, which may offer an attractive novel target for therapeutic intervention in ovarian cancer. PMID:27313681

  1. Sulforaphane induced cell cycle arrest in the G2/M phase via the blockade of cyclin B1/CDC2 in human ovarian cancer cells

    PubMed Central

    2013-01-01

    Background Malignant tumors are the single most common cause of death and the mortality rate of ovarian cancer is the highest among gynecological disorders. The excision of benign tumors is generally followed by complete recovery; however, the activity of cancer cells often results in rapid proliferation even after the tumor has been excised completely. Thus, clinical treatment must be supplemented by auxiliary chemotherapy or radiotherapy. Sulforaphane (SFN) is an extract from the mustard family recognized for its anti-oxidation abilities, phase 2 enzyme induction, and anti-tumor activity. Methods This study investigated the cell cycle arrest in G2/M by SFN and the expression of cyclin B1, Cdc2, and the cyclin B1/CDC2 complex in PA-1 cells using western blotting and co-IP western blotting. Results This study investigated the anticancer effects of dietary isothiocyanate SFN on ovarian cancer, using cancer cells line PA-1. SFN-treated cells accumulated in metaphase by CDC2 down-regulation and dissociation of the cyclin B1/CDC2 complex. Conclusion Our findings suggest that, in addition to the known effects on cancer prevention, SFN may also provide antitumor activity in established ovarian cancer. PMID:23799914

  2. Ovarian cancer, Part II: Treatment.

    PubMed

    Ozols, R F

    1992-01-01

    . Unfortunately, 30% to 50% of these patients will have recurrent disease; clinical trials are currently in progress to determine whether any form of therapy following the initial induction regimen can prevent or delay recurrences. Based on laboratory investigations in relevant models of human ovarian cancer, clinical trials are also in progress with novel new agents that may be capable of reversing drug resistance to platinum compounds and alkylating agents. For patients with germ cell tumors of the ovary, platinum-based combination chemotherapy has produced the same dramatic effects as in testicular cancer. Clinical trials are now focused on retaining therapeutic efficacy but decreasing the toxicity of treatment in these tumors that frequently affect women in their reproductive ages.

  3. Talc and ovarian cancer

    SciTech Connect

    Hartge, P.; Hoover, R.; Lesher, L.P.; McGowan, L.

    1983-01-01

    The potential link between epithelial talc use and ovarian cancer was examined in records of women treated for pathologically confirmed epitherial ovarian cancer. We estimated the relative risk to talc users as 0.7 (95% confidence interval (CI) = 0.4 to 1.1). The estimate was unaffected by adjustment for race, age, and gravidity. Neither women who used talc on their diaphragms nor those who used it as body powder seemed to be at excess risk. Our data thus indicate no overall association between talc use and risk of ovarian cancer. Although a small group of women who specifically reported genital use of body talcum powders showed an excess relative risk, use of talc on a diaphragm, which would be the closest exposure to the ovaries, did not seem to elevate risk.

  4. Ovarian Lymphoma and Hydronephrosis

    PubMed Central

    Bernardini, Luca; Angeloni, Moira; Gogna, Paolo; Intersimone, Donatella; Fedeli, Franco

    2013-01-01

    Introduction: Ovarian lymphoma is a rare entity, and hydronephrosis from lymphoma is even rarer. Most reports describe a laparoscopic approach to the disease, but we report a case of hydroureteronephrosis associated with ovarian lymphoma managed completely by mini-invasive techniques. Case Report: A 51-year-old woman was referred to us for back pain and renal colic and computed tomography scan findings of right hydroureteronephrosis and a mass in the right mesorectum and uterosacral ligament. After magnetic resonance imaging was performed, the patient underwent laparoscopic adnexectomy and ureterolysis after ureteroscopy and stenting. Histology results showed diffuse B-cell lymphoma of the ovary occluding the ureter without infiltration. The patient has undergone 6 cycles of chemotherapy. Discussion: This is the first report to describe ovarian lymphoma and hydroureteronephrosis managed completely by laparoscopic surgery and endoscopy. Frequency in clinical practice, differential diagnosis, and endoscopic approach are discussed. The advantages of a multidisciplinary endoscopic team are underlined. PMID:24398216

  5. Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor.

    PubMed

    Zhang, Ying; Wang, Jian; Xiang, Debing; Wang, Dong; Xin, Xiaoyan

    2009-11-01

    Resistance to platinum is a major limitation for the treatment of ovarian cancer. In an effort to overcome the platinum resistance problem in ovarian cancer treatment, we explored the correlation between cisplatin resistance and the human AP endonuclease (APE1 or Ref-1). APE1/Ref-1 is a multifunctional protein that is not only an essential enzyme in base excision repair pathway, but also acts as a major redox-signaling factor that has a wide variety of important cellular functions including transcription factor regulation, oxidative signaling and cell cycle control. In this study, we examined APE1/Ref-1 expression by immunohistochemistry in sections of ovarian cancers from 78 patients who were administered standard adjuvant chemotherapy based on platinum post-operatively. Altered levels and subcellular APE1/Ref-1 expression was found in patients not responding to platinum-based chemotherapy comparing with those who responded to platinum-based chemotherapy. Meanwhile, we detected the APE1/Ref-1 expression in A2780 and CP70 cell lines which have different sensitivity to cisplatin. We found similar altered APE1/Ref-1 expression in them. We hypothesized that the APE1/Ref-1 expression is responsible in part for the cisplatin resistance. To answer this hypothesis, we decreased the APE1/Ref-1 level by silencing RNA targeting technology in A2780 and CP70 cell lines. The A2780 cells treated with APE1-siRNA had IC50 values ranging from 6.70 to 1.74 microM cisplatin compared with 15.81 microM for control A2780 cells. The CP70 cells treated with APE1-siRNA had 1.62-4.63-fold enhancement in cisplatin sensitivity. The apoptosis assays using TUNEL analysis showed that decreased APE1/Ref-1 level resulted in increased apoptosis levels in A2780 and CP70 cell lines compared with the control-treated cells. These data suggest that APE1/Ref-1 levels play an important role in the sensitization of ovarian cancer cells to apoptosis. In vitro studies revealed that it is possible to

  6. Retropancreatic Ovarian Tumor.

    PubMed

    Acharya, Soumyo Ranjan; Dasgupta, Prosenjit; Das, Subhobroto; Halder, Sandip; Panda, Nilanjan

    2016-06-01

    Retroperitoneal mucinous cystadenomas are rare lesions (less than 50 reported) characterized by presence of ovary like stroma of unknown origin. However, germinal component of ovary has never been found in them. The pancreas occasionally gives rise to mucinous cystadenomas, but they are always intrapancreatic. We report a unique case of a rare retroperitoneal mucinous cystadenomas with presence of ovarian follicles in a 45-year-old lady who presented with an abdominal mass. This was successfully excised. Though retroperitoneal mucinous cystadenomas are rare, presence of ovarian follicle (germ cell) in them has never been reported before. PMID:27358520

  7. Three-photon imaging of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Barton, Jennifer K.; Amirsolaimani, Babak; Rice, Photini; Hatch, Kenneth; Kieu, Khanh

    2016-02-01

    Optical imaging methods have the potential to detect ovarian cancer at an early, curable stage. Optical imaging has the disadvantage that high resolution techniques require access to the tissue of interest, but miniature endoscopes that traverse the natural orifice of the reproductive tract, or access the ovaries and fallopian tubes through a small incision in the vagina wall, can provide a minimally-invasive solution. We have imaged both rodent and human ovaries and fallopian tubes with a variety of endoscope-compatible modalities. The recent development of fiber-coupled femtosecond lasers will enable endoscopic multiphoton microscopy (MPM). We demonstrated two- and three-photon excited fluorescence (2PEF, 3PEF), and second- and third-harmonic generation microscopy (SHG, THG) in human ovarian and fallopian tube tissue. A study was undertaken to understand the mechanisms of contrast in these images. Six patients (normal, cystadenoma, and ovarian adenocarcinoma) provided ovarian and fallopian tube biopsies. The tissue was imaged with three-dimensional optical coherence tomography, multiphoton microscopy, and frozen for histological sectioning. Tissue sections were stained with hematoxylin and eosin, Masson's trichrome, and Sudan black. Approximately 1 μm resolution images were obtained with an excitation source at 1550 nm. 2PEF signal was absent. SHG signal was mainly from collagen. 3PEF and THG signal came from a variety of sources, including a strong signal from fatty connective tissue and red blood cells. Adenocarcinoma was characterized by loss of SHG signal, whereas cystic abnormalities showed strong SHG. There was limited overlap of two- and three- photon signals, suggesting that three-photon imaging can provide additional information for early diagnosis of ovarian cancer.

  8. Ovarian adult stem cells: hope or pitfall?

    PubMed Central

    2014-01-01

    For many years, ovarian biology has been based on the dogma that oocytes reserve in female mammals included a finite number, established before or at birth and it is determined by the number and quality of primordial follicles developed during the neonatal period. The restricted supply of oocytes in adult female mammals has been disputed in recent years by supporters of postnatal neo-oogenesis. Recent experimental data showed that ovarian surface epithelium and cortical tissue from both mouse and human were proved to contain very low proportion of cells able to propagate themselves, but also to generate immature oocytes in vitro or in vivo, when transplanted into immunodeficient mice ovaries. By mentioning several landmarks of ovarian stem cell reserve and addressing the exciting perspective of translation into clinical practice as treatment for infertility pathologies, the purpose of this article is to review the knowledge about adult mammalian ovarian stem cells, a topic that, since the first approach quickly attracted the attention of both the scientific media and patients. PMID:25018783

  9. Orthotopic and heterotopic ovarian tissue transplantation

    PubMed Central

    Demeestere, I.; Simon, P.; Emiliani, S.; Delbaere, A.; Englert, Y.

    2009-01-01

    BACKGROUND Transplantation of ovarian tissue is, at present, the only clinical option available to restore fertility using cryopreserved ovarian tissue. More than 30 transplantations of cryopreserved tissue have been reported, and six babies have been born, worldwide, following this procedure. Despite these encouraging results, it is essential to optimize the procedure by improving the follicular survival, confirming safety and developing alternatives. Here, we review the different factors affecting follicular survival and growth after grafting. METHODS Relevant studies were identified by searching Pubmed up to January 2009 with English language limitation. The following key words were used: (ovarian tissue or whole ovary) AND (transplantation) AND (cryopreservation or pregnancy). Using the literature and personal experience, we examined relevant data on the different exogenous and clinical factors affecting follicular development after grafting. RESULTS Clinical factors such as the patient's age and the transplantation sites influenced the lifespan of the graft. A heterotopic transplantation site is not optimal but offers some advantages and it may also promote the hormonal environment after a combined heterotopic and orthotopic transplantation. Exogenous factors such as antioxidants, growth factors or hormones were tested to improve follicular survival; however, their efficiency regarding further follicular development and fertility potential remains to be established. CONCLUSION Additional evidence is required to define optimal conditions for ovarian tissue transplantation. Alternatives such as whole ovary or isolated follicles transplantations require further investigation but are likely to be successful in humans in the future. PMID:19474206

  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. Ovarian Cancer Statistics

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 22,280 % of All New Cancer Cases 1.3% Estimated Deaths in 2016 14,240 % of All Cancer ... of This Cancer : In 2013, there were an estimated 195,767 women living with ovarian cancer in ...

  12. Mifepristone and ovarian function.

    PubMed

    Curry, T E; Nothnick, W B

    1996-06-01

    In summary, RU 486 has been a powerful instrument in delineating progesterone action on the ovary. However, early experiments using RU 486 must be interpreted with the understanding that systemic administration of the antiprogestin may have had extraovarian sites of action, such as at the hypothalamic-pituitary axis or at the adrenal, that in turn led to indirect ovarian responses. Treatment with progesterone, agonist, or antagonist at periods during which the ovary lacks progesterone receptors would further suggest extraovarian sites of action or nongenomic mechanisms of action. Furthermore, the dose of ligand or antagonist administered and the hormonal milieu at the time of administration may dictate the ovarian response (Espey L, personal communication). For example, low doses of exogenous progesterone may elicit a biologic response, whereas high doses are without effect or may inhibit the biologic effect observed at lower doses. Although RU 486 is classically described as an antiprogestin, agonist actions have been observed in addition to its the well documented antiglucocorticoid effects. All of these variables may contribute to the confounding observations of progesterone and RU 486 action on the ovary. Regardless of these caveats, experimental paradigms have demonstrated that RU 486, either indirectly or directly, regulates ovarian folliculogenesis, stimulates and/or inhibits steroidogenesis depending on the species and time of RU 486 administration, inhibits ovulation, and modulates luteal function. These findings supports a progesterone-dependent mechanism in these varied aspects of ovarian function.

  13. Premature Ovarian Failure

    MedlinePlus

    Premature ovarian failure (POF) is when a woman's ovaries stop working before she is 40. POF is different from premature menopause. With premature menopause, ... be a disease, surgery, chemotherapy, or radiation. With POF, some women still have occasional periods. They may ...

  14. The eukaryotic translation elongation factor eEF1A2 induces neoplastic properties and mediates tumorigenic effects of ZNF217 in precursor cells of human ovarian carcinomas

    SciTech Connect

    Sun, Yu; Wong, Nicholas; Guan, Yinghui; Salamanca, Clara M.; Cheng, Jung Chien; Lee, Jonathan M.; Gray, Joe W.; Auersperg, Nelly

    2008-04-25

    Ovarian epithelial carcinomas (OEC) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In this study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities, and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression.

  15. EGFR/HER-targeted therapeutics in ovarian cancer.

    PubMed

    Wilken, Jason A; Badri, Tayf; Cross, Sarah; Raji, Rhoda; Santin, Alessandro D; Schwartz, Peter; Branscum, Adam J; Baron, Andre T; Sakhitab, Adam I; Maihle, Nita J

    2012-03-01

    Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally. During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies. Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer. Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings.

  16. EGFR/HER-targeted therapeutics in ovarian cancer

    PubMed Central

    Wilken, Jason A; Badri, Tayf; Cross, Sarah; Raji, Rhoda; Santin, Alessandro D; Schwartz, Peter; Branscum, Adam J; Baron, Andre T; Sakhitab, Adam I; Maihle, Nita J

    2013-01-01

    Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally. During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies. Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer. Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings. PMID:22416774

  17. Review of ovarian tumors in children and adolescents: radiologic-pathologic correlation.

    PubMed

    Heo, Suk Hee; Kim, Jin Woong; Shin, Sang Soo; Jeong, Seo In; Lim, Hyo Soon; Choi, Yoo Duk; Lee, Kyoung Hwa; Kang, Woo Dae; Jeong, Yong Yeon; Kang, Heoung Keun

    2014-01-01

    The incidence, histologic distribution, and clinical manifestations of ovarian tumors in the pediatric population are distinct from those in adults. Although ovarian neoplasms in childhood and adolescence are rare, the diagnosis should be considered in young girls with abdominal pain and a palpable mass. Differential diagnosis in children and adolescents with ovarian tumors should be conducted on the basis of unique clinical manifestations, elevated serum tumor marker levels, and distinctive imaging findings. Although the clinical manifestations are nonspecific and may overlap, they may assist in diagnosis of some types of ovarian tumors. Children who present with a palpable mass or symptoms of precocious puberty have a high likelihood of malignancy. Many ovarian tumors are associated with abnormal hormonal activity and/or abnormal sexual development. Elevated levels of serum tumor markers, including α-fetoprotein, the beta subunit of human chorionic gonadotropin, and CA-125, raise concern for ovarian malignancies. However, negative tumor markers do not exclude the possibility of malignancy. Identification of imaging features at ultrasonography, computed tomography, and magnetic resonance imaging can help differentiate benign from malignant ovarian tumors and, in turn, plays a crucial role in determining treatment options. At imaging, malignant ovarian tumors usually appear predominantly solid or heterogeneous and are larger than benign tumors. Because surgery is the primary treatment for ovarian tumors, ovarian salvage with fertility preservation and use of a minimally invasive surgical technique are important in children and adolescents.

