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Ovarian Cancers (ovarian + cancers)
Kinds of Ovarian Cancers Selected AbstractsAllelotype Analysis of Common Epithelial Ovarian Cancers with Special Reference to Comparison between Clear Cell Adenocarcinoma with Other Histological TypesCANCER SCIENCE, Issue 7 2002Satoshi Okada Determination of the histological type of epithelial ovarian cancer is clinically important to predict patient prognosis. To estimate accurately the chromosomal regions that frequently show loss of heterozygosity (LOH) in each histological type, LOH at 55 loci on 38 chromosomal arms was examined by means of laser capture microdissection and PCR-LOH analysis in 45 epithelial ovarian cancers composed of clear cell adenocarcinoma (CCA), serous adenocarcinoma (SEA), endometrioid adenocarcinoma (EMA) and mucinous adenocarcinoma (MUA). In addition, p53 (exons 5,8) gene mutations and the nuclear immunoreactivity of p53 proteins in these tumors were examined by PCR-SSCP and immunohistochemistry. In CCA, LOH was detected primarily on 1p (69%) followed by 19p (45%) and 11q (43%). On the other hand, in SEA, LOH was detected in at least 50% of cases on 1p, 4p, 5q, 6p, 8p, 9q, 12q, 13q, 15q, 16p, 17p, 17q, 18p, 18q, 19p, 20p and Xp. The incidences of LOH on 5q, 12q, 13q and 17p were significantly lower in CCA than in SEA (P=0.019, 0.031, 0.0035 and 0.012). EMA showed a tendency for frequent LOH on 7p, whereas MUA showed significantly high occurrence of LOH at 17p13.1. The incidences of p53 mutation and p53 nuclear immunoreactivity also differed between CCA and SEA: 0% and 7% in the former and 64% and 45% in the latter (P=0.0006 and 0.039). These findings clarify that there are differences in LOH distribution patterns among different histological subtypes of epithelial ovarian cancer. In CCA, p53 tumor-suppressor gene (TSG) is not involved in carcinogenesis and tumor-suppressor genes located on 1p are considered to play an important role in tumor development. [source] Autoantibodies against stress-induced phosphoprotein-1 as a novel biomarker candidate for ovarian cancerGENES, CHROMOSOMES AND CANCER, Issue 7 2010Sunghoon Kim Detection of autoantibodies against tumor-associated antigens (TAA) has recently been shown to be a powerful tool for early detection of various cancers. The aim of this study was to investigate the possibility of using autoantibodies against TAA as novel biomarkers by a proteomics-based approach in patients with ovarian cancer. We used two-dimensional differential gel electrophoresis analysis of immuno-precipitated tumor antigens (2D-DITA) to compare the levels of autoandibodies in pretreatment and posttreatment sera of patients with ovarian cancers. The identified autoantibodies were validated by SYBR Green real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). We further evaluated the level of autoantibody in sera of 68 ovarian cancer patients by an enzyme-linked immunosorbent assay (ELISA). The autoantibody directed against stress-induced phosphoprotein-1 (STIP-1) emerged as a novel biomarker candidate for ovarian cancer. SYBR Green PCR and IHC confirmed that the STIP-1 mRNA and protein expression levels were significantly up-regulated in ovarian cancers compared with normal and benign tumors (P = 0.003 and P < 0.001, respectively). A preliminary ELISA study showed that the serum levels of anti-STIP-1 autoantibodies were significantly elevated in ovarian cancer patients compared with healthy controls (P = 0.03). The results suggest that 2D-DITA is a useful tool to detect autoantibodies and that STIP-1 is a potential biomarker candidate for ovarian cancers. © 2010 Wiley-Liss, Inc. [source] Chromosomes 6 and 18 induce neoplastic suppression in epithelial ovarian cancer cells,INTERNATIONAL JOURNAL OF CANCER, Issue 5 2009Dimitra Dafou Abstract Metaphase comparative genomic hybridisation (CGH) studies indicate that chromosomes 4, 5, 6, 13, 14, 15 and 18 are frequently deleted in primary ovarian cancers (OCs). Therefore we used microcell-mediated chromosome transfer (MMCT) to establish the functional effects of transferring normal copies of these chromosomes into 2 epithelial OC cell lines (TOV112D and TOV21G). The in vitro neoplastic phenotype (measured as anchorage dependent and independent growth and invasion) was compared between recipient OC cell lines and multiple MMCT hybrids. Chromosomes 6 and 18 showed strong evidence of functional, neoplastic suppression for