  18. Review of ovarian tumors in children and adolescents: radiologic-pathologic correlation.

    PubMed

    Heo, Suk Hee; Kim, Jin Woong; Shin, Sang Soo; Jeong, Seo In; Lim, Hyo Soon; Choi, Yoo Duk; Lee, Kyoung Hwa; Kang, Woo Dae; Jeong, Yong Yeon; Kang, Heoung Keun

    2014-01-01

    The incidence, histologic distribution, and clinical manifestations of ovarian tumors in the pediatric population are distinct from those in adults. Although ovarian neoplasms in childhood and adolescence are rare, the diagnosis should be considered in young girls with abdominal pain and a palpable mass. Differential diagnosis in children and adolescents with ovarian tumors should be conducted on the basis of unique clinical manifestations, elevated serum tumor marker levels, and distinctive imaging findings. Although the clinical manifestations are nonspecific and may overlap, they may assist in diagnosis of some types of ovarian tumors. Children who present with a palpable mass or symptoms of precocious puberty have a high likelihood of malignancy. Many ovarian tumors are associated with abnormal hormonal activity and/or abnormal sexual development. Elevated levels of serum tumor markers, including α-fetoprotein, the beta subunit of human chorionic gonadotropin, and CA-125, raise concern for ovarian malignancies. However, negative tumor markers do not exclude the possibility of malignancy. Identification of imaging features at ultrasonography, computed tomography, and magnetic resonance imaging can help differentiate benign from malignant ovarian tumors and, in turn, plays a crucial role in determining treatment options. At imaging, malignant ovarian tumors usually appear predominantly solid or heterogeneous and are larger than benign tumors. Because surgery is the primary treatment for ovarian tumors, ovarian salvage with fertility preservation and use of a minimally invasive surgical technique are important in children and adolescents. PMID:25384300

  19. Quantitative analysis of cell-free DNA in ovarian cancer

    PubMed Central

    SHAO, XUEFENG; He, YAN; JI, MIN; CHEN, XIAOFANG; QI, JING; SHI, WEI; HAO, TIANBO; JU, SHAOQING

    2015-01-01

    The aim of the present study was to investigate the association between cell-free DNA (cf-DNA) levels and clinicopathological characteristics of patients with ovarian cancer using a branched DNA (bDNA) technique, and to determine the value of quantitative cf-DNA detection in assisting with the diagnosis of ovarian cancer. Serum specimens were collected from 36 patients with ovarian cancer on days 1, 3 and 7 following surgery, and additional serum samples were also collected from 22 benign ovarian tumor cases, and 19 healthy, non-cancerous ovaries. bDNA techniques were used to detect serum cf-DNA concentrations. All data were analyzed using SPSS version 18.0. The cf-DNA levels were significantly increased in the ovarian cancer group compared with those of the benign ovarian tumor group and healthy ovarian group (P<0.01). Furthermore, cf-DNA levels were significantly increased in stage III and IV ovarian cancer compared with those of stages I and II (P<0.01). In addition, cf-DNA levels were significantly increased on the first day post-surgery (P<0.01), and subsequently demonstrated a gradual decrease. In the ovarian cancer group, the area under the receiver operating characteristic curve of cf-DNA and the sensitivity were 0.917 and 88.9%, respectively, which was higher than those of cancer antigen 125 (0.724, 75%) and human epididymis protein 4 (0.743, 80.6%). There was a correlation between the levels of serum cf-DNA and the occurrence and development of ovarian cancer in the patients evaluated. bDNA techniques possessed higher sensitivity and specificity than other methods for the detection of serum cf-DNA in patients exhibiting ovarian cancer, and bDNA techniques are more useful for detecting cf-DNA than other factors. Thus, the present study demonstrated the potential value for the use of bDNA as an adjuvant diagnostic method for ovarian cancer. PMID:26788153

  20. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    SciTech Connect

    Guo, Jiajia; Yuan, Yun; Lu, Danfeng; Du, Baowen; Xiong, Liang; Shi, Jiangong; Yang, Lijuan; Liu, Wanli; Yuan, Xiaohong; Zhang, Guolin; Wang, Fei

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC{sub 50}: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They

  1. Association between individual ovarian dimensions with ovarian reserve indices

    PubMed Central

    Naeini, Elham Hashemian; Neyestanak, Mohammad Zare; Berjis, Katayon; Shokoohi, Mostafa

    2013-01-01

    Introduction: In some young female candidates of assisted reproductive technology (ART), ovarian response to simulative treatments is less than what is expected. More precise assessment of oocyte quality and quantity through studying ovarian dimensions can be useful for determining the dose of ovarian stimulant drugs and for preventing ART cycles cancellation. The aim of the present study is to determine the association between ovarian dimensions and ovarian reserve (OR) indices and whether ovarian dimensions can predict ovarian reserve. Methods: In this cross-sectional study, 85 infertile women were studied. In early follicular phase, ovarian diameters (including length and width of the ovaries) were measured using transvaginal ultrasonography. Mean ovarian diameters (MOD) were calculated according to average length and width of the ovaries. A serum sample was taken from all patients to measure the level of Follicular Stimulating Hormone (FSH) and oestradiol as OR indices. Results: The results of univariate analysis showed that FSH and oestradiol had a negative significant association with width, length and MOD (P < 0.01). The results of multivariate regression analysis showed that FSH and oestradiol had a negative significant association with width (βFSH = -0.59, P = 0.001 and βOestradiol = -0.019, P = 0.029) and MOD (βFSH = -0.52, P = 0.003 and βOestradiol = -0.021, P = 0.017) and had a borderline negative significant correlation with ovarian length (βFSH = -0.49, P=0.077 and βOestradiol = 0.022, P = 0.08) Conclusions: The results of this study revealed that despite a moderate correlation, ovarian diameters could be an applicable index for predicting OR. Using this method along with other methods may be useful in treatment with ovarian stimulants. PMID:26966426

  2. An overview of optical coherence tomography for ovarian tissue imaging and characterization

    PubMed Central

    Wang, Tianheng; Brewer, Molly; Zhu, Quing

    2014-01-01

    Ovarian cancer has the lowest survival rate among all the gynecologic cancers because it is predominantly diagnosed at late stages due to the lack of reliable symptoms and efficacious screening techniques. Optical coherence tomography (OCT) is an emerging technique that provides high-resolution images of biological tissue in real time, and demonstrates great potential for imaging of ovarian tissue. In this paper, we review OCT studies for visualization and diagnosis of human ovaries as well as quantitative extraction of ovarian tissue optical properties for classifying normal and malignant ovaries. OCT combined with other imaging modalities to further improve ovarian tissue diagnosis is also reviewed. PMID:25329515

  3. Do We Know What Causes Ovarian Cancer?

    MedlinePlus

    ... ovarian cancer be prevented? Do we know what causes ovarian cancer? We don’t yet know exactly what causes ... Another theory is that male hormones (androgens) can cause ovarian cancer. Researchers have made great progress in understanding how ...

  4. The mechanism and significance of synergistic induction of the expression of plasminogen activator inhibitor-1 by glucocorticoid and transforming growth factor beta in human ovarian cancer cells.

    PubMed

    Pan, Xiao-yu; Wang, Yan; Su, Jie; Huang, Gao-xiang; Cao, Dong-mei; Qu, Shen; Lu, Jian

    2015-05-15

    Plasminogen activator inhibitor-1 (PAI-1) plays a key role in tissue remodeling and tumor development by suppression of plasminogen activator function. Glucocorticoids (GCs) and transforming growth factor beta (TGF-β) signal pathways cross-talk to regulate gene expression, but the mechanism is poorly understood. Here we investigated the mechanism and significance of co-regulation of PAI-1 by TGF-β and dexamethasone (DEX), a synthetic glucocorticoid in ovarian cancer cells. We found that TGF-β and DEX showed rapidly synergistic induction of PAI-1 expression, which contributed to the early pro-adhesion effects. The synergistic induction effect was accomplished by several signal pathways, including GC receptor (GR) pathway and TGF-β-activated p38MAPK, ERK and Smad3 pathways. TGF-β-activated p38MAPK and ERK pathways cross-talked with GR pathway to augment the expression of PAI-1 through enhancing DEX-induced GR phosphorylation at Ser211 in ovarian cancer cells. These findings reveal possible novel mechanisms by which TGF-β pathways cooperatively cross-talk with GR pathway to regulate gene expression.

  5. Effect of Amino Acids on the Generation of Ginsenoside Rg3 Epimers by Heat Processing and the Anticancer Activities of Epimers in A2780 Human Ovarian Cancer Cells

    PubMed Central

    Park, Jun Yeon; Choi, Pilju; Lee, Dahae; Kim, Taejung; Jung, Eun Bee; Hwang, Buyng-Su; Kang, Ki Sung; Ham, Jungyeob

    2016-01-01

    Ginsenosides are the active components of Panax ginseng. Many research studies indicate that these deglycosylated, less-polar ginsenosides have better bioactivity than the major ginsenosides. In the present study, we sought to verify the enhanced anticancer effect of P. ginseng extract after undergoing the Maillard reaction as well as elucidate the underlying mechanism of action. The effects of 9 amino acids were tested; among them, the content of 20(S)-Rg3 in the ginseng extract increased to more than 30, 20, and 20% when processed with valine, arginine, and alanine, respectively, compared with that after normal heat processing. The ginseng extract that was heat-processed with arginine exhibited the most potent inhibitory effect on A2780 ovarian cancer cell proliferation. Therefore, the generation of 20(S)-Rg3 was suggested to be involved in this effect. Moreover, the inhibitory effect of 20(S)-Rg3 on A2780 cell proliferation was significantly stronger than that of 20(R)-Rg3. Protein expression levels of cleaved caspase-3, caspase-8, caspase-9, and PARP in the A2780 ovarian cancer cells markedly increased, whereas the expression of BID decreased after 20(S)-Rg3 treatment. Therefore, we confirmed that the anticancer effects of the products of ginseng that was heat-processed with arginine are mediated mainly via the generation of the less-polar ginsenoside 20(S)-Rg3. PMID:27051448

  6. O-Linked glycome and proteome of high-molecular-mass proteins in human ovarian cancer ascites: Identification of sulfation, disialic acid and O-linked fucose.

    PubMed

    Karlsson, Niclas G; McGuckin, Michael A

    2012-07-01

    The O-linked glycosylation of the main acidic high-molecular-weight glycoprotein from ascites fluid from patients with ovarian cancer were analyzed. The O-linked oligosaccharides were shown to consist of mainly highly sialylated core 1 and 2 structures with a smaller amount of sulfated core 2 structures. These structures were shown to be able to be further extended into small keratan sulfate (KS)-type oligosaccharides with up to four N-acetyllactosamine units. Proteomic studies of the acidic fraction of ascites fluid from patients with ovarian cancer showed that this fraction was enriched in proteoglycans. Among them, lumican, agrin, versican and dystroglycans were potential candidates, with threonine- and serine-rich domains that could carry a significant amount of O-linked glycosylation, including also the O-linked KS. Glycomic analysis using liquid chromatography (LC)-tandem mass spectrometry (MS/MS) also showed that the disialic acid NeuAc-NeuAc- was frequently found as the terminating structure on the O-linked core 1 and 2 oligosaccharides from one ascites sample. Also, a small amount of the epidermal growth factor (EGF)-associated O-linked fucose structure Gal-GlcNAc-Fucitol was detected with and without sialic acid in the LC-MS/MS analysis. Candidate proteins containing O-linked fucose were suggested to be proteoglycan-type molecules containing the O-linked fucose EGF consensus domain.

  7. Deregulated miR-296/S100A4 axis promotes tumor invasion by inducing epithelial-mesenchymal transition in human ovarian cancer

    PubMed Central

    Yan, Wang; Chen, Jiaqi; Chen, Zhaoying; Chen, Huimin

    2016-01-01

    S100A4 represents an important member of the S100 family of small calcium-binding proteins. Increased expression of S100A4 has been observed in chronic inflammatory and autoimmune diseases, such as idiopathic inflammatory myopathies. The majority of studies of S100A4 are focused on cancer research; however, the oncogenic roles of S100A4 in epithelial ovarian cancer (EOC) remain largely unexplored. In this study, S100A4 expression is significantly up-regulated in ovarian cancer and associated with the clinical stage of EOC patients. Attenuation of S100A4 expression results in decreased cell mobility and metastatic capacity, whereas overexpression of S100A4 enhanced the invasive ability of EOC cells. Then by an integrated informatics analysis and luciferase reporter assay, we identify that miR-296 is a critical upstream regulator of S100A4. In addition, deregulated miR-296/S100A4 axis facilitates epithelial-mesenchymal transition (EMT) process as demonstrated by altered expression of EMT-related markers. In conclusion, our study reveals that deregulated miR-296/S100A4 promotes tumor progression in EOC, and provides evidence that miR-296/S100A4 axis-related signaling may represent a potential target for EOC therapy. PMID:27186401

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

    ClinicalTrials.gov

    2016-10-10

    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

  9. Poor ovarian reserve.

    PubMed

    Jirge, Padma Rekha

    2016-01-01

    Poor ovarian reserve (POR) is an important limiting factor for the success of any treatment modality for infertility. It indicates a reduction in quantity and quality of oocytes in women of reproductive age group. It may be age related as seen in advanced years of reproductive life or may occur in young women due to diverse etiological factors. Evaluating ovarian reserve and individualizing the therapeutic strategies are very important for optimizing the success rate. Majority or women with POR need to undergo in vitro fertilization to achieve pregnancy. However, pregnancy rate remains low despite a plethora of interventions and is associated with high pregnancy loss. Early detection and active management are essential to minimize the need for egg donation in these women. PMID:27382229

  10. Poor ovarian reserve

    PubMed Central

    Jirge, Padma Rekha

    2016-01-01

    Poor ovarian reserve (POR) is an important limiting factor for the success of any treatment modality for infertility. It indicates a reduction in quantity and quality of oocytes in women of reproductive age group. It may be age related as seen in advanced years of reproductive life or may occur in young women due to diverse etiological factors. Evaluating ovarian reserve and individualizing the therapeutic strategies are very important for optimizing the success rate. Majority or women with POR need to undergo in vitro fertilization to achieve pregnancy. However, pregnancy rate remains low despite a plethora of interventions and is associated with high pregnancy loss. Early detection and active management are essential to minimize the need for egg donation in these women. PMID:27382229

  11. Critical appraisal of bevacizumab in the treatment of ovarian cancer.

    PubMed

    Yoshida, Hiroyuki; Yabuno, Akira; Fujiwara, Keiichi

    2015-01-01

    Bevacizumab is the first molecular-targeted agent to be used for the treatment of ovarian cancer. Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor. Two randomized Phase III trials evaluated the combination of bevacizumab plus standard cytotoxic chemotherapy for first-line treatment of advanced ovarian cancer. Additional Phase III trials evaluated bevacizumab combined with cytotoxic chemotherapy in platinum-sensitive and platinum-resistant recurrent ovarian cancer. All these trials reported a statistically significant improvement in progression-free survival but not in overall survival. Furthermore, bevacizumab effectively improved the quality of life with regard to abdominal symptoms in recurrent ovarian cancer patients. Bevacizumab is associated with adverse events not commonly observed with cytotoxic agents used to treat gynecological cancers, such as hypertension, bleeding, thromboembolism, proteinuria, delayed wound healing, and gastrointestinal events. However, most of these events can be adequately managed by gynecologists. The clinical trial results with bevacizumab have supported its recent approval in Europe and the United States as a treatment for ovarian cancer. This review presents the latest evidence for bevacizumab therapy of ovarian cancer and describes selection of patients for personalized treatment. PMID:25960638

  12. Primary Ovarian Insufficiency.

    PubMed

    Laven, Joop S E

    2016-07-01

    Primary ovarian insufficiency (POI), also known as premature ovarian failure or premature menopause, is defined as cessation of menstruation before the expected age of menopause. Potential etiologies for POI can be divided into genetic, autoimmune, and iatrogenic categories. This review will try to summarize the genetic basis of POI focusing on recent data that are available using newer genetic techniques such as genome-wide association studies, whole-exome sequencing (WES), or next-generation sequencing techniques. By using these techniques, many genes have arisen that play some role in the pathophysiology of POI. Some of them have been replicated in other studies; however, the majority has not been proven yet to be unequivocally causative through functional validation studies. Elucidating the genetic and molecular basis of POI is of paramount importance not only in understanding ovarian physiology but also in providing genetic counseling and fertility guidance. Once additional variants are detected, it might become possible to predict the age of (premature) menopause in women at risk for POI. Women having certain perturbations of POI can be offered the option of oocyte cryopreservation, with later thawing and use in assisted reproductive technology at an appropriate age. PMID:27513024

  13. Chitosan coated polylactic acid nanoparticle-mediated combinatorial delivery of cisplatin and siRNA/Plasmid DNA chemosensitizes cisplatin-resistant human ovarian cancer cells.