multiple hybrids in both cell lines. We also found evidence in 1 cancer cell line suggesting that chromosomes 4, 13 and 14 may also cause functional suppression. Array CGH and microsatellite analyses were used to characterise the extent of genomic transfer in chromosome 6 and 18 hybrids. A 36 MB deletion on chromosome 6 in 2 hybrids from 1 cell line mapped the candidate region proximal to 6q15 and distal to 6q22.2; and an ,10 MB candidate region spanning the centromere on chromosome 18 was identified in 2 hybrids from the other cell line. These data support reported functional effects of chromosome 6 in OC cell lines; but to our knowledge, this is the first time that functional suppression for chromosome 18 has been reported. This suggests that these chromosomes may harbour tumour suppressor-"like" genes. The future identification of these genes may have a significant impact on the understanding and treatment of the disease and the identification of novel therapeutic targets. © 2008 Wiley-Liss, Inc. [source] Reduced expression of MYO18B, a candidate tumor-suppressor gene on chromosome arm 22q, in ovarian cancerINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Nozomu Yanaihara Abstract Allelic imbalance on chromosome arm 22q has been detected in 50,70% of ovarian cancers, suggesting the presence of a tumor-suppressor gene on this chromosome arm that is involved in ovarian carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, which is deleted, mutated and hypermethylated in approximately 50% of lung cancers. In our study, we analyzed genetic and epigenetic alterations of the MYO18B gene in ovarian cancers. Missense MYO18B mutations were detected in 1 of 4 (25%) ovarian cancer cell lines and in 1 of 17 (5.9%) primary ovarian cancers. MYO18B expression was reduced in all 4 ovarian cancer cell lines and in 12 of 17 (71%) of primary ovarian cancers. MYO18B expression was restored by treatment with 5-aza-2,-deoxycytidine and/or trichostatin A in 3 of 4 cell lines with reduced MYO18B expression, and hypermethylation of the promoter CpG island for MYO18B was observed in 2 of these 3 cell lines. Its hypermethylation was also observed in 2 of 15 (13%) primary ovarian cancers. Thus, it was indicated that MYO18B expression is reduced in a considerable fraction of ovarian cancers by several mechanisms, including hypermethylation, while the MYO18B gene is mutated in a small subset of ovarian cancers. The present results suggest that MYO18B alterations, including both epigenetic and genetic alterations, play an important role in ovarian carcinogenesis. © 2004 Wiley-Liss, Inc. [source] Third S. S. Ratnam Memorial Lecture 2007.JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 3 2009Ovarian cancer: Is there hope for women? Abstract Ovarian cancer is today the most lethal female cancer with an overall survival of only 49.9%. The currently available screening modalities are disappointing in detecting highly curable early stage ovarian cancer. Natural history of ovarian cancer is unknown; it appears it can develop quickly from normal looking ovaries. Timely referral of women with non-specific symptoms (such as abdominal bloating, pelvic pain) for an ultrasound scan or blood CA125 assessments may help in the early diagnosis. Patients with Stage IA or IB disease with grade 1 tumors have a cure rate of >90%; this is likely to be compromised by laparoscopic surgery. In selected patients fertility preservation with good obstetric outcome is possible. However, the relapse rate in ,high risk' early stage ovarian cancers is 40,45%; adjuvant chemotherapy is needed. Only 20,25% of those with stage III and IV disease are cured. Despite a high primary response (70%) majority (70,75%) will relapse and all are likely to succumb. Optimal debulking surgery followed by adjuvant chemotherapy are needed for stages III and IV disease; the outcome is superior if managed by gynecologic oncologists. Where cost of drugs is an important consideration, an alternative is carboplatin (an affordable and equally effective drug). The role of vaccines needs further study. When relapses occur palliation will be the aim in most instances. Oral contraceptives, breast feeding, tubal sterilization and hysterectomy also have a protective effect. Risk-reducing salpingo-oopherectomy has been suggested in women with BRCA mutations. [source] Loss of heterozygosity and transcriptome analyses of a 1.2 Mb candidate ovarian cancer tumor suppressor locus region at 17q25.1-q25.2MOLECULAR CARCINOGENESIS, Issue 3 2005Nadège Presneau Abstract Loss of heterozygosity (LOH) analysis was performed in epithelial ovarian cancers (EOC) to further characterize a previously identified candidate tumor suppressor gene (TSG) region encompassing D17S801 at chromosomal region 17q25.1. LOH of at least one informative marker was observed for 100 (71%) of 140 malignant EOC samples in an analysis of 6 polymorphic markers (cen - D17S1839 - D17S785 - D17S1817 - D17S801 - D17S751 - D17S722 - tel). The combined LOH analysis revealed a 453 kilobase (Kb) minimal region of deletion (MRD) bounded by D17S1817 and D17S751. Human and mouse genome assemblies were used to resolve marker inconsistencies in the D17S1839 - D17S722 interval and identify candidates. The region contains 32 known and strongly predicted genes, 9 of which overlap the MRD. The reference genomic sequences share nearly identical gene structures and the organization of the region is highly collinear. Although, the region does not show any large internal duplications, a 1.5 Kb inverted duplicated sequence of 87% nucleotide identity was observed in a 13 Kb region surrounding D17S801. Transcriptome analysis by Affymetrix GeneChip® and reverse transcription (RT)-polymerase chain reaction (PCR) methods of 3 well characterized EOC cell lines and primary cultures of normal ovarian surface epithelial (NOSE) cells was performed with 32 candidates spanning D17S1839 - D17S722 interval. RT-PCR analysis of 8 known or strongly predicted genes residing in the MRD in 10 EOC samples, that exhibited LOH of the MRD, identified FLJ22341 as a strong candidate TSG. The proximal repeat sequence of D17S801 occurs 8 Kb upstream of the putative promoter region of FLJ22341. RT-PCR analysis of the EOC samples and cell lines identified DKFZP434P0316 that maps proximal to the MRD, as a candidate. While Affymetrix technology was useful for initially eliminating less promising candidates, subsequent RT-PCR analysis of well-characterized EOC samples was essential to prioritize TSG candidates for further study. © 2005 Wiley-Liss, Inc. [source] Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsulaANNALS OF HUMAN GENETICS, Issue 1 2002A. VEGA An estimated 5,10% of all breast and ovarian cancers are due to an inherited predisposition, representing a rather large number of patients. In Spain 1/13,1/14 women will be diagnosed with breast cancer during their lifetime. Two major breast cancer genes, BRCA1 and BRCA2, have been identified. To date, several hundred pathogenic mutations in these two genes have been published or reported to the Breast Cancer Information Core, BIC database (http://www.nhgri.nih.gov/Intramural_research_Labtransfer/Bic/index.html). In the present study, 30 Spanish breast and breast/ovarian cancer families (29 from Galicia, NW Spain, and 1 from Catalonia, NE Spain) were screened for mutations in the BRCA1 and BRCA2 genes. The analysis of these genes was carried out by SSCP for shorter exons and direct sequencing in the case of longer ones. Mutations were found in 8 of the 30 families studied (26.66%). It is important to note that all mutations were detected within the BRCA1 gene: 330 A>G, 910_913delGTTC, 2121 C>T, 3958_3962delCTCAGinsAGGC, and 5530 T>A. The BRCA1 330 A>G mutation was found in four unrelated families and accounted for 50% of all identified mutations. [source] The expression of six biomarkers in the four most common ovarian cancers: correlation with clinicopathological parametersAPMIS, Issue 3 2009CHIH-KUNG LIN This study aimed to evaluate the relationship of fascin-1, matrix metalloproteinase (MMP)-2, MMP-9, cortactin, survivin, and epidermal growth factor receptor (EGFR) expression with clinicopathological parameters for the four most common ovarian surface epithelial carcinomas. Six biomarkers were investigated immunohistochemically using tissue microarrays of 185 specimens including 79 serous cystadenocarcinomas, 47 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas, and 14 clear cell carcinomas. The four most common ovarian carcinomas showed significant expression of fascin-1, cortactin, survivin, and EGFR, but not of MMP-2 and MMP-9. In addition, higher immunostaining scores for fascin-1 in mucinous cystadenocarcinomas correlated with T stage, N stage, American Joint Committee on Cancer AJCC clinical stage, and a poorer survival rate; for cortactin in serous cystadenocarcinomas correlated with T stage; for cortactin