    PubMed

    Babu, Anish; Wang, Qi; Muralidharan, Ranganayaki; Shanker, Manish; Munshi, Anupama; Ramesh, Rajagopal

    2014-08-01

    Development of resistance toward anticancer drugs results in ineffective therapy leading to increased mortality. Therefore, overriding resistance and restoring sensitivity to anticancer drugs will improve treatment efficacy and reduce mortality. While numerous mechanisms for drug resistance in cancer have previously been demonstrated, recent studies implicate a role for proteasome and the autophagy regulatory protein P62/SQSTM1 (P62) in contributing to drug resistance. Specifically, reduction in the expression of the β5 subunit of the proteasome and/or enhanced P62 protein expression is known to contribute to cancer drug resistance such as cisplatin (CDDP) in ovarian cancer cells. Therefore, we hypothesized that restoration of β5 expression and/or suppression of P62 protein expression in CDDP-resistant ovarian cancer cells will lead to restoration of sensitivity to CDDP and enhanced cell killing. To test our hypothesis we developed a biodegradable multifunctional nanoparticle (MNP) system that codelivered P62siRNA, β5 plasmid DNA, and CDDP and tested its efficacy in CDDP resistant 2008/C13 ovarian cancer cells. MNP consisted of CDDP loaded polylactic acid nanoparticle as inner core and cationic chitosan (CS) consisting of ionically linked P62siRNA (siP62) and/or β5 expressing plasmid DNA (pβ5) as the outer layer. The MNPs were spherical in shape with a hydrodynamic diameter in the range of 280-350 nm, and demonstrated encapsulation efficiencies of 82% and 78.5% for CDDP and siRNA respectively. MNPs efficiently protected the siRNA and showed superior serum stability compared to naked siRNA as measured by gel retardation and spectrophotometry assays. The MNPs successfully delivered siP62 and pβ5 to cause P62 knockdown and restoration of β5 expression in 2008/C13 cells. Combined delivery of siP62, pβ5, and CDDP using the MNPs resulted in a marked reduction in the IC50 value of CDDP in 2008/C13 cells from 125 ± 1.3 μM to 98 ± 0.6 μM (P < 0.05; 21

  14. Chitosan coated polylactic acid nanoparticle-mediated combinatorial delivery of cisplatin and siRNA/Plasmid DNA chemosensitizes cisplatin-resistant human ovarian cancer cells.

    PubMed

    Babu, Anish; Wang, Qi; Muralidharan, Ranganayaki; Shanker, Manish; Munshi, Anupama; Ramesh, Rajagopal

    2014-08-01

    Development of resistance toward anticancer drugs results in ineffective therapy leading to increased mortality. Therefore, overriding resistance and restoring sensitivity to anticancer drugs will improve treatment efficacy and reduce mortality. While numerous mechanisms for drug resistance in cancer have previously been demonstrated, recent studies implicate a role for proteasome and the autophagy regulatory protein P62/SQSTM1 (P62) in contributing to drug resistance. Specifically, reduction in the expression of the β5 subunit of the proteasome and/or enhanced P62 protein expression is known to contribute to cancer drug resistance such as cisplatin (CDDP) in ovarian cancer cells. Therefore, we hypothesized that restoration of β5 expression and/or suppression of P62 protein expression in CDDP-resistant ovarian cancer cells will lead to restoration of sensitivity to CDDP and enhanced cell killing. To test our hypothesis we developed a biodegradable multifunctional nanoparticle (MNP) system that codelivered P62siRNA, β5 plasmid DNA, and CDDP and tested its efficacy in CDDP resistant 2008/C13 ovarian cancer cells. MNP consisted of CDDP loaded polylactic acid nanoparticle as inner core and cationic chitosan (CS) consisting of ionically linked P62siRNA (siP62) and/or β5 expressing plasmid DNA (pβ5) as the outer layer. The MNPs were spherical in shape with a hydrodynamic diameter in the range of 280-350 nm, and demonstrated encapsulation efficiencies of 82% and 78.5% for CDDP and siRNA respectively. MNPs efficiently protected the siRNA and showed superior serum stability compared to naked siRNA as measured by gel retardation and spectrophotometry assays. The MNPs successfully delivered siP62 and pβ5 to cause P62 knockdown and restoration of β5 expression in 2008/C13 cells. Combined delivery of siP62, pβ5, and CDDP using the MNPs resulted in a marked reduction in the IC50 value of CDDP in 2008/C13 cells from 125 ± 1.3 μM to 98 ± 0.6 μM (P < 0.05; 21

  15. Protection of ovarian function during chemotherapy for ovarian cancer.

    PubMed

    Tianmin, X; Weiqin, C; Shuying, W; Yang, L; Manhua, C

    2014-01-01

    The protection of ovarian function during chemotherapy is an urgent issue to be resolved after the fertility preserving surgery on patients with ovarian cancer. The paper summarizes and analyzes the research progress on the protective measures in the aspects of gonadotropin releasing hormone analogue (GnRHa), cell protecting agents, and traditional Chinese medical science and drugs.

  16. Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model.

    PubMed

    Mony, Jyothi Thyagabhavan; Zhang, Lixin; Ma, Tianzhou; Grabosch, Shannon; Tirodkar, Tejas S; Brozick, Joan; Tseng, George; Elishaev, Esther; Edwards, Robert P; Huang, Xin; Vlad, Anda M

    2015-09-01

    Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance anti-tumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death-ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8 × 10(5) syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 μg/dose) for a total of three doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p = 0.001) compared to isotype control-treated mice. When the same therapy was administered to wild-type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer.

  17. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19).

    PubMed

    Guo, Jiajia; Yuan, Yun; Lu, Danfeng; Du, Baowen; Xiong, Liang; Shi, Jiangong; Yang, Lijuan; Liu, Wanli; Yuan, Xiaohong; Zhang, Guolin; Wang, Fei

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds-trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)-were found to potently inhibit estrogen biosynthesis (IC50: 1μM and 0.5μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. PMID:24853760

  18. Reduced Ovarian Glyoxalase-I Activity by Dietary Glycotoxins and Androgen Excess: A Causative Link to Polycystic Ovarian Syndrome

    PubMed Central

    Kandaraki, Eleni; Chatzigeorgiou, Antonis; Piperi, Christina; Palioura, Eleni; Palimeri, Sotiria; Korkolopoulou, Penelope; Koutsilieris, Michael; Papavassiliou, Athanasios G

    2012-01-01

    Glyoxalase detoxification system composed of glyoxalase (GLO)-I and GLO-II is ubiquitously expressed and implicated in the protection against cellular damage because of cytotoxic metabolites such as advanced glycation end products (AGEs). Recently, ovarian tissue has emerged as a new target of excessive AGE deposition and has been associated with either a high AGE diet in experimental animals or hyperandrogenic disorders such as polycystic ovarian syndrome (PCOS) in humans. This study was designed to investigate the impact of dietary AGEs and androgens in rat ovarian GLO-I activity of normal nonandrogenized (NAN, group A, n = 18) and androgenized prepubertal (AN) rats (group B, n = 29). Both groups were further randomly assigned, either to a high-AGE (HA) or low-AGE (LA) diet for 3 months. The activity of ovarian GLO-I was significantly reduced in normal NAN animals fed an HA diet compared with an LA diet (p = 0.006). Furthermore, GLO-I activity was markedly reduced in AN animals compared with NAN (p ≤ 0.001) when fed with the corresponding diet type. In addition, ovarian GLO-I activity was positively correlated with the body weight gain (rs = 0.533, p < 0.001), estradiol (rs = 0.326, p = 0.033) and progesterone levels (rs = 0.500, p < 0.001). A negative correlation was observed between GLO-I activity and AGE expression in the ovarian granulosa cell layer of all groups with marginal statistical significance (rs = −0.263, p = 0.07). The present data demonstrate that ovarian GLO-I activity may be regulated by dietary composition and androgen levels. Modification of ovarian GLO-I activity, observed for the first time in this androgenized prepubertal rat model, may present a contributing factor to the reproductive dysfunction characterizing PCOS. PMID:22859292

  19. Expanded metabolomics approach to profiling endogenous carbohydrates in the serum of ovarian cancer patients.

    PubMed

    Cheng, Yu; Li, Li; Zhu, Bangjie; Liu, Feng; Wang, Yan; Gu, Xue; Yan, Chao

    2016-01-01

    We applied hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry to the quantitative analysis of serum from 58 women, including ovarian cancer patients, ovarian benign tumor patients, and healthy controls. All of these ovarian cancer and ovarian benign tumor patients have elevated cancer antigen 125, which makes them clinically difficult to differentiate the malignant from the benign. All of the 16 endogenous carbohydrates were quantitatively detected in the human sera, of which, eight endogenous carbohydrates were significantly different (P-value < 0.05) between the ovarian cancer and healthy control. According to the receiver operating characteristic curve analysis, arabitol was the most potentially specific biomarker for discriminating ovarian cancer from healthy control, having an area under the curve of 0.911. A panel of metabolite markers composed of maltose, maltotriose, raffinose, and mannitol was selected, which was able to discriminate the ovarian cancer from the benign ovarian tumor counterparts, with an area under concentration-time curve value of 0.832. Endogenous carbohydrates in the expanded metabolomics approach after the global metabolic profiling are characterized and are potential biomarkers for the early diagnosis of ovarian cancer.

  20. The diagnostic value of serum HE4 and CA-125 and ROMA index in ovarian cancer

    PubMed Central

    WEI, SU; LI, HUI; ZHANG, BEI

    2016-01-01

    Ovarian cancer is a common malignancy of the female reproductive system. Tumor markers serve as tools in the diagnosis of the disease. The aim of the present study was to determine the diagnostic value of sera levels of carbohydrate antigen-125 (CA-125), human epididymis protein 4 (HE4) as well as the area under the curve of the receiver operating characteristic (ROC) and the risk of ovarian malignancy algorithm (ROMA) index in ovarian cancer. The sera were measured using an electrochemiluminescence immunoassay on 158 individuals (64 patients with ovarian cancer, 64 with ovarian benign tumor and 30 healthy individuals) between September 2013 and May 2015. The results showed that levels of HE4 and CA-125 in the sera of the ovarian benign tumor group as well as their ROMA index were significantly higher (P<0.05) than those of the ovarian benign tumor and control groups, regardless of pre- or postmenopausal status. However, the level of CA-125 was significantly higher (P<0.05) in the ovarian benign tumor group compared with the healthy group, while the level of HE4 was similar in the two groups. The sensitivity of the ROMA index was higher (P<0.01) with detection of HE4 and CA-125. In the ovarian cancer group, the areas under ROC curves of ROMA, HE4 and CA-125 were 0.994, 0.990 and 0.941, respectively. The specificity and positive predictive value of HE4 in the premenopausal ovarian cancer group reached 98.36 and 95%, respectively. In conclusion, the results showed that the serum level of HE4 and the ROMA index are important indicators in the diagnosis of ovarian cancer. However, in addition to HE4 and CA-125 detection, the ROMA index is extremely valuable in improving the diagnostic efficiency of ovarian cancer. PMID:27347403

  1. Can Ovarian Cancer Be Prevented?

    MedlinePlus

    ... ovaries removed with your doctor. Prevention strategies for women with a family history of ovarian cancer or BRCA mutation If your ... what the results mean to you. For some women with a strong family history of ovarian cancer, knowing they do not have ...

  2. 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

  3. Ovarian disorders in domestic animals.

    PubMed Central

    MacLachlan, N J

    1987-01-01

    The histologic appearance of the ovaries and persistence of corpora lutea vary considerably among domestic animals, particularly between spontaneous and induced ovulators. The seasonally polyestrous mare has a variety of unique characteristics in ovarian structure and general reproductive function. Among the anomalies of ovarian development is the bovine freemartin with gonads containing a mixture of male and female elements. A variety of ovarian cysts occur in domestic animals, and persistent corpora lutea with associated reproductive perturbations occur in several species. Ovarian tumors are relatively uncommon in domestic animals, with most examples described in dogs, cats, and horses. These ovarian neoplasms are generally classified as epithelial, germ cell, or sex cord-stromal tumors. PMID:3665869

  4. Ixabepilone and Liposomal Doxorubicin in Advanced Ovarian Cancer

    ClinicalTrials.gov

    2016-02-11

    Fallopian Tube Cancer; Female Reproductive Cancer; Recurrent Breast Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer

  5. Somatostatin receptors in differentiated ovarian tumors.

    PubMed Central

    Reubi, J. C.; Horisberger, U.; Klijn, J. G.; Foekens, J. A.

    1991-01-01

    The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands, 125I-[Tyr11]-somatostatin-14, 125I-[Leu8, D-Trp22, Tyr25]-somatostatin-28, or 125I-[Tyr3]-SMS 201-995. Three cases, all belonging to epithelial tumors, were receptor positive; specifically 1 of 42 adenocarcinomas, 1 of 3 borderline malignancies, and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas, 1 Brenner tumor), 4 sex cord-stromal tumors (2 fibrothecomas, 2 granulosa cell tumors), and 2 germ cell tumors (1 dysgerminoma, 1 teratoma) were receptor negative. In the positive cases, the somatostatin receptors were localized on epithelial cells exclusively, were of high affinity (KD = 4.6 nmol/l [nanomolar]), and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide [Tyr3]-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors, therefore, was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands. Images Figure 1 Figure 2 Figure 3 PMID:1850962

  6. Somatostatin receptors in differentiated ovarian tumors

    SciTech Connect

    Reubi, J.C.; Horisberger, U.; Klijn, J.G.; Foekens, J.A. )

    1991-05-01

    The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands, {sup 125}I-(Tyr11)-somatostatin-14, {sup 125}I-(Leu8, D-Trp22, Tyr25)-somatostatin-28, or {sup 125}I-(Tyr3)-SMS 201-995. Three cases, all belonging to epithelial tumors, were receptor positive; specifically 1 of 42 adenocarcinomas, 1 of 3 borderline malignancies, and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas, 1 Brenner tumor), 4 sex cord-stromal tumors (2 fibrothecomas, 2 granulosa cell tumors), and 2 germ cell tumors (1 dysgerminoma, 1 teratoma) were receptor negative. In the positive cases, the somatostatin receptors were localized on epithelial cells exclusively, were of high affinity (KD = 4.6 nmol/l (nanomolar)), and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide (Tyr3)-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors, therefore, was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands.

  7. Transplantation Into the Mouse Ovarian Fat Pad.

    PubMed

    Flesken-Nikitin, Andrea; Harlan, Blaine A; Nikitin, Alexander Yu

    2016-01-01

    Orthotopic transplantation assays in mice are invaluable for studies of cell regeneration and neoplastic transformation. Common approaches for orthotopic transplantation of ovarian surface and tubal epithelia include intraperitoneal and intrabursal administration of cells. The respective limitations of these methods include poorly defined location of injected cells and limited space volume. Furthermore, they are poorly suited for long-term structural preservation of transplanted organs. To address these challenges, we have developed an alternative approach, which is based on the introduction of cells and tissue fragments into the mouse fat pad. The mouse ovarian fat pad is located in the immediate vicinity of the ovary and uterine tube (aka oviduct, fallopian tube), and provides a familiar microenvironment for cells and tissues of these organs. In our approach fluorescence-labeled mouse and human cells, and fragments of the uterine tube are engrafted by using minimally traumatic dorsal incision surgery. Transplanted cells and their outgrowths are easily located in the ovarian fat pad for over 40 days. Long-term transplantation of the entire uterine tube allows correct preservation of all principle tissue components, and does not result in adverse side effects, such as fibrosis and inflammation. Our approach should be uniquely applicable for answering important biological questions such as differentiation, regenerative and neoplastic potential of specific cell populations. Furthermore, it should be suitable for studies of microenvironmental factors in normal development and cancer. PMID:27684746

  8. Development of the ovarian follicular epithelium.

    PubMed

    Rodgers, R J; Lavranos, T C; van Wezel, I L; Irving-Rodgers, H F

    1999-05-25

    A lot is known about the endocrine control of the development of ovarian follicles, but a key question now facing researchers is which molecular and cellular processes take part in control of follicular growth and development. The growth and development of ovarian follicles occurs postnatally and throughout adult life. In this review, we focus on the follicular epithelium (membrana granulosa) and its basal lamina. We discuss a model of how granulosa cells arise from a population of stem cells and then enter different lineages before differentiation. The structure of the epithelium at the antral stage of development is presented, and the effects that follicle growth has on the behavior of the granulosa cells are discussed. Finally, we discuss the evidence that during follicle development the follicular basal lamina changes in composition. This would be expected if the behavior of the granulosa cells changes, or if the permeability of the basal lamina changes. It will be evident that the follicular epithelium has similarities to other epithelia in the body, but that it is more dynamic, as gross changes occur during the course of follicle development. This basic information will be important for the development of future reproductive technologies in both humans and animals, and possibly for understanding polycystic ovarian syndrome in women. PMID:10411332

  9. Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice

    PubMed Central

    Ringelstetter, Ashley; Khatib, Hasan; Abbott, David H.; Salih, Sana M.

    2015-01-01

    Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2–24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the “infertility index” (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse

  10. Ovarian programming and GIFT.

    PubMed

    Rolet, F; Gadaud, S; Zorn, J R; Boyer, P; Guichard, A; Cedard, L

    1988-05-01

    The procedures used for programming and ovarian stimulation in GIFT are identical to those used for in-vitro fertilization. At the Baudelocque Hospital, the hypophyseal gonadal axis is suppressed by administering a gonadotrophin-releasing hormone analogue (Decapeptyl, D-Trp-6-LHRH). Programming for the week of GIFT is then possible by controlling three stages: the beginning of treatment, which is independent of the date of the patient's period, the duration of treatment, which has 5 days' maximum variation, and an end-point of suppressing the spontaneous LH surge.

  11. Characterization of long non-coding RNA-associated ceRNA network to reveal potential prognostic lncRNA biomarkers in human ovarian cancer.