in clear cell carcinomas correlated with T and clinical AJCC stages; and for survivin in clear cell carcinomas correlated with T stage and AJCC clinical stage. In addition, higher immunostaining scores for fascin-1, cortactin, and survivin correlated with poorer tumor differentiation in serous, mucinous, and endometrioid adenocarcinomas. Thus, the expression of fascin-1, cortactin, and survivin may be helpful in evaluating the aggressiveness of ovarian mucinous, serous, and clear cell adenocarcinoma. Additionally, the expression of fascin-1 may be an independent prognostic risk factor in mucinous cystadenocarcinoma. [source] Granulosa cell tumours of the ovaryAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 3 2010Puliyath GEETHA Granulosa cell tumours are rare, potentially malignant sex cord stromal tumours of the ovary. They are unique in their presentation and histological features. Many of them are hormone-producing and this property helps them to present early unlike other epithelial ovarian cancers. As a result, most of them will be in an early stage at the time of initial diagnosis. The tumour can manifest in young girls as a juvenile form and conservative management with unilateral salpingo-opherectomy may be an option in them as 95% are unilateral. Surgery is the treatment of choice and initial staging laparatomy a determinant recurrence. Advance stage of the tumour, its size (>5 cm), mitotic figures (>10/hpf), nuclear atypia and absence of call-exner bodies are poor prognostic factors. Such tumours are characterised by late recurrences and this necessitates a prolonged follow-up. Tumour markers such as inhibin and estradiol are useful in follow-up. Chemotherapy, radiotherapy and hormone replacement therapy have very little role in the initial treatment and may be suggested in case of recurrences. With appropriate treatment, a better survival rate can be achieved as against other ovarian malignancies. Methods used for locating, selecting and synthesising data:, A search of Medline and Cochrane data base for the period from 1999 to 2010 was carried out to include relevant systematic reviews, meta-analysis, randomised controlled and other clinical and rare case reports. The date of the last search was January 2010. [source] Expression and promoter methylation status of mismatch repair gene hMLH1 and hMSH2 in epithelial ovarian cancerAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 5 2008Hui ZHANG Objective: The purpose of this study is to determine the relationship between methylation and loss of hMLH1 and hMSH2 expression in ovarian cancer. Methods: We examined the methylation status of hMLH1 and hMSH2 promoter region by methylation-specific polymerase chain reaction (MSP) in 56 primary ovarian cancer tissues and 20 normal ovarian tissues, the relationship between the methylation status of these two genes and clinicopathological characteristics were analysed. We then treated SKOV3 and 3AO ovarian cancer cell lines with the demethylating agent 5-aza-2,-deoxycytidine (5-aza-dc). The hMLH1 and hMSH2 methylation was further assessed by MSP, and their mRNA expression was compared by reverse transcription polymerase chain reaction (RT-PCR) before and after 5-aza-dc treatment in these two cell lines. Results: The methylation frequency of hMLH1 and hMSH2 was 30.4% (17 of 56) and 51.7% (29 of 56) in ovarian cancers, respectively, while no methylation was detected in normal ovarian tissues (P = 0.015). There is a significant correlation between hMLH1 promoter hypermethylation and histological grade (P = 0.028) as well as lymphatic metastasis (P = 0.003). Methylation of hMSH2 correlated with histological grade (P = 0.035) and lymphatic metastasis (P = 0.015). Besides, the methylation rates of hMSH2 were significantly higher in endometrioid adenocarcinoma tissues than in other pathological types of ovarian cancer. After 5-aza-dc treatment, the expression of hMLH1 and hMSH2 was reversed in two cell lines. Conclusion: Our results indicate that promoter hypermethylation is an important mechanism for loss of hMLH1 and hMSH2 expression in human ovarian cancer and may be a potential prognostic factor in ovarian cancer. [source] In vivo magnetic resonance spectroscopy of gynaecological tumours at 3.0 TeslaBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 2 2009SJ Booth Background, Magnetic resonance spectroscopy (MRS) uses the same hardware as MR imaging and allows us to analyse the biochemistry of tissues in vivo. Published data for gynaecological lesions are limited and are largely based on MRS carried out at the lower magnetic field strength of 1.5 Tesla (T). Objective, The purpose of this study was to determine whether in vivo proton MRS could be performed at the higher magnetic field strength of 3 T to characterise the spectra of a variety of benign and malignant gynaecological lesions. Design, Prospective, non-randomised study. Setting, MRI department within a tertiary referral centre for gynaecological cancers. Sample, All women with a pelvic mass under going 3T MRI. Methods, We carried out MRS on nonrandomised women undergoing routine 3 T MRI within our MRI department during investigation for gynaecological lesions from February 2006 to April 2008. Only those women for whom histopathological data were available were included. Main outcome measures, The presence of choline detected by in vivo 3T MRS. Results, Eighty-seven women underwent MRS, 57 of whom had newly diagnosed neoplasms. MRS data for 39 of these new women (18 were excluded because of technical errors or missing data) were used to detect the presence of choline, an indicator of basement membrane turnover. Overall, choline was present in 13 of the 14 ovarian cancers, 8 of the 11 cervical tumours and all 4 of the uterine cancers. There was no statistical significant difference between choline levels in various lesion types (P= 0.735) or between benign and malignant disease (P= 0.550). Conclusions,In vivo MRS can be performed at 3 T to provide biochemical information on pelvic lesions. The way in which this information can be utilised is less clear but may be incorporated into monitoring tissue response in cancer treatments. [source] Fertility preservation in young women with epithelial ovarian cancerCANCER, Issue 18 2009Jason D. Wright MD Abstract BACKGROUND: Surgical management of ovarian cancer consists of hysterectomy with bilateral oophorectomy. In young women, this results in the loss of reproductive function and estrogen deprivation. In the current study, the authors examined the safety of fertility-conserving surgery in premenopausal women with epithelial ovarian cancers. METHODS: Women aged ,50 years with stage IA or IC epithelial ovarian cancer who were registered in the Surveillance, Epidemiology, and End Results database were examined. Patients who underwent bilateral oophorectomy were compared with those who underwent ovarian conservation. A second analysis examined uterine conservation versus hysterectomy. Multivariate Poisson regression models were developed to describe predictors of fertility preservation. Survival was examined using Cox proportional hazards models and the Kaplan-Meier method. RESULTS: In total, 1186 women, including 754 women (64%) who underwent bilateral oophorectomy and 432 women (36%) who underwent ovarian preservation, were identified. Younger age, later year of diagnosis, and residence in the eastern or western United States were associated with ovarian preservation (P < .05 for all). Women with endometrioid and clear cell histologies and stage IC disease were less likely to have ovarian conservation (P < .05). In a Cox model, ovarian preservation had no effect on survival (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.39-1.20). Young age, later year of diagnosis, residence in the eastern or western United States, single women, mucinous tumors, and patients with stage IA disease were more likely to have uterine preservation (P < .05 for all). In a multivariate model, uterine preservation had no effect on survival (HR, 0.87; 95% CI, 0.62-1.22). CONCLUSIONS: Ovarian and uterine-conserving surgery were safe in young women who had stage IA and IC epithelial ovarian cancer. Cancer 2009. © 2009 American Cancer Society. [source] CA-125 change after chemotherapy in prediction of treatment outcome among advanced mucinous and clear cell epithelial ovarian cancers,CANCER, Issue 7 2009A Gynecologic Oncology Group study Abstract BACKGROUND: There are limited data regarding unique clinical or laboratory features associated with advanced clear cell (CC) and mucinous (MU) epithelial ovarian cancers (EOC), particularly the relationship between CA-125 antigen levels and prognosis. METHODS: A retrospective review of 7 previously reported Gynecologic Oncology Group phase 3 trials in patients with stage III/IV EOC was conducted. A variety of clinical parameters were examined, including the impact of baseline