    PubMed

    Zhou, Meng; Wang, Xiaojun; Shi, Hongbo; Cheng, Liang; Wang, Zhenzhen; Zhao, Hengqiang; Yang, Lei; Sun, Jie

    2016-03-15

    Accumulating evidence has underscored the important roles of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in cancer initiation and progression. In this study, we used an integrative computational method to identify miRNA-mediated ceRNA crosstalk between lncRNAs and mRNAs, and constructed global and progression-related lncRNA-associated ceRNA networks (LCeNETs) in ovarian cancer (OvCa) based on "ceRNA hypothesis". The constructed LCeNETs exhibited small world, modular architecture and high functional specificity for OvCa. Known OvCa-related genes tended to be hubs and occurred preferentially in the functional modules. Ten lncRNA ceRNAs were identified as potential candidates associated with stage progression in OvCa using ceRNA-network driven method. Finally, we developed a ten-lncRNA signature which classified patients into high- and low-risk subgroups with significantly different survival outcomes. Our study will provide novel insight for better understanding of ceRNA-mediated gene regulation in progression of OvCa and facilitate the identification of novel diagnostic and therapeutic lncRNA ceRNAs for OvCa. PMID:26863568

  12. Guizhi Fuling Wan, a Traditional Chinese Herbal Formula, Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Inactivation of the PI3K/AKT/mTOR Pathway

    PubMed Central

    Guo, Xiaojuan; Bian, Hua; Yang, Lei; Chen, Zhong; Zang, Wenhua; Yang, Jingke

    2016-01-01

    The aim of the study was to explore the possible mechanisms that Guizhi Fuling Wan (GFW) enhances the sensitivity of the SKOV3/DDP ovarian cancer cells and the resistant xenograft tumours to cisplatin. Rat medicated sera containing GFW were prepared by administering GFW to rats, and the primary bioactive constituents of the sera were gallic acid, paeonol, and paeoniflorin analysed by HPLC/QqQ MS. Cell counting kit-8 analysis was shown that coincubation of the sera with cisplatin/paclitaxel enhanced significantly the cytotoxic effect of cisplatin or paclitaxel in SKOV3/DDP cells. The presence of the rat medicated sera containing GFW resulted in an increase in rhodamine 123 accumulation by flow cytometric assays and a decrease in the protein levels of P-gp, phosphorylation of AKT at Ser473, and mTOR in a dose-dependent manner in SKOV3/DDP cells by western blot analysis, but the sera had no effect on the protein levels of PI3K p110α and total AKT. The low dose of GFW enhanced the anticancer efficacy of cisplatin and paclitaxel treatment in resistant SKOV3/DDP xenograft tumours. GFW could sensitize cisplatin-resistant SKOV3/DDP cells by inhibiting the protein level and function of P-gp, which may be medicated through inactivation of the PI3K/AKT/mTOR pathway. PMID:27293459

  13. Recombinant human follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-hFSH alone for ovarian stimulation during assisted reproductive technology: systematic review and meta-analysis

    PubMed Central

    2014-01-01

    Background The potential benefit of adding recombinant human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) during ovarian stimulation is a subject of debate, although there is evidence that it may benefit certain subpopulations, e.g. poor responders. Methods A systematic review and a meta-analysis were performed. Three databases (MEDLINE, Embase and CENTRAL) were searched (from 1990 to 2011). Prospective, parallel-, comparative-group randomized controlled trials (RCTs) in women aged 18–45 years undergoing in vitro fertilization, intracytoplasmic sperm injection or both, treated with gonadotrophin-releasing hormone analogues and r-hFSH plus r-hLH or r-hFSH alone were included. The co-primary endpoints were number of oocytes retrieved and clinical pregnancy rate. Analyses were conducted for the overall population and for prospectively identified patient subgroups, including patients with poor ovarian response (POR). Results In total, 40 RCTs (6443 patients) were included in the analysis. Data on the number of oocytes retrieved were reported in 41 studies and imputed in two studies. Therefore, data were available from 43 studies (r-hFSH plus r-hLH, n = 3113; r-hFSH, n = 3228) in the intention-to-treat (ITT) population (all randomly allocated patients, including imputed data). Overall, no significant difference in the number of oocytes retrieved was found between the r-hFSH plus r-hLH and r-hFSH groups (weighted mean difference −0.03; 95% confidence interval [CI] −0.41 to 0.34). However, in poor responders, significantly more oocytes were retrieved with r-hFSH plus r-hLH versus r-hFSH alone (n = 1077; weighted mean difference +0.75 oocytes; 95% CI 0.14–1.36). Significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH versus r-hFSH alone in the overall population analysed in this review (risk ratio [RR] 1.09; 95% CI 1.01–1.18) and in poor responders (n = 1179; RR 1.30; 95% CI 1

  14. "Incessant ovulation" and ovarian cancer.

    PubMed

    Casagrande, J T; Louie, E W; Pike, M C; Roy, S; Ross, R K; Henderson, B E

    1979-07-28

    A case-control study of 150 ovarian cancer patients under the age of 50 and individually matched controls was done to study the influence of fertility and oral contraceptive use on the risk of ovarian cancer. The risk decreased with increasing numbers of live births, with increasing numbers of incomplete pregnancies, and with the use of oral contraceptives. These three factors can be amalgamated into a single index of protection--"protected time"--by considering them all as periods of anovulation. The complement of protected time--viz., "ovulatory age", the period between menarche and diagnosis of ovarian cancer (or cessation of menses) minus "protected time"--was strongly related to risk of ovarian cancer. Other factors found to be associated with increased ovarian cancer risk were obesity, cervical polyps, and gallbladder disease. Women who had an "immediate" intolerance to oral contraceptive use had a fourfold increased risk of ovarian cancer. 7 patients, but no controls, could recall a family history of ovarian cancer.

  15. A Molecularly Targeted Theranostic Probe for Ovarian Cancer

    PubMed Central

    Chen, Wenxue; Bardhan, Rizia; Bartels, Marc; Perez-Torres, Carlos; Pautler, Robia G.; Halas, Naomi J.; Joshi, Amit

    2014-01-01

    Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in ovarian cancer because of its participation in signaling pathway regulating cellular proliferation, differentiation, motility, and survival. Currently, effective diagnostic and therapeutic schemes are lacking for treating ovarian cancer and consequently ovarian cancer has a high mortality rate. While HER2 receptor expression does not usually affect the survival rates of ovarian cancer to the same extent as in breast cancer, it can be employed as a docking site for directed nanotherapies in cases with de novo or acquired chemotherapy resistance. In this study, we have exploited a novel gold nanoshell-based complex (nanocomplex) for targeting, dual modal imaging, and photothermal therapy of HER2 overexpressing and drug resistant ovarian cancer OVCAR3 cells in vitro. The nanocomplexes are engineered to simultaneously provide contrast as fluorescence optical imaging probe and a magnetic resonance imaging (MRI) agent. Both immunofluorescence staining and MRI successfully demonstrate that nanocomplex-anti-HER2 conjugates specifically bind to OVCAR3 cells as opposed to the control, MDA-MB-231 cells, which have low HER2 expression. In addition, nanocomplexes targeted to OVCAR3 cells, when irradiated with near infrared (NIR) laser result in selective destruction of cancer cells through photothermal ablation. We also demonstrate that NIR light therapy and the nanocomplexes by themselves are non-cytotoxic in vitro. To the best of our knowledge, this is the first demonstration of a successful integration of dual modal bioimaging with photothermal cancer therapy for treatment of ovarian cancer. Based on their efficacy in vitro, these nanocomplexes are highly promising for image guided photo-thermal therapy of ovarian cancer as well as other HER2 overexpressing cancers. PMID:20371708

  16. The epidemiology of ovarian cancer.

    PubMed

    Tortolero-Luna, G; Mitchell, M F

    1995-01-01

    Ovarian cancer is the second most common cancer of the female reproductive system and the leading cause of death from gynecologic malignancies. In 1995, 26,600 women will be diagnosed with ovarian cancer in the U.S., and 14,500 women will die from the disease. Between 1986-1900, the overall age-adjusted incidence was 14.3/100,000 women; mortality was 7.8/100,000 women. Ovarian cancer, rare before age 40, increases steeply thereafter and peaks at ages 65-75. Incidence and mortality rates are higher among white women than among African-American women. Over the last three decades, ovarian cancer incidence has remained stable in high-risk countries, while an increasing trend has been reported in low-risk countries. Despite recent advancements in treatment, the overall five-year survival rates continues to be low (39%). Over 70% of ovarian tumors are diagnosed when regional or distant involvement has already occurred, causing survival rates to remain stable. The etiology of ovarian cancer is poorly understood. Most studies have focused on the epidemiology of invasive epithelial ovarian tumors, while few have explored the epidemiology of epithelial tumors of low malignant potential and nonepithelial tumors. Factors associated with an increased risk for invasive epithelial ovarian cancer include age, race, nulliparity, family history of ovarian cancer, and history of endometrial or breast cancer. Factors associated with a reduced risk are history of one or more full-term pregnancies, use of oral contraceptives, history of breast feeding, tubal ligation, and hysterectomy. Other factors such as infertility drugs, hormone replacement therapy, age at menarche, age at menopause, dietary factors, lactose intolerance, talc use, coffee and alcohol consumption have been suggested, but their role is still inconclusive.

  17. Ovarian cancer-induced immunosuppression: relationship to tumor necrosis factor-alpha (TNF-alpha) release from ovarian tissue.

    PubMed

    Hassan, M I; Kassim, S K; Saeda, L; Laban, M; Khalifa, A

    1999-01-01

    Cytokines have been reported to be potential biological markers of, disease status in cancer patients. Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine released from monocytes and macrophages. TNF-alpha is involved in essential biological functions such as immunoregulation, modulation of cell growth and differentiation. In this work, the role of TNF-alpha release in ovarian cancer patients was investigated. Fifty-five patients with ovarian cancer and 20 controls of matched age and parity were included in this study. TNF-alpha concentrations were measured in sera and cytosolic fractions of both groups. The results demonstrated a significant increase in TNF-alpha concentrations among patients compared to the control subjects (P < 0.001). Furthermore, a non-significant increase (P = 0.05, was observed between the different types (serous, Mucinous, and endometrioid) of epithelial ovarian cancers. Also TNF-alpha concentrations did not correlate with the disease stage. Moreover, immunohistochemical analysis of tissue specimens stained for TNF-alpha was positive in malignant lesions and negative for the normal ovarian tissue. These findings confirmed the TNF-alpha kinetics obtained by ELISA assays. Interestingly, TNF-alpha levels were also elevated in culture supernatants of PBMC stimulated by cytosolic fractions from malignant ovarian tissues. Blastogenic assays using cytosolic fractions from malignant ovarian specimens to stimulate healthy donor peripheral blood mononuclear cells (PBMC) showed a marked decrease in 3H-thymidine uptake compared to the cells stimulated by normal cytosols. To establish a cause-effect relationship between TNF-alpha release and inhibition of cell proliferation, the experiments showed that 3H-thymidine uptake by PBMC was markedly inhibited by recombinant human TNF-alpha (rh TNF-alpha) and that inhibition was significantly reversed when TNF-alpha monoclonal antibody was added to the cells. The data presented in this work indicate that

  18. Comparative gene expression analysis of ovarian carcinoma and normal ovarian epithelium by serial analysis of gene expression.

    PubMed

    Peters, David G; Kudla, Donna M; Deloia, Julie A; Chu, Tian Jiao; Fairfull, Liane; Edwards, Robert P; Ferrell, Robert E

    2005-07-01

    Despite the poor prognosis of ovarian cancer and the importance of early diagnosis, there are no reliable noninvasive biomarkers for detection in the early stages of disease. Therefore, to identify novel ovarian cancer markers with potential utility in early-stage screening protocols, we have undertaken an unbiased and comprehensive analysis of gene expression in primary ovarian tumors and normal human ovarian surface epithelium (HOSE) using Serial Analysis of Gene Expression (SAGE). Specifically, we have generated SAGE libraries from three serous adenocarcinomas of the ovary and, using novel statistical tools, have compared these to SAGE data derived from two pools of normal HOSE. Significantly, in contrast to previous SAGE-based studies, our normal SAGE libraries are not derived from cultured cell lines. We have also compared our data with publicly available SAGE data obtained from primary tumors and "normal" HOSE-derived cell lines. We have thus identified several known and novel genes whose expressions are elevated in ovarian cancer. These include but are not limited to CLDN3, WFDC2, FOLR1, COL18A1, CCND1, and FLJ12988. Furthermore, we found marked differences in gene expression patterns in primary HOSE tissue compared with cultured HOSE. The use of HOSE tissue as a control for these experiments, along with hierarchical clustering analysis, identified several potentially novel biomarkers of ovarian cancer, including TACC3, CD9, GNAI2, AHCY, CCT3, and HMGA1. In summary, these data identify several genes whose elevated expressions have not been observed previously in ovarian cancer, confirm the validity of several existing markers, and provide a foundation for future studies in the understanding and management of this disease. PMID:16030107

  19. The science behind 25 years of ovarian stimulation for in vitro fertilization.

    PubMed

    Macklon, Nick S; Stouffer, Richard L; Giudice, Linda C; Fauser, Bart C J M

    2006-04-01

    To allow selection of embryos for transfer after in vitro fertilization, ovarian stimulation is usually carried out with exogenous gonadotropins. To compensate for changes induced by stimulation, GnRH analog cotreatment, oral contraceptive pretreatment, late follicular phase human chorionic gonadotropin, and luteal phase progesterone supplementation are usually added. These approaches render ovarian stimulation complex and costly. The stimulation of multiple follicular development disrupts the physiology of follicular development, with consequences for the oocyte, embryo, and endometrium. In recent years, recombinant gonadotropin preparations have become available, and novel stimulation protocols with less detrimental effects have been developed. In this article, the scientific background to current approaches to ovarian stimulation for in vitro fertilization is reviewed. After a brief discussion of the relevant aspect of ovarian physiology, the development, application, and consequences of ovarian stimulation strategies are reviewed in detail.

  20. Spy1 participates in the proliferation and apoptosis of epithelial ovarian cancer.

    PubMed

    Lu, Shumin; Liu, Rong; Su, Min; Wei, Yingze; Yang, Shuyun; He, Song; Wang, Xia; Qiang, Fulin; Chen, Chen; Zhao, Shuyang; Zhang, Weiwei; Xu, Pan; Mao, Guoxin

    2016-02-01

    This study focused on determining the role of Spy1 in human epithelial ovarian cancer (EOC). Speedy is a novel cell cycle protein capable of promoting cell proliferation. In this study, western blot and immunohistochemistrical analyses were performed to detect the expression of Spy1 in ovarian cancer. Spy1 protein levels increased with ovarian cancer grade, and Kaplan-Meier curve showed that overexpression of Spy1 was significantly correlated with reduced patient survival. In vitro, Spy1 depletion in ovarian cell lines led to reduced proliferation according to CCK8 and plate colony assays. The expression of Spy1 was positively related to pThr187-p27. Flow cytometry revealed that the reduced expression of Spy1 induced the apoptosis of the EOC cells. In summary, our findings suggested that Spy1 may be a novel independent prognostic predictor of survival for ovarian patients.

  1. 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

  2. Ovarian Tumor Cells Studied Aboard the International Space Station (ISS)

    NASA Technical Reports Server (NTRS)

    2001-01-01

    In August 2001, principal investigator Jeanne Becker sent human ovarian tumor cells to the International Space Station (ISS) aboard the STS-105 mission. The tumor cells were cultured in microgravity for a 14 day growth period and were analyzed for changes in the rate of cell growth and synthesis of associated proteins. In addition, they were evaluated for the expression of several proteins that are the products of oncogenes, which cause the transformation of normal cells into cancer cells. This photo, which was taken by astronaut Frank Culbertson who conducted the experiment for Dr. Becker, shows two cell culture bags containing LN1 ovarian carcinoma cell cultures.

  3. Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression

    PubMed Central

    Nordin, Noraziah; Majid, Nazia Abdul; Hashim, Najihah Mohd; Rahman, Mashitoh Abd; Hassan, Zalila; Ali, Hapipah Mohd

    2015-01-01

    Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression

  4. The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells.

    PubMed

    Brozovic, Anamaria; Duran, George E; Wang, Yan C; Francisco, E Brian; Sikic, Branimir I

    2015-10-01

    We studied the role of miRNA-200 family members in cellular sensitivity to paclitaxel and carboplatin, using two ovarian cancer cell lines, OVCAR-3 and MES-OV, and their paclitaxel resistant variants OVCAR-3/TP and MES-OV/TP. Both resistant variants display a strong epithelial-mesenchymal transition (EMT) phenotype, with marked decreases in expression of miR-200c and miR-141 in OVCAR-3/TP, and down-regulation of all five members of the miR-200 family in MES-OV/TP. Lentiviral transfection of inhibitors of miR-200c or miR-141 in parental OVCAR-3 triggered EMT and rendered the cells resistant to paclitaxel and carboplatin. Conversely, the infection of OVCAR-3/TP cells with retroviral particles carrying the miR-200ab429 and 200c141 clusters triggered a partial mesenchymal to epithelial transition (MET). This partial MET was not sufficient to re-sensitize OVCAR-3/TP cells to paclitaxel. However, the miR-200c/miR-141 cluster transfectants became 6-8x resistant to carboplatin, an unexpected result, whereas miR-200a/miR-200b/miR-429 had no effect. Transfecting the OVCAR-3/TP GFP cells with specific miRNA mimics confirmed these data. MiR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

  5. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer.

    PubMed

    Matsuzaki, Junko; Gnjatic, Sacha; Mhawech-Fauceglia, Paulette; Beck, Amy; Miller, Austin; Tsuji, Takemasa; Eppolito, Cheryl; Qian, Feng; Lele, Shashikant; Shrikant, Protul; Old, Lloyd J; Odunsi, Kunle

    2010-04-27

    NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.

  6. Prediction of Postchemotherapy Ovarian Function Using Markers of Ovarian Reserve

    PubMed Central

    Xia, Rong; Schott, Anne F.; McConnell, Daniel; Banerjee, Mousumi; Hayes, Daniel F.

    2014-01-01

    Background. Reproductive-aged women frequently receive both chemotherapy and endocrine therapy as part of their treatment regimen for early stage hormone receptor-positive breast cancer. Chemotherapy results in transient or permanent ovarian failure in the majority of women. The difficulty in determining which patients will recover ovarian function has implications for adjuvant endocrine therapy decision making. We hypothesized that pretreatment serum anti-Müllerian hormone (AMH) and inhibin B concentrations would predict for ovarian function following chemotherapy. Methods. Pre- and perimenopausal women aged 25–50 years with newly diagnosed breast cancer were enrolled. Subjects underwent phlebotomy for assessment of serum AMH, inhibin B, follicle-stimulating hormone, and estradiol prior to chemotherapy and 1 month and 1 year following completion of treatment. Associations among hormone concentrations, clinical factors, and biochemically assessed ovarian function were assessed. Results. Twenty-seven subjects were evaluable for the primary endpoint. Median age was 41. Twenty subjects (74.1%) experienced recovery of ovarian function within 18 months. Of the 26 evaluable subjects assessed prior to chemotherapy, 19 (73.1%) had detectable serum concentrations of AMH. The positive predictive value of a detectable baseline serum AMH concentration for recovery of ovarian function was 94.7%, and the negative predictive value was 85.7%. On univariate analysis, younger age and detectable serum AMH concentration at chemotherapy initiation were predictive of increased likelihood of recovery of ovarian function. Conclusion. Prechemotherapy assessment of serum AMH may be useful for predicting postchemotherapy ovarian function. This finding has implications for decision making about adjuvant endocrine therapy in premenopausal women treated with chemotherapy. PMID:24319018

  7. Mass Spectrometric Screening of Ovarian Cancer with Serum Glycans

    PubMed Central

    Kim, Jae-Han; Park, Chang Won; Um, Dalho; Baek, Ki Hwang; Jo, Yohahn; An, Hyunjoo; Kim, Yangsun; Kim, Tae Jin

    2014-01-01

    Changes of glycosylation pattern in serum proteins have been linked to various diseases including cancer, suggesting possible development of novel biomarkers based on the glycomic analysis. In this study, N-linked glycans from human serum were quantitatively profiled by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and compared between healthy controls and ovarian cancer patients. A training set consisting of 40 healthy controls and 40 ovarian cancer cases demonstrated an inverse correlation between P value of ANOVA and area under the curve (AUC) of each candidate biomarker peak from MALDI-TOF MS, providing standards for the classification. A multibiomarker panel composed of 15 MALDI-TOF MS peaks resulted in AUC of 0.89, 80~90% sensitivity, and 70~83% specificity in the training set. The performance of the biomarker panel was validated in a separate blind test set composed of 23 healthy controls and 37 ovarian cancer patients, leading to 81~84% sensitivity and 83% specificity with cut-off values determined by the training set. Sensitivity of CA-125, the most widely used ovarian cancer marker, was 74% in the training set and 78% in the test set, respectively. These results indicate that MALDI-TOF MS-mediated serum N-glycan analysis could provide critical information for the screening of ovarian cancer. PMID:24648610

  8. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo

    SciTech Connect

    Hashimoto, Kae; Morishige, Ken-ichirou . E-mail: mken@gyne.med.osaka-u.ac.jp; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  9. Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer.

    PubMed

    Wu, Buchu; Hu, Ke; Li, Shu; Zhu, Jing; Gu, Liying; Shen, Haoran; Hambly, Brett D; Bao, Shisan; Di, Wen

    2012-01-01

    Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration. PMID:22025319

  10. Distinct prognostic values of four-Notch-receptor mRNA expression in ovarian cancer.

    PubMed

    Zhou, Xinling; Teng, Lingling; Wang, Min

    2016-05-01

    Notch signaling pathway includes ligands and Notch receptors, which are frequently deregulated in several human malignancies including ovarian cancer. Aberrant activation of Notch signaling has been linked to ovarian carcinogenesis and progression. In the current study, we used the "Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information from a total of 1306 ovarian cancer patients were used to access the prognostic value of four Notch receptors in ovarian cancer patients. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Notch1 messenger RNA (mRNA) high expression was not found to be correlated to overall survival (OS) for all ovarian cancer, as well as in serous and endometrioid cancer patients followed for 20 years. However, Notch1 mRNA high expression is significantly associated with worsen OS in TP53 wild-type ovarian cancer patients, while it is significantly associated with better OS in TP53 mutation-type ovarian cancer patients. Notch2 mRNA high expression was found to be significantly correlated to worsen OS for all ovarian cancer patients, as well as in grade II ovarian cancer patients. Notch3 mRNA high expression was found to be significantly correlated to better OS for all ovarian cancer patients, but not in serous cancer patients and endometrioid cancer patients. Notch4 mRNA high expression was not found to be significantly correlated to OS for all ovarian cancer patients, serous cancer patients, and endometrioid cancer patients. These results indicate that there are distinct prognostic values of four Notch receptors in ovarian cancer. This information will be useful for better understanding of the heterogeneity and complexity in the molecular biology of ovarian cancer and for developing tools to more accurately predict their prognosis. Based on our results, Notch1 could be a potential drug target of TP53 wild-type ovarian cancer and Notch2 could be a potential drug

  11. Possible role of ovarian epithelial inflammation in ovarian cancer.

    PubMed

    Ness, R B; Cottreau, C

    1999-09-01

    Ovarian cancer is a commonly fatal disease for which prevention strategies have been limited, in part because of a lack of understanding of the underlying biology. This paper reviews the epidemiologic literature in the English language on risk factors and protective factors for ovarian cancer and proposes a novel hypothesis that a common mechanism underlying this disease is inflammation. Previous hypotheses about the causes of ovarian cancer have attributed risk to an excess number of lifetime ovulations or to elevations in steroid hormones. Inflammation may underlie ovulatory events because an inflammatory reaction is induced during the process of ovulation. Additional risk factors for ovarian cancer, including asbestos and talc exposure, endometriosis (i.e., ectopic implantation of uterine lining tissue), and pelvic inflammatory disease, cannot be directly linked to ovulation or to hormones but do cause local pelvic inflammation. On the other hand, tubal ligation and hysterectomy act as protective factors, perhaps by diminishing the likelihood that the ovarian epithelium will be exposed to environmental initiators of inflammation. Inflammation entails cell damage, oxidative stress, and elevations of cytokines and prostaglandins, all of which may be mutagenic. The possibility that inflammation is a pathophysiologic contributor to the development of ovarian cancer suggests a directed approach to future research

  12. Pregnancy following homologous prepubertal ovarian transplantation in the dog

    PubMed Central

    Pullium, Jennifer K; Milner, Ross; Tuma, Gary A

    2008-01-01

    In several canine models of hereditary human disease the homozygote dogs die prior to puberty, or have substantially reduced fertility. To create a clinically healthy animal that can be bred, but can also transmit the gene of interest, a model of homologous ovarian transplantation in prepubertal dogs was developed. Six dog leukocyte antigen (DLA) identical littermates underwent transplantation of ovarian cortical strips (n = 2) or the entire ovary (n = 4). Immunosuppression was maintained with cyclosporine and MMF in the immediate post-operative period and cyclosporine alone thereafter. All 6 dogs entered puberty and normal semiannual estrus cycles as demonstrated by both physical changes and increasing serum progesterone. Four dogs were bred to a proven stud male, and one became pregnant. Three viable fetuses with observable heartbeats were detected on ultrasound examination. Although the dog eventually aborted the litter, this work represents the first pregnancy achieved following a prepubertal ovarian transplant in the dog. PMID:18430233

  13. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

    PubMed Central

    Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

    2015-01-01

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  14. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    PubMed

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  15. MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2

    SciTech Connect

    Xia, Ying; Gao, Yan

    2014-05-09

    Highlights: • miR-181b is upregulated in human ovarian cancer tissues. • miR-181b promotes ovarian cancer cell proliferation and invasion. • LATS2 is a direct target of miR-181b. • LATS2 is involved in miR-181b-induced ovarian cancer cell growth and invasion. - Abstract: MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.

  16. The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels.

    PubMed

    Alsina-Sanchis, Elisenda; Figueras, Agnès; Lahiguera, Álvaro; Vidal, August; Casanovas, Oriol; Graupera, Mariona; Villanueva, Alberto; Viñals, Francesc

    2016-10-15

    In a search for new therapeutic targets for treating epithelial ovarian cancer, we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition.

  17. Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth.

    PubMed

    Kim, Ki-Yon; Kim, Seung U; Leung, Peter C K; Jeung, Eui-Bae; Choi, Kyung-Chul

    2010-04-01

    Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrated toward ovarian cancer cells. A [(3)H] thymidine incorporation assay was conducted to measure the proliferative index. Treatment of human epithelial ovarian cancer cell line (SKOV-3, an ovarian adenocarcinoma derived from the ascites of an ovarian cancer patient) with the prodrugs 5-fluorocytosine (5-FC) or camptothecin-11 (CPT-11) in the presence of HB1.F3.CD or HB1.F3.CE cells resulted in the inhibition of ovarian cancer cell growth. Based on the data presented herein, we suggest that GESTECs expressing CD/CE may have a potent advantage to selectively treat ovarian cancers.

  18. GnRH agonist trigger with intensive luteal phase support vs. human chorionic gonadotropin trigger in high responders: an observational study reporting pregnancy outcomes and incidence of ovarian hyperstimulation syndrome.

    PubMed

    Christopoulos, Georgios; Vlismas, Antonios; Carby, Anna; Lavery, Stuart; Trew, Geoffrey

    2016-09-01

    A retrospective, cohort study of high-risk patients undergoing IVF treatment was performed to assess if there is a difference in clinical pregnancy rate, live birth rate and the incidence of ovarian hyperstimulation syndrome, when a GnRH agonist (GnRHa) trigger with intensive luteal support is compared to human chorionic gonadotropin (hCG) with standard luteal support. The control group consisted of 382 high-risk patients having a GnRH antagonist protocol with 194 receiving an hCG trigger. All patients had ≥18 follicles ≥11mm or serum oestradiol >18,000pmol/l on the day of trigger. Patients had a single or double embryo transfer at cleavage or blastocyst stage. Logistic regression was used to adjust for differences between the groups. An intention-to-treat analysis of all cycles was performed. No statistically significant differences were observed in terms of positive pregnancy test, clinical pregnancy rate and live birth rate. Only one patient (0.3%) was hospitalized with severe OHSS in the GnRHa group, compared to 26 patients (13%) in the hCG group. In conclusion, GnRHa trigger is associated with similar pregnancy rates with hCG trigger and a significant reduction in hospitalization for severe OHSS after an intention to treat analysis was performed. PMID:27662416

  19. Molecular Imaging of Ovarian Cancer

    PubMed Central

    Sharma, Sai Kiran; Nemieboka, Brandon; Sala, Evis; Lewis, Jason S.; Zeglis, Brian M.

    2016-01-01

    Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Over the past decade, medical imaging has played an increasingly valuable role in the diagnosis, staging, and treatment planning of the disease. In this “Focus on Molecular Imaging” review, we seek to provide a brief yet informative survey of the current state of the molecular imaging of ovarian cancer. The article is divided into sections according to modality, covering recent advances in the MR, PET, SPECT, ultrasound, and optical imaging of ovarian cancer. Although primary emphasis is given to clinical studies, preclinical investigations that are particularly innovative and promising are discussed as well. Ultimately, we are hopeful that the combination of technologic innovations, novel imaging probes, and further integration of imaging into clinical protocols will lead to significant improvements in the survival rate for ovarian cancer. PMID:27127223

  20. A rare benign ovarian tumour.

    PubMed

    Palmeiro, Marta Morna; Cunha, Teresa Margarida; Loureiro, Ana Luisa; Esteves, Gonçalo

    2016-01-01

    Sclerosing stromal tumour (SST) of the ovary is an extremely rare and benign ovarian neoplasm, accounting for 6% of the sex cord stromal ovarian tumours subtype. Usually, it is found during the second and third decades of life. Patients commonly present with pelvic pain, a palpable pelvic mass or menstrual irregularity. We report a case of a 20-year-old woman reporting of mild pelvic pain, with normal laboratory data. On imaging examinations, a large right adnexal tumour was found, with features suggesting an ovarian sex cord tumour. The patient underwent right salpingo-oophorectomy, diagnosing a SST of the ovary. This paper also reviews the literature, and emphasises the typical pathological and imaging characteristics of these rare benign ovarian lesions, and their impact, in a conservative surgery. PMID:26933186

  1. The Anterior Gradient Homolog 3 (AGR3) Gene Is Associated with Differentiation and Survival in Ovarian Cancer

    PubMed Central

    King, Erin R.; Tung, Celestine S.; Tsang, Yvonne T.M.; Zu, Zhifei; Lok, Gabriel T.M.; Deavers, Michael T.; Malpica, Anais; Wolf, Judith K.; Lu, Karen H.; Birrer, Michael J.; Mok, Samuel C.; Gershenson, David M.; Wong, Kwong-Kwok

    2011-01-01

    Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 24 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas. PMID:21451362

  2. 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

  3. Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion

    PubMed Central

    Griner, Samantha E.; Joshi, Jayashree P.; Nahta, Rita

    2015-01-01

    Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable overexpression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15-mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression. PMID:23085437

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

    ClinicalTrials.gov

    2016-09-26

    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

  5. Recurrent ovarian cancer.

    PubMed

    Pujade-Lauraine, E; Combe, P

    2016-04-01

    Recurrence still occurs in a majority of patients with advanced ovarian cancer. However, progress in the management has allowed a significant prolongation of survival for relapsing disease. These last years, the field of interest has moved from chemotherapy to targeted therapy which is dominated by anti-angiogenic and anti-PARP agents. It is assumed that platinum-free interval will not remain the main prognostic and predictive criterion in the future, and will be replaced by a multi-factorial approach. This trend for personalization of therapy has highlighted important neglected fields for clinical research such as multi-line (≥3) relapse, frail patients including elderly and symptomatic and supportive measures. PMID:27141075

  6. Premature ovarian failure.

    PubMed

    Vujović, Svetlana; Ivović, Miomira; Tancić-Gajić, Milina; Marina, Ljiljana; Barać, Marija; Arizanović, Zorana; Nenezić, Ana; Ivanisević, Maja; Micić, Jelena; Sajić, Silvija; Micić, Dragan

    2012-01-01

    Premature ovarian failure (POF) is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions) or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc.The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone), karyotype (<30 years of age), ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc. PMID:23350261

  7. [Premature ovarian failures].

    PubMed

    Bricaire, Léopoldine; Laroche, Emmanuelle; Bourcigaux, Nathalie; Donadille, Bruno; Christin-Maitre, Sophie

    2013-11-01

    Premature ovarian failure (POF) is clinically suspected by amenorrhea and confirmed by an elevated FSH serum level above 40 mUI/L (even 20 mUI/L) twice, in a woman before the age of 40. Prevalence of POF is between 1 to 2% in women. In 90% of cases, no aetiology is identified. Obvious causes are chemotherapy, pelvic radiotherapy, ovarian surgery and diethylstilbestrol exposure in utero. A karyotype should be performed as Turner Syndrome is the most frequent genetic cause of POF. Some X abnormalities such as X deletion or X autosome translocation can be found. FMR1 pre-mutation (fragile X syndrome) should be searched for, even though no cases of mental retardation are known, in the family. Other genetic abnormalities can be suggested by associated symptoms (i.e.: FOXL2, SF1 mutations). Auto-immune aetiology can be suspected if other auto-immune features are present, however, there are no reliable auto-antibodies to confirm auto-immunity in POF. Treatment of POF is based on hormonal replacement therapy in order to avoid estrogen deficiency, suppress vasomotor symptoms and avoid bone loss as well as cardiovascular risk. Estrogens should be associated with progesterone or a progestin, at least up to the age of 51. Patients with POF should be informed that spontaneous pregnancies may occur (in 5% of cases). In case of desire of pregnancy, the patient should be oriented to a specialized unit for in vitro fertilization with oocyte donation. Psychological support is essential and should be part of the treatment. POF is associated with an increased risk of emotional distress and depression. No preventive treatment of POF is available so far. PMID:24157186

  8. Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis.

    PubMed

    Fuseya, Chiho; Horiuchi, Akiko; Hayashi, Akiko; Suzuki, Akihisa; Miyamoto, Tsutomu; Hayashi, Takuma; Shiozawa, Tanri

    2012-11-01

    Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that

  9. Survivorship Care Planning in Improving Quality of Life in Survivors of Ovarian Cancer

    ClinicalTrials.gov

    2016-08-19

    Cancer Survivor; Stage IA Ovarian Epithelial Cancer; Stage IB Ovarian Epithelial Cancer; Stage IC Ovarian Epithelial Cancer; Stage IIA Ovarian Epithelial Cancer; Stage IIB Ovarian Epithelial Cancer; Stage IIC Ovarian Epithelial Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer

  10. Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer.

    PubMed

    Merritt, Melissa A; Green, Adèle C; Nagle, Christina M; Webb, Penelope M

    2008-01-01

    Chronic inflammation has been proposed as the possible causal mechanism that explains the observed association between certain risk factors, such as the use of talcum powder (talc) in the pelvic region and epithelial ovarian cancer. To address this issue we evaluated the potential role of chronic local ovarian inflammation in the development of the major subtypes of epithelial ovarian cancer. Factors potentially linked to ovarian inflammation were examined in an Australia-wide case-control study comprising 1,576 women with invasive and low malignant potential (LMP) ovarian tumours and 1,509 population-based controls. We confirmed a statistically significant increase in ovarian cancer risk associated with use of talc in the pelvic region (adjusted odds ratio 1.17, 95% CI: 1.01-1.36) that was strongest for the serous and endometrioid subtypes although the latter was not statistically significant (adjusted odds ratios 1.21, 95% CI 1.03-1.44 and 1.18, 95% CI 0.81-1.70, respectively). Other factors potentially associated with ovarian inflammation (pelvic inflammatory disease, human papilloma virus infection and mumps) were not associated with risk but, like others, we found an increased risk of endometrioid and clear cell ovarian cancer only among women with a history of endometriosis. Regular use of aspirin and other nonsteroidal anti-inflammatory drugs was inversely associated with risk of LMP mucinous ovarian tumours only. We conclude that on balance chronic inflammation does not play a major role in the development of ovarian cancer.

  11. Exercise May Help Thwart Ovarian Cancer

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159486.html Exercise May Help Thwart Ovarian Cancer Chronic inactivity linked ... TUESDAY, June 21, 2016 (HealthDay News) -- Lack of exercise is associated with an increased risk of ovarian ...

  12. FDA Warns Ovarian Cancer Tests Not Reliable

    MedlinePlus

    ... medlineplus.gov/news/fullstory_160880.html FDA Warns Ovarian Cancer Tests Not Reliable May delay preventive therapies for ... Sept. 9, 2016 (HealthDay News) -- Screening tests for ovarian cancer are not reliable and should not be used, ...

  13. 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.

  14. Ovarian cancer: etiology, risk factors, and epidemiology.

    PubMed

    Hunn, Jessica; Rodriguez, Gustavo C

    2012-03-01

    Little is known regarding the early aspects of ovarian carcinogenesis. As a consequence, the identification of women at risk for the disease is based primarily on clinical grounds, with family history being the most important risk factor. In this review, we will discuss the various hypotheses regarding ovarian etiology and pathogenesis. In addition, we will discuss the epidemiology of ovarian cancer, including hereditary, reproductive, hormonal, inflammatory, dietary, surgical, and geographic factors that influence ovarian cancer risk.

  15. Overexpression of centromere protein K (CENPK) in ovarian cancer is correlated with poor patient survival and associated with predictive and prognostic relevance.

    PubMed

    Lee, Yi-Chao; Huang, Chi-Chen; Lin, Ding-Yen; Chang, Wen-Chang; Lee, Kuen-Haur

    2015-01-01

    Ovarian cancer has a poor prognosis. Most patients are diagnosed with ovarian cancer when the disease has reached an advanced stage and cure rates are generally under 30%. Hence, early diagnosis of ovarian cancer is the best means to control the disease in the long term and abate mortality. So far, cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) are the gold-standard tumor markers for ovarian cancer; however, these two markers can be elevated in a number of conditions unrelated to ovarian cancer, resulting in decreased specifically and positive predictive value. Therefore, it is urgent to identify novel biomarkers with high reliability and sensitivity for ovarian cancer. In this study for the first time, we identified a member of the centromere protein (CENP) family, CENPK, which was specifically upregulated in ovarian cancer tissues and cell lines and the overexpression of which was associated with poor prognoses in patients with ovarian cancer. In addition, the presence of CENPK significantly improved the sensitivity of CA125 or HE4 for predicting clinical outcomes of ovarian cancer patients. In conclusion, we identified that CENPK was specifically upregulated in ovarian cancer cells and can be used as a novel tumor marker of ovarian cancer. PMID:26587348

  16. An Update on Ovarian Aging and Ovarian Reserve Tests

    PubMed Central

    Amanvermez, Ramazan; Tosun, Migraci

    2016-01-01

    Ovaries are the female organs that age more quickly than other tissues such as the uterus, the pituitary gland or pancreas. Different from males, an interesting question is why and how the females lose fertility so rapidly. During the aging process, both the number and quality of the oocytes in the ovaries decrease and reach to a point beyond that no more viable offspring may be produced and the associated cyclic endocrinological activities cease, entering the menopause in females at an average age of 50 years. Females who delayed childbearing with or without their willing until their 30 years or 40 years constitute the largest portion of the total infertility population. Ovarian reserve tests (ORTs) provide an indirect estimate of a female’s diminishing ovarian reserve or remaining follicular pool. This article briefly reviews recent progresses in relation to ovarian aging and ORTs. PMID:26985328

  17. Ovarian teratoma and endometritis in a mare

    PubMed Central

    2005-01-01

    Abstract An 8-year-old Arabian mare was admitted for a large ovarian anovulatory follicle. A clinical diagnosis of ovarian tumor and endometritis was established. Histological examinations revealed an ovarian teratoma and a grade II endometritis. Three months after unilateral ovariectomy, the mare was confirmed pregnant and eventually gave birth uneventfully. PMID:16363331

  18. Pediatric ovarian torsion: a pictorial review.

    PubMed

    Ngo, Anh-Vu; Otjen, Jeffrey P; Parisi, Marguerite T; Ferguson, Mark R; Otto, Randolph K; Stanescu, A Luana

    2015-11-01

    Imaging is crucial in expediting the diagnosis and guiding definitive therapy in children with ovarian torsion. This article reviews the multimodality spectrum of imaging findings in pediatric ovarian torsion, focusing primarily on US appearances. We describe predisposing conditions that can lead to torsion, the pathological basis of the radiologic findings in ovarian torsion, and the common diagnostic pitfalls.

  19. The epidemiology of ovarian cancer.

    PubMed

    Greene, M H; Clark, J W; Blayney, D W

    1984-09-01

    Although no unequivocally effective ovarian cancer prevention strategies have emerged, epidemiologic studies have identified high-risk populations. The striking international variation (apparently a fivefold difference) can probably be explained on the basis of differential parity, differing classification measures, and differences in the underlying population age distribution. United States age-adjusted mortality has increased slightly in the past 30 years, and the cancer remains predominantly a disease of older adult white women of northern European extraction. The increases in age-specific mortality and age-adjusted mortality over time may be related to a decrease in average family size. Pregnancy, especially pregnancy before age 25 years, and use of oral contraceptives are protective; the risk of ovarian cancer increases with increasing years of ovulation. A positive family history is also associated with a substantial increase in ovarian cancer risk. Survivors of ovarian cancer are more susceptible to cancers of the breast, endometrium, and colon than are similarly-aged normal women, most probably because all four cancers share some common risk factor(s). Various alkylating agents are clearly leukemogenic in survivors of ovarian cancer, an observation that suggests caution in the use of adjuvant chemotherapy in women at relatively low risk of relapse.

  20. Regulation of ovarian hyperluteinization.

    PubMed

    Ivanisevic-Milovanovic, O K; Demajo, M A; Karakasevic, A M; Pantic, V R

    1998-01-01

    Adult female rats with neonatally damaged posterior hypothalamus, made by a transversal cut, were investigated. Plasma levels of prolactin (PRL), gonadotropic hormones (GTH) and female gonadal steroids (GS) were determined by radioimmunoassay. The animals were sacrificed, at the ages of 4 and 6 months and their hypothalamus, pituitary gland, ovary and uterus were examined using light microscopy. The results can be summarized as follows: body mass of animals, with damaged posterior hypothalamus, was significantly reduced. Masses of luteinized ovaries were increased and uterine tissues decreased. Serum levels of PRL were significantly increased and luteinizing hormone (LH) decreased. Ultrastructural changes in the corpora lutea (CL), previously described, showed clear signs of their reduced capacities to produce GS, both estradiol (Oe) and progesterone (Pg) per total ovarian mass. However, prostaglandin 2 alfa (PGF2alpha) known as a luteolytic factor, was also diminished in the evidently retarded endometrium. As a result of decreased plasma values of LH, Pg and PGF2 alpha, luteolysis of CL in hyperluteinized ovaries did not occur, and their new generations were accumulated during subsequent cycles. The character of interruption and recovery of aminergic and peptidergic neurons, involved in regulation of hypothalamic-pituitary gonadal axis and feed-back effects of steroid hormones, require further studies.

  1. 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

  2. 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

  3. 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

  4. Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer

    PubMed Central

    Scorilas, A; Kyriakopoulou, L; Katsaros, D; Diamandis, E P

    2001-01-01

    By using the positional cloning gene approach, we were able to identify a novel gene encoding for a serine/arginine-rich protein, which appears to be the human homologue of the rat A1 gene. We named this new gene SR-A1. Members of the SR family of proteins have been shown to interact with the C-terminal domain (CTD) of the large subunit of RNA polymerase II and participate in pre-mRNA splicing. We have localized the SR-A1 gene between the known genes IRF3 and RRAS on chromosome 19q13.3. The novel gene spans 16.7 kb of genomic sequence and it is formed of 11 exons and 10 intervening introns. The SR-A1 protein is composed of 1312 amino acids, with a molecular mass of 139.3 kDa and a theoretical isoelectric point of 9.31. The SR-A1 protein contains an SR-rich domain as well as a CTD-binding domain present only in a subset of SR-proteins. Through interactions with the pre-mRNA and the CTD domain of the Polymerase II, SR proteins have been shown to regulate alternative splicing. The SR-A1 gene is expressed in all tissues tested, with highest levels found in fetal brain and fetal liver. Our data suggest that this gene is overexpressed in a subset of ovarian cancers which are clinically more aggressive. Studies with the steroid hormone receptor-positive breast and prostate carcinoma cell lines ZR-75-1, BT-474 and LNCaP, respectively, suggest that SR-A1 is constitutively expressed. Furthermore, the mRNA of the SR-A1 gene in these cell lines appears to increase by estrogens, androgens and glucocorticoids, and to a lesser extend by progestins. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11461075

  5. Comparing long term impact on ovarian reserve between laparoscopic ovarian cystectomy and open laprotomy for ovarian endometrioma

    PubMed Central

    2013-01-01

    Objective To compare the long term impact on ovarian reserve between laparoscopic ovarian cystectomy with bipolar electrocoagulation and laparotomic cystectomy with suturing for ovarian endometrotic cyst. Patient and method(s) 121 patients with benign ovarian endometroitic cysts were randomised to either laparoscopic ovarian cystectomy using bipolar electrocoagulation (61 patients) or laparotomic ovarian cystectomy using sutures (60 patients). Serum follicle-stimulating hormone, Antimullerian hormon, Basal antral follicle Count, mean ovarian diameter, and ovarian stromal blood flow velocity were measured at 6, 12 and 18 months after surgery and compared in both groups. Result(s) A statistically significant increase of serum FSH was found in the laproscopic bipolar group at 6-, 12 and 18-month postoperativly compared to open laparotomy suture group. Also, a statistically significant decrease of the mean AMH value occurred in laproscopic bipolar group at 6-, 12 and 18-month follow- up compared to open laparotomy suture group. Basal antral follicle number, mean ovarian diameter and peak systolic velocity were significantly decreased during the 6-, 12,18 -month follow-up in laproscopic bipolar group compared to open laparotomy suture group. Conclusion(s) After laproscopic ovarian cystecomy for endometrioma all pareameter of ovarian reseve are significantly decreased on long term follow up as compared to open laprotomy. PMID:24180348

  6. Molecular imaging in ovarian cancer.

    PubMed

    Reyners, A K L; Broekman, K E; Glaudemans, A W J M; Brouwers, A H; Arts, H J G; van der Zee, A G J; de Vries, E G E; Jalving, M

    2016-04-01

    Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer. PMID:27141066

  7. Ovarian cancer stem cells enrichment.

    PubMed

    Yang, Lijuan; Lai, Dongmei

    2013-01-01

    The concept of cancer stem cells (CSCs) provides a new paradigm for understanding cancer biology. Cancer stem cells are defined as a minority of cancer cells with stem cell properties responsible for maintenance and growth of tumors. The targeting of CSCs is a potential therapeutic strategy to combat ovarian cancer. Ovarian epithelial cancer cells cultured in serum-free medium can form sphere cells. These sphere cells may be enriched for cancer stem cells (CSCs). The isolation of sphere cells from solid tumors is an important technique in studying cancer cell biology. Here we describe the isolation of sphere cells from primary ovarian cancer tissue, ascites fluid, and the cancer cell line SKOV3 with stem cell selection medium. PMID:23913228

  8. Serial Patterns of Ovarian Cancer Biomarkers in a Prediagnosis Longitudinal Dataset.

    PubMed

    Blyuss, Oleg; Gentry-Maharaj, Alex; Fourkala, Evangelia-Orania; Ryan, Andy; Zaikin, Alexey; Menon, Usha; Jacobs, Ian; Timms, John F

    2015-01-01

    Early detection of ovarian cancer through screening may have impact on mortality from the disease. Approaches based on CA125 cut-off have not been effective. Longitudinal algorithms such as the Risk of Ovarian Cancer Algorithm (ROCA) to interpret CA125 have been shown to have higher sensitivity and specificity than a single cut-off. The aim of this study was to investigate whether other ovarian cancer-related biomarkers, Human Epididymis 4 (HE4), glycodelin, mesothelin, matrix metalloproteinase 7 (MMP7), and cytokeratin 19 fragment (CYFRA 21-1), could improve the performance of CA125 in detecting ovarian cancer earlier. Serum samples (single and serial) predating diagnosis from 47 women taking part in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) who went on to develop primary invasive ovarian, fallopian tube, or peritoneal cancer (index cancer) (170 samples) and 179 matched controls (893 samples) were included in the study. A multiplex immunobased assay platform (Becton Dickinson) allowing simultaneous measurement of the six serum markers was used. The area under the ROC curve for the panel of three biomarkers (CA125, HE4, and glycodelin) was higher than for CA125 alone for all analysed time groups, indicating that these markers can improve on sensitivity of CA125 alone for ovarian cancer detection.

  9. Serial Patterns of Ovarian Cancer Biomarkers in a Prediagnosis Longitudinal Dataset.

    PubMed

    Blyuss, Oleg; Gentry-Maharaj, Alex; Fourkala, Evangelia-Orania; Ryan, Andy; Zaikin, Alexey; Menon, Usha; Jacobs, Ian; Timms, John F

    2015-01-01

    Early detection of ovarian cancer through screening may have impact on mortality from the disease. Approaches based on CA125 cut-off have not been effective. Longitudinal algorithms such as the Risk of Ovarian Cancer Algorithm (ROCA) to interpret CA125 have been shown to have higher sensitivity and specificity than a single cut-off. The aim of this study was to investigate whether other ovarian cancer-related biomarkers, Human Epididymis 4 (HE4), glycodelin, mesothelin, matrix metalloproteinase 7 (MMP7), and cytokeratin 19 fragment (CYFRA 21-1), could improve the performance of CA125 in detecting ovarian cancer earlier. Serum samples (single and serial) predating diagnosis from 47 women taking part in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) who went on to develop primary invasive ovarian, fallopian tube, or peritoneal cancer (index cancer) (170 samples) and 179 matched controls (893 samples) were included in the study. A multiplex immunobased assay platform (Becton Dickinson) allowing simultaneous measurement of the six serum markers was used. The area under the ROC curve for the panel of three biomarkers (CA125, HE4, and glycodelin) was higher than for CA125 alone for all analysed time groups, indicating that these markers can improve on sensitivity of CA125 alone for ovarian cancer detection. PMID:26819954

  10. Diagnostic tool for early detection of ovarian cancers using Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Lieber, Chad A.; Molpus, Kelly; Brader, Kevin; Mahadevan-Jansen, Anita

    2000-05-01

    With an overall survival rate of about 35 percent, ovarian cancer claims more than 13,000 women in the US each year. It is estimated that roughly 1 in 70 women will develop ovarian cancer. Current screening techniques are challenged due to cost-effectiveness, variable false-positive results, and the asymptomatic nature of the early stages of ovarian cancer. The predominant screening method for ovarian cancers is transvaginal sonography (TVS). TVS is fairly accomplished at ovarian cancer detection, however it is inefficient in distinguishing between benign and malignant masses. Accurate diagnosis of the ovarian tumor relies on exploratory laparotomy, thus increasing the cost and hazard of false- positive screening methods. Raman spectroscopy has been sued successfully as a diagnostic tool in several organ systems in vitro. These studies have shown that Raman spectroscopy can be used to provide diagnosis of subtle changes in tissue pathology with high accuracy. Based on this success, we have developed a Raman spectroscopic system for application in the ovary. Using this system, the Raman signatures of normal and various types of non-normal human ovarian tissues were characterized in vitro. Raman spectra are being analyzed, and empirical as well as multivariate discriminatory algorithms developed. Based on the result of this study, a strategy for in vivo trials will be planned.

  11. Photoacoustic characterization of ovarian tissue

    NASA Astrophysics Data System (ADS)

    Aguirre, Andres; Gamelin, John; Guo, Puyun; Yan, Shikui; Sanders, Mary; Brewer, Molly; Zhu, Quing

    2009-02-01

    Ovarian cancer has the highest mortality of all gynecologic cancers with a five-year survival rate of only 30%. Because current imaging techniques (ultrasound, CT, MRI, PET) are not capable of detecting ovarian cancer early, most diagnoses occur in later stages (III/IV). Thus many women are not correctly diagnosed until the cancer becomes widely metastatic. On the other hand, while the majority of women with a detectable ultrasound abnormality do not harbor a cancer, they all undergo unnecessary oophorectomy. Hence, new imaging techniques that can provide functional and molecular contrasts are needed for improving the specificity of ovarian cancer detection and characterization. One such technique is photoacoustic imaging, which has great potential to reveal early tumor angiogenesis through intrinsic optical absorption contrast from hemoglobin or extrinsic contrast from conjugated agents binding to appropriate molecular receptors. To better understand the cancer disease process of ovarian tissue using photoacoustic imaging, it is necessary to first characterize the properties of normal ovarian tissue. We have imaged ex-vivo ovarian tissue using a 3D co-registered ultrasound and photoacoustic imaging system. The system is capable of volumetric imaging by means of electronic focusing. Detecting and visualizing small features from multiple viewing angles is possible without the need for any mechanical movement. The results show strong optical absorption from vasculature, especially highly vascularized corpora lutea, and low absorption from follicles. We will present correlation of photoacoustic images from animals with histology. Potential application of this technology would be the noninvasive imaging of the ovaries for screening or diagnostic purposes.

  12. Etiology, biology, and epidemiology of ovarian cancer.

    PubMed

    Baker, T R; Piver, M S

    1994-01-01

    Epithelial ovarian cancer kills more women per year than all other gynecologic cancers combined. Pregnancy, oral contraceptive use, and tubal ligation decrease the risk of the disease, whereas risk is increased for women whose family history is consistent with one of the familial ovarian cancer syndromes. Several theories have been postulated concerning the etiology of ovarian cancer, including the incessant ovulation theory and that based on the model of hypergonadotropic hypogonadism. Chromosomal abnormalities and allele losses have been described in ovarian cancers. Involvement of oncogenes and tumor suppressor genes has been investigated as well. Genetic linkage studies are ongoing in families whose history is consistent with one of the familial ovarian cancer syndromes.

  13. Motility Related Actinin Alpha-4 Is Associated with Advanced and Metastatic Ovarian Carcinoma

    PubMed Central

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

    2010-01-01

    Advanced and metastatic ovarian cancer is a leading cause of death from gynecologic malignancies. A more detailed understanding of the factors controlling invasion and metastasis may lead to novel anti-metastatic therapies. To model cellular interactions that occur during intraperitoneal metastasis, comparative cDNA microarray analysis and confirmatory real time RT-PCR were employed to uncover changes in gene expression that may occur in late stage ovarian cancer in response to microenvironmental cues, particularly native three-dimensional collagen I. Gene expression in human ovarian carcinoma tissues was evaluated on the RNA and protein level using real time RT-PCR and immunohistochemistry. Cell invasion and migration were evaluated in a collagen invasion assay and a scratch wound assay. Three-dimensional collagen I culture led to differential expression of several genes. The role of actinin alpha-4 (ACTN4), a cytosketeton-associated protein implicated in regulation of cell motility, was examined in detail. ACTN4 RNA and protein expression were associated with advanced and metastatic human ovarian carcinoma. This report demonstrates that a cytoskeletal-associated protein ACTN4 is upregulated by three-dimensional collagen culture conditions, leading to increased invasion and motility of ovarian cancer cells. Expression of ACTN4 in human ovarian tumors was found to be associated with advanced stage disease and peritoneal metastases. PMID:18362906

  14. Massive Ovarian Oedema- A Case Report.

    PubMed

    Harke, Arun B; Sigamani, Karthik; Thukkaram, Chitra; Ramamurthy, Madhumittha; Sekar, Manjani

    2016-08-01

    Massive ovarian oedema is defined by WHO as formation of tumour like enlargement of one or both ovaries by oedema fluid. We report a case of a 18-year-old unmarried girl who presented with three months amenorrhoea and left sided lower abdominal pain with clinical and radiological diagnosis of cystic ovarian neoplasm. Patient underwent lapratomy with left salpingo-oophorectomy. A definitive diagnosis of Massive Ovarian Oedema (MOE) was offered on histopathological examination. The MOE should be differentiated from ovarian fibromatosis, ovarian fibroma, sclerosing stromal tumour and ovarian myxoma. The usual management of massive oedema of ovary is unilateral salpingo-oophorectomy, as the lesion is mistaken for primary ovarian neoplasm at laparotomy. Recognition of MOE is of great importance to prevent unnecessary oophorectomy in young patients and can be managed conservatively. We report this case of MOE for its rarity. PMID:27656451

  15. Defining ovarian reserve to better understand ovarian aging

    PubMed Central

    2011-01-01

    Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes. PMID:21299886

  16. Palliative Care in Improving Quality of Life and Symptoms in Patients With Stage III-IV Pancreatic or Ovarian Cancer

    ClinicalTrials.gov

    2014-12-18

    Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer

  17. Mammaglobin B (SCGB2A1) is a novel tumour antigen highly differentially expressed in all major histological types of ovarian cancer: implications for ovarian cancer immunotherapy

    PubMed Central

    Bellone, S; Tassi, R; Betti, M; English, D; Cocco, E; Gasparrini, S; Bortolomai, I; Black, J D; Todeschini, P; Romani, C; Ravaggi, A; Bignotti, E; Bandiera, E; Zanotti, L; Pecorelli, S; Ardighieri, L; Falchetti, M; Donzelli, C; Siegel, E R; Azodi, M; Silasi, D-A; Ratner, E; Schwartz, P E; Rutherford, T J; Santin, A D

    2013-01-01

    Background: We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. Methods: We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear-cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours. Results: Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-γ secretion) in SCGB2A1-specific CTLs. Conclusion: SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy. PMID:23807163

  18. MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells.

    PubMed

    Chen, Liang; Zhang, Fang; Sheng, Xiu-Gui; Zhang, Shi-Qian; Chen, Yue-Ting; Liu, Bo-Wen

    2016-10-01

    Ovarian cancer is a leading cause of malignant gynecological tumor-related mortality among women. The treatment of ovarian cancer patients continues to be challenging. MicroRNA‑106a (miR‑106a) is widely expressed in diverse human tumors. In the present study, we investigated the biological and pathological roles of miR-106a in ovarian cancers. We found that miR-106a expression was significantly increased in primary ovarian cancer tissues and ovarian cancer cells compared with the level in normal tissues. Ectopic expression of an miR-106a inhibitor attenuated ovarian cancer cell proliferation and invasion. miR-106a promoted the growth and invasion of SKOV3 cells by targeting phosphatase and tensin homolog (PTEN). Furthermore, the present study revealed that IL-6 inhibited miR-106a expression by activating STAT3. Tocilizumab, a humanized anti-human IL-6R antibody, that competitively inhibits IL-6/IL-6R signaling, did not inhibit the proliferation and invasion of SKOV3 cells. In conclusion, our studies revealed that miR-106a was significantly increased in the ovarian cancer tissues and cell lines. Downregulation of the expression of miR-106a inhibited cell growth and metastasis of ovarian cancer cells. Together, the present study suggests that miR‑106a acts as an oncogene in ovarian cancers. PMID:27510094

  19. Primary Human Uterine Leiomyoma Cell Culture Quality Control: Some Properties of Myometrial Cells Cultured under Serum Deprivation Conditions in the Presence of Ovarian Steroids

    PubMed Central

    Sumikawa, Joana Tomomi; Batista, Fabrício Pereira; Paredes-Gamero, Edgar J.; Girão, Manoel J. B. C.; Oliva, Maria Luiza V.

    2016-01-01

    Cell culture is considered the standard media used in research to emulate the in vivo cell environment. Crucial in vivo experiments cannot be conducted in humans and depend on in vitro methodologies such as cell culture systems. However, some procedures involving the quality control of cells in culture have been gradually neglected by failing to acknowledge that primary cells and cell lines change over time in culture. Thus, we report methods based on our experience for monitoring primary cell culture of human myometrial cells derived from uterine leiomyoma. We standardized the best procedure of tissue dissociation required for the study of multiple genetic marker systems that include species-specific antigens, expression of myofibroblast or myoblast markers, growth curve, serum deprivation, starvation by cell cycle synchronization, culture on collagen coated plates, and 17 β-estradiol (E2) and progesterone (P4) effects. The results showed that primary myometrial cells from patients with uterine leiomyoma displayed myoblast phenotypes before and after in vitro cultivation, and leiomyoma cells differentiated into mature myocyte cells under the appropriate differentiation-inducing conditions (serum deprivation). These cells grew well on collagen coated plates and responded to E2 and P4, which may drive myometrial and leiomyoma cells to proliferate and adhere into a focal adhesion complex involvement in a paracrine manner. The establishment of these techniques as routine procedures will improve the understanding of the myometrial physiology and pathogenesis of myometrium-derived diseases such as leiomyoma. Mimicking the in vivo environment of fibrotic conditions can prevent false results and enhance results that are based on cell culture integrity. PMID:27391384

  20. Genetically modified mouse models for premature ovarian failure (POF).

    PubMed

    Jagarlamudi, Krishna; Reddy, Pradeep; Adhikari, Deepak; Liu, Kui

    2010-02-01

    Premature ovarian failure (POF) is a complex disorder that affects approximately 1% of women. POF is characterized by the depletion of functional ovarian follicles before the age of 40 years, and clinically, patients may present with primary amenorrhea or secondary amenorrhea. Although some genes have been hypothesized to be candidates responsible for POF, the etiology of most of the cases is idiopathic, with the underlying causes still unidentified because of the heterogeneity of the disease. In this review, we consider some mutant mouse models that exhibit phenotypes which are comparable to human POF, and we suggest that the use of these mouse models may help us to gain a better understanding of the molecular mechanisms underlying POF in humans.

  1. Quantification of photoacoustic microscopy images for ovarian cancer detection

    NASA Astrophysics Data System (ADS)

    Wang, Tianheng; Yang, Yi; Alqasemi, Umar; Kumavor, Patrick D.; Wang, Xiaohong; Sanders, Melinda; Brewer, Molly; Zhu, Quing

    2014-03-01

    In this paper, human ovarian tissues with malignant and benign features were imaged ex vivo by using an opticalresolution photoacoustic microscopy (OR-PAM) system. Several features were quantitatively extracted from PAM images to describe photoacoustic signal distributions and fluctuations. 106 PAM images from 18 human ovaries were classified by applying those extracted features to a logistic prediction model. 57 images from 9 ovaries were used as a training set to train the logistic model, and 49 images from another 9 ovaries were used to test our prediction model. We assumed that if one image from one malignant ovary was classified as malignant, it is sufficient to classify this ovary as malignant. For the training set, we achieved 100% sensitivity and 83.3% specificity; for testing set, we achieved 100% sensitivity and 66.7% specificity. These preliminary results demonstrate that PAM could be extremely valuable in assisting and guiding surgeons for in vivo evaluation of ovarian tissue.

  2. Ovarian Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  3. Association between P16INK4a Promoter Methylation and Ovarian Cancer: A Meta-Analysis of 12 Published Studies

    PubMed Central

    Niu, Xun; Shi, Hao; Zhong, Yi

    2016-01-01

    Background Ovarian cancer is the primary cause of death in women diagnosed with gynecological malignancies worldwide. Absence of early symptoms prevents prompt diagnosis or successful therapeutic intervention. P16INK4a is a well-known tumor suppressor gene (TSG). Aberrant methylation of TSG promoter is an important epigenetic silencing mechanism leading to ovarian cancer progression. Studies have reported differences in methylation frequencies of the p16INK4a promoter between ovarian cancer and the corresponding control group. However, the association between p16INK4a promoter methylation and ovarian cancer remains unclear and controversial. Therefore, a meta-analysis was conducted to clarify the relationship between p16INK4a promoter methylation and ovarian cancer. Methods PubMed, Web of Science, EMBASE and CNKI were searched to identify eligible studies for the evaluation of the association between p16INK4a promoter methylation and ovarian cancer. Odds ratio (ORs) and 95% confidence intervals (95%CI) were calculated to determine the strength of association between p16INK4a promoter methylation and ovarian cancer. Results A total of 612 ovarian cancer patients and 289 controls from 12 eligible studies were included in the meta-analysis. Overall, a significant association was observed between p16INK4a methylation status and ovarian cancer risk using a fixed-effects model (OR = 2.02, 95% CI = 1.39–2.94). Conclusion The results of our meta-analysis show that aberrant methylation of p16INK4a promoter was significantly associated with ovarian cancer. It may represent a promising molecular marker to monitor the disease and provides new insights into the treatment of human ovarian cancer. PMID:27648827

  4. Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the morris water maze.

    PubMed

    Markham, J A; Pych, J C; Juraska, J M

    2002-11-01

    Ovarian steroids have been suggested to aid in preserving cognitive functioning during aging in both humans and other animals. Spatial memory relies heavily on the hippocampus, a structure that is sensitive to the influence of both ovarian hormones and aging. The present study investigated the outcome of ovarian hormone replacement during aging on performance in a spatial version of the Morris water maze. Female rats were ovariectomized at 14 months of age and received one of three types of replacement prior to testing at 16 months: acute estrogen replacement (2 days), chronic estrogen replacement (28 days), or chronic replacement of both estrogen and progesterone (28 days). Control animals, which did not receive replacement hormones, displayed significant overnight forgetting during acquisition of the task. Ovarian hormone replacement, both acute and chronic, prevented forgetting. Previous studies have demonstrated that high levels of ovarian hormones are detrimental to performance of young adult female rats on this task (Warren and Juraska, 1997; Chesler and Juraska, 2000). The current study found an opposite effect during aging: ovarian hormone replacement was beneficial. This suggests that animal models of menopause, aimed at exploring the protective effects of hormone replacement therapy on cognition during human female aging, require the use of aged female animals.

  5. JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer.

    PubMed

    Qiu, Haifeng; Jackson, Amanda L; Kilgore, Joshua E; Zhong, Yan; Chan, Leo Li-Ying; Gehrig, Paola A; Zhou, Chunxiao; Bae-Jump, Victoria L

    2015-03-30

    Amplification and overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types. Using ovarian cancer cell lines, a transgenic mouse model, and primary cell cultures from human ovarian cancer tissues, we demonstrated that JQ1 significantly suppressed cellular proliferation and induced cell cycle arrest and apoptosis in ovarian cancer cells and mouse model via targeting c-Myc. In addition, JQ1 had multiple influences on cancer metabolism, particularly in the aerobic glycolysis pathway. JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors. Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.

  6. c-erbB-2 oncoprotein assay in ovarian carcinoma and its clinical correlation with prognostic factors.

    PubMed

    Kim, Y T; Kim, J W; Lee, J W

    1998-10-23

    Overexpression of the c-erbB-2 oncoprotein has been detected in human adenocarcinoma of the breast, cervix and salivary gland, in all of which an association between the overexpression of the c-erbB-2 and a poor prognosis of the disease has been reported. However, the prognostic role of c-erbB-2 oncoprotein in ovarian carcinoma remains controversial. We measured c-erbB-2 oncoprotein with an enzyme-linked immunosorbent assay (ELISA). Patients with invasive ovarian cancer were found to have significantly higher median c-erbB-2 oncoprotein expression than patients with either benign ovarian cyst (P = 0.002) or control groups (P = 0.001). Overexpression of c-erbB-2 oncoprotein was found in seven (21.9%) of 32 epithelial ovarian cancers. Our results suggest that quantitative analysis of c-erbB-2 oncoprotein may be used to define the prognostic significance of ovarian carcinoma.

  7. [Presumed ovarian benign tumors and fertility].

    PubMed

    Aubard, Y; Poirot, C

    2013-12-01

    We reviewed the studies about fertility-sparing in young patient presenting a benign ovarian tumor. It appears that more than the histologic nature of the ovarian cysts, it is the surgical treatment of the cyst which may decrease fertility. Some good practice of surgical procedures must be kept in mind when one manages a benign ovarian tumor in a young patient wishing to preserve her fertility: surgery should be avoided as much as possible; kystectomy is better than oophorectomy; no radical surgery should be done without pathological certitudes; electrocoagulation must be avoided on the cyst walls. In some situations, fertility is specially endangered: bilateral ovarian cysts, recurrence or strong probability of recurrence (endometriomas), poor ovarian reserve (previous chemo- or radiotherapy, age>35, premature ovarian failure). In these situations, a pre-operative assessment of the ovarian reserve could be useful. Beside the surgical 'good procedures', gamete cryopreservation procedures could be used. Cryopreservation of mature oocytes (after ovarian hyperstimulation) or in vitro mature oocytes (after antral follicle retrieval) can be proposed. Ovarian tissue cryopreservation is another option. Oocyte (or embryos) cryopreservation can be proposed before or after the surgery. The global management of benign ovarian tumors in young patients should be decided between surgeons and specialists in reproductive biology.

  8. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism.

    PubMed

    Ai, Zhihong; Lu, Yang; Qiu, Songbo; Fan, Zhen

    2016-04-01

    Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer.

  9. PIK3CA alterations in Middle Eastern ovarian cancers

    PubMed Central

    Abubaker, Jehad; Bavi, Prashant; Al-Haqawi, Wael; Jehan, Zeenath; Munkarah, Adnan; Uddin, Shahab; Al-Kuraya, Khawla S

    2009-01-01

    Background PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC). Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs. Results Fluorescence in situ hybridization (FISH) technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA protein expression (p110 α), PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 α overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67. Conclusion Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers. PMID:19638206

  10. Microsatellite instability is rare in sporadic ovarian cancer

    SciTech Connect

    Chen, S.S.; Han, H.; Schwartz, P.E.

    1994-09-01

    Microsatellite instability was first demonstrated to be a common underlying mechanism in hereditary nonpolyposis colorectal cancer (HNPCC) and has recently been implicated in the development of several other human cancers. Although numerous genetic changes have been documented in ovarian cancer, their molecular bases are poorly understood. In investigating the molecular genetics of ovarian cancer, we analyzed twelve short tandem repeats that were amplified by PCR from DNA of 48 tumors and their corresponding lymphocyte samples. All of the 48 cases studied have no noticeable family history and, of them, 42 are epithelial (benign/borderline, 5; grade I, 4; GII, 4; GIII, 29) and 6 are nonepithelial. A microsatellite instability has been shown to be inversely correlated with the occurrence of allelic losses, half of those cases chosen have a fractional allele loss of {le}15 (median = .18 of 50 tumors tested for 86 loci from every chromosomal arm). The loci examined included eight dinucleotide repeats (D2S123, D9S104, D10S197, D11S904, D16S408, D16S421, D17S250, and D17S579), two trinucleotide repeats (DM and AR) and two tetranucleotide repeats (DXS981 and VWF). Despite the fact that HNPCC phenotype includes ovarian cancer and that microsatellite instability has been shown in one ovarian cancer from an HNPCC family, the allele sizes of 12 loci were found to be identical in all paired tumor and normal samples we studied except for one tumor at a single locus. The band shift displayed on polyacrylamide gel representing an additional allele of VWF was only observed in one grade III tumor. Our results are thus a strong indication that the alteration of microsatellite repeats may not play a major role in the development of sporadic ovarian cancer.

  11. Effects of BMAL1-SIRT1-positive cycle on estrogen synthesis in human ovarian granulosa cells: an implicative role of BMAL1 in PCOS.

    PubMed

    Zhang, Jiaou; Liu, Jiansheng; Zhu, Kai; Hong, Yan; Sun, Yun; Zhao, Xiaoming; Du, Yanzhi; Chen, Zi-Jiang

    2016-08-01

    Brain and muscle ARNT-like protein 1 (BMAL1) is necessary for fertility and has been found to be essential to follicle growth and steroidogenesis. Sirtuin1 (SIRT1) has been reported to interact with BMAL1 and function in a circadian manner. Evidence has shown that SIRT1 regulates aromatase expression in estrogen-producing cells. We aimed to ascertain if there is a relationship between polycystic ovary syndrome (PCOS) and BMAL1, and whether and how BMAL1 takes part in estrogen synthesis in human granulosa cells (hGCs). Twenty-four women diagnosed with PCOS and 24 healthy individuals undergoing assisted reproduction were studied. BMAL1 expression in their granulosa cells (GCs) was observed by quantitative real-time polymerase chain reaction (qRT-PCR). The level of expression in the PCOS group was lower than that of the group without PCOS (p < 0.05). We also analyzed estrogen synthesis and aromatase expression in KGN cell lines. Both were downregulated after BMAL1 and SIRT1 knock-down and, conversely, upregulated after overexpression treatments of these two genes in KGN cells. Both BMAL1 and SIRT1 had a mutually positive regulation, as did the phosphorylation of JNK. Furthermore, JNK overexpression increased estrogen synthesis activity and the expression levels of aromatase, BMAL1, and SIRT1. In KGN and hGCs, estrogen synthesis and aromatase expression were downregulated after treatment with JNK and SIRT1 inhibitors. In addition, BMAL1, SIRT1, and JNK expression levels were all downregulated. Our results demonstrate the effects of BMAL1 on estrogen synthesis in hGCs and suggest a BMAL1-SIRT1-JNK positive feedback cycle in this process, which points out an important role of BMAL1 in the development of PCOS. PMID:27117143

  12. Effects of BMAL1-SIRT1-positive cycle on estrogen synthesis in human ovarian granulosa cells: an implicative role of BMAL1 in PCOS.

    PubMed

    Zhang, Jiaou; Liu, Jiansheng; Zhu, Kai; Hong, Yan; Sun, Yun; Zhao, Xiaoming; Du, Yanzhi; Chen, Zi-Jiang

    2016-08-01

    Brain and muscle ARNT-like protein 1 (BMAL1) is necessary for fertility and has been found to be essential to follicle growth and steroidogenesis. Sirtuin1 (SIRT1) has been reported to interact with BMAL1 and function in a circadian manner. Evidence has shown that SIRT1 regulates aromatase expression in estrogen-producing cells. We aimed to ascertain if there is a relationship between polycystic ovary syndrome (PCOS) and BMAL1, and whether and how BMAL1 takes part in estrogen synthesis in human granulosa cells (hGCs). Twenty-four women diagnosed with PCOS and 24 healthy individuals undergoing assisted reproduction were studied. BMAL1 expression in their granulosa cells (GCs) was observed by quantitative real-time polymerase chain reaction (qRT-PCR). The level of expression in the PCOS group was lower than that of the group without PCOS (p < 0.05). We also analyzed estrogen synthesis and aromatase expression in KGN cell lines. Both were downregulated after BMAL1 and SIRT1 knock-down and, conversely, upregulated after overexpression treatments of these two genes in KGN cells. Both BMAL1 and SIRT1 had a mutually positive regulation, as did the phosphorylation of JNK. Furthermore, JNK overexpression increased estrogen synthesis activity and the expression levels of aromatase, BMAL1, and SIRT1. In KGN and hGCs, estrogen synthesis and aromatase expression were downregulated after treatment with JNK and SIRT1 inhibitors. In addition, BMAL1, SIRT1, and JNK expression levels were all downregulated. Our results demonstrate the effects of BMAL1 on estrogen synthesis in hGCs and suggest a BMAL1-SIRT1-JNK positive feedback cycle in this process, which points out an important role of BMAL1 in the development of PCOS.

  13. Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium

    PubMed Central

    Bajwa, Preety; Nagendra, Prathima B.; Nielsen, Sarah; Sahoo, Subhransu S.; Bielanowicz, Amanda; Lombard, Janine M.; Wilkinson, Erby J.; Miller, Richard A.; Tanwar, Pradeep S.

    2016-01-01

    Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer. PMID:27036037

  14. Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium.

    PubMed

    Bajwa, Preety; Nagendra, Prathima B; Nielsen, Sarah; Sahoo, Subhransu S; Bielanowicz, Amanda; Lombard, Janine M; Wilkinson, J Erby; Miller, Richard A; Tanwar, Pradeep S

    2016-04-12

    Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer.

  15. ZNF300P1 Encodes a lincRNA that regulates cell polarity and is epigenetically silenced in type II epithelial ovarian cancer

    PubMed Central

    2014-01-01

    Background We previously identified that the CpG island-associated promoter of the novel lincRNA ZNF300P1 (also known as LOC134466) is frequently hypermethylated and silenced in ovarian cancer tissues. However, the function of ZNF300P1 was unknown. In this report we demonstrate that ZNF300P1 is involved in the regulation of key cell cycle and cell motility networks in human ovarian surface epithelial cells, and may play a role in promoting metastasis in ovarian cancer cells. Methods We applied methylated DNA immunoprecipitation on whole genome promoter tiling arrays and Sequenom assays to examine methylation status of ZNF300P1 in multiple ovarian cancer cell lines, as well as in normal ovarian and ovarian tumor tissues. Transcript profiling was used to investigate the effects of ZNF300P1 suppression in ovarian cancer cells. We utilized siRNA knockdown in normal ovarian surface epithelial cells and performed cellular proliferation, migration and adhesion assays to validate and explore the profiling results. Results We demonstrate that ZNF300P1 is methylated in multiple ovarian cancer cell lines. Loss of ZNF300P1 results in decreased cell proliferation and colony formation. In addition, knockdown of the ZNF300P1 transcript results in aberrant and less persistent migration in wound healing assays due to a loss of cellular polarity. Using an ex vivo peritoneal adhesion assay, we also reveal a role for ZNF300P1 in the attachment of ovarian cancer cells to peritoneal membranes, indicating a potential function of ZNF300P1 expression in metastasis of ovarian cancer cells to sites within the peritoneal cavity. Conclusion Our findings further support ZNF300P1 as frequently methylated in ovarian cancer and reveal a novel function for ZNF300P1 lincRNA expression in regulating cell polarity, motility, and adhesion and loss of expression may contribute to the metastatic potential of ovarian cancer cells. PMID:24393131

  16. Effects of two human chorionic gonadotropin doses administered to the ovarian states during the in vitro fertilization and embryo transfer program

    PubMed Central

    MA, MINGXING; WANG, JIALIN; XU, LIJUN; ZHANG, QINXI; DU, BOTAO; JIANG, XIAOYING; SHI, QINGLI; ZHOU, LILI; LI, BAOXIN; SAITO, HIDEKAZU; KURACHI, HIROHISA

    2015-01-01

    The aim of the present study was to examine the effects of the human chorionic gonadotropin (hCG) dose on the pulsatility indices (PI) of the intraovarian artery on the day of follicle aspiration and the oocyte quality, intrafollicular oxidative stress and luteinization. PI was also measured on the day of hCG administration. A total of 15 patients were undergoing the in vitro fertilization and embryo transfer (IVF-ET) program. To estimate whether there was any difference between the intraovarian artery blood flow and oocyte development of the same patients treated with 5,000 or 10,000 IU hCG, the intraovarian artery blood flow was measured by transvaginal color ultrasonography pulsed wave Doppler, and the follicular fluids and the granulosa cells were collected at follicle aspiration. There were statistically significant differences between the same patients undergoing the two different hCG-dose treatments in which the first protocol included 10,000 IU and the second protocol included 5,000 IU hCG treatment. These differences were apparent in the PI of intraovarian artery blood flow on the day of follicle aspiration (P=0.0023), in the incidence of apoptosis in cumulus (ApoC) and mural (ApoM) granulosa cells (ApoC, P=0.0077; ApoM, P=0.0128), in the total oocytes retrieved (P=0.0342) and in the follicle fluid progesterone concentration (P=0.0044). There were no significant differences between the two protocols in the PI of intraovarian artery blood flow on the day of hCG administration (P=0.4326), serum steroid on the day of follicle aspiration [serum P, P>0.9999; serum estradiol (E2), P=0.8589], follicle fluid E2 concentration (P=0.8939), mature oocyte rate (P=0.3743) and total mature oocytes retrieved (P=0.2026). In conclusion, the dose of hCG administration can significantly affect the intraovarian artery blood flow and the development of follicles and oocytes in an IVF-ET program. PMID:26075075

  17. Early Detection Biomarkers for Ovarian Cancer

    PubMed Central

    Sarojini, Sreeja; Tamir, Ayala; Lim, Heejin; Li, Shihong; Zhang, Shifang; Goy, Andre; Pecora, Andrew; Suh, K. Stephen

    2012-01-01

    Despite the widespread use of conventional and contemporary methods to detect ovarian cancer development, ovarian cancer remains a common and commonly fatal gynecological malignancy. The identification and validation of early detection biomarkers highly specific to ovarian cancer, which would permit development of minimally invasive screening methods for detecting early onset of the disease, are urgently needed. Current practices for early detection of ovarian cancer include transvaginal ultrasonography, biomarker analysis, or a combination of both. In this paper we review recent research on novel and robust biomarkers for early detection of ovarian cancer and provide specific details on their contributions to tumorigenesis. Promising biomarkers for early detection of ovarian cancer include KLK6/7, GSTT1, PRSS8, FOLR1, ALDH1, and miRNAs. PMID:23319948

  18. Analysis of falsely elevated risk of ovarian malignancy algorithm in women with ovarian endometrioma

    PubMed Central

    Shin, Jae Jun; Lee, Ye Ji; Kim, Ranah; Lee, Da Yong; Won, Kyu-Hee

    2016-01-01

    Objective To estimate the incidence of falsely elevated risk of ovarian malignancy algorithm (ROMA) in a group of women with pathologically confirmed endometrioma and to investigate the associated factors. Methods One hundred premenopausal women surgically diagnosed with ovarian endometrioma were selected. Preoperative clinical, laboratory, and surgical characteristics were compared between the elevated-risk group (ROMA-premenopausal value, ≥7.4%) and normal-risk group (ROMA-premenopausal value, <7.4%). Results Elevated ROMA was observed in 15 women (false positive rate, 15%). Excluding one woman with known chronic renal failure, we compared the characteristics of 99 women between the elevated-risk group (n=14) and the normalrisk group (n=85). None of the clinical and surgical variables distinguished the two groups. Serum level of CA 125 >82.3 U/mL and serum level of human epididymis protein 4 (HE4) >46 pmol/L could predict an elevated ROMA test with a statistical significance. When serum level of HE4 ≤46 pmol/L, none of the women showed an elevated ROMA test, regardless of serum level of CA 125; however, 55.6% of the women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 ≤82.3 U/mL and all women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL. Conclusion The incidence of falsely elevated ROMA was 15% in the group of women with pathologically confirmed endometrioma. Interpretation of the ROMA results should be cautious when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL in women with suspicious ovarian endometrioma. PMID:27462596

  19. GCIG Consensus Review: Uterine and Ovarian Leiomyosarcomas

    PubMed Central

    Hensley, Martee L.; Barrette, Brigitte A.; Baumann, Klaus; Gaffney, David; Hamilton, Anne L.; Kim, Jae-Weon; Maenpaa, Johanna U.; Pautier, Patricia; Siddiqui, Nadeem Ahmad; Westermann, Anneke M.; Ray-Coquard, Isabelle

    2016-01-01

    Objective The GCIG aimed to provide an overview of uterine and ovarian leiomyosarcoma management. Methods Published articles and author experience were used to draft management overview. The draft manuscript was circulated to international members of the GCIG for review and comment, and appropriate revisions were made. Results The approach to management of uterine and ovarian leiomyosarcoma management is reviewed. Conclusions Uterine and ovarian leiomyosarcomas are rare, aggressive cancers that require specialized expertise for optimal management. PMID:25341583

  20. Early Preinvasive Lesions in Ovarian Cancer

    PubMed Central

    Chene, Gautier; Lamblin, Gery; Le Bail-Carval, Karine; Chabert, Philippe; Bakrin, Naoual; Mellier, Georges

    2014-01-01

    Faced with the catastrophic prognosis for ovarian cancer due to the fact that it is most often diagnosed late at the peritoneal carcinomatosis stage, screening and early detection could probably reduce the mortality rate. A better understanding of the molecular characteristics of the different ovarian cancer subtypes and their specific molecular signatures is indispensable prior to development of new screening strategies. We discuss here the early natural history of ovarian cancer and its origins. PMID:24804229

  1. Multisystem manifestations of benign ovarian teratomas.

    PubMed

    Murdoch, William; Sadoski, Jill; Rosin, Frederick C

    2014-01-01

    A 26-year-old woman presented with acute onset of right-sided pelvic pain and had a medical history significant for