and changes in the CA-125 level after treatment of CC and MU EOC on progression-free (PFS) and overall survival (OS). RESULTS: Clinical outcomes among patients with advanced CC and MU EOC were significantly worse when compared with other cell types (median PFS, 9.7 vs 7.0 vs 16.7 months, respectively, P < .001; median OS, 19.4 vs 11.3 vs 40.5 months, respectively, P < .001). Suboptimal debulking was associated with significantly decreased PFS and OS among both. Although baseline CA-125 values were lower in CC (median, 154 ,/mL) and MU (100 ,/mL), compared with other cell types (275 ,/mL), this level did not appear to influence outcome among these 2 specific subtypes of EOC. However, an elevated level of CA-125 at the end of chemotherapy was significantly associated with decreased PFS and OS (P < .01 for all). CONCLUSIONS: Surgical debulking status is the most important variable at prechemotherapy predictive of prognosis among advanced CC and MU EOC patients. Changes in the CA-125 levels at the end treatment as compared with baseline can serve as valid indicators of PFS and OS, and likely the degree of inherent chemosensitivity. Cancer 2009. © 2009 American Cancer Society. [source] Anthropometric variables, physical activity, and incidence of ovarian cancerCANCER, Issue 7 2004The Iowa Women's Health Study Abstract BACKGROUND Reports on the relation between anthropometric variables (height, weight) and physical activity with ovarian cancer have been inconclusive. The objective of the current study was to extend investigation of potential associations in the Iowa Women's Health Study cohort. METHODS The relation between self-reported anthropometric variables and incident ovarian cancer was studied in a prospective cohort of women ages 55,69 years who were followed for 15 years. Two hundred twenty-three incident cases of epithelial ovarian cancer were identified by linkage to a cancer registry. RESULTS No association was found overall between ovarian cancer and height, but a positive association was observed for serous ovarian cancers (relative risk [RR], 1.86 for highest quartile vs. lowest quartile; 95% confidence interval [95% CI], 1.06,3.29). Although current body mass index (BMI) was not associated with ovarian cancer, a BMI , 30 kg/m2 at age 18 years appeared to be associated positively with ovarian cancer (multivariate-adjusted RR, 1.83 for BMI , 30 kg/m2 vs. BMI < 25 kg/m2; 95% CI, 0.90,3.72), and this association was stronger after exclusion of the first 2 years of follow-up (RR, 2.15; 95% CI, 1.05,4.40). In a multivariate analysis, waist-to-hip ratio was associated with ovarian cancer (RR, 1.59 for highest quartile vs. lowest quartile; 95% CI, 1.05,2.40), but a linear dose response was not found. An index that combined the frequency and intensity of leisure-time physical activity was associated positively with ovarian cancer incidence (multivariate-adjusted RR, 1.42 for high activity vs. low activity; 95% CI, 1.03,1.97). This association was particularly strong for frequency of vigorous physical activity (multivariate-adjusted RR, 2.38 for > 4 times per week vs. rarely/never; 95% CI, 1.29,4.38). CONCLUSIONS Anthropometric variables were not major risk factors for ovarian cancer in the cohort studied; however, high BMI in early adulthood and frequent and vigorous physical activity may increase the risk of ovarian cancer among postmenopausal women. Cancer 2004;100:1515,21. © 2004 American Cancer Society. [source] Prognostic significance of Notch 3 gene expression in ovarian serous carcinomaCANCER SCIENCE, Issue 9 2010Sang G. Jung The Notch signaling pathway is an important cell signaling system, which regulates cell differentiation, proliferation, and apoptosis, and is aberrantly activated in a wide range of cancer, including ovarian cancers. However, it remains unclear as to whether Notch signaling plays a role in the progression and prognosis of ovarian cancer. We examined the mRNA and protein expression of Notch 3, Jagged 1, and Jagged 2 in 98 ovarian epithelial tumors via real-time PCR and in 175 tumors with immunohistochemical analysis, and then correlated their expression levels with clinicopathological parameters and patient survival. In this study, we detected high levels of Notch3 mRNA and protein expression especially in serous ovarian carcinomas compared to their benign counterparts, accompanied by a positive correlation with the expressions of Jagged 1 and Jagged 2. High levels of Notch 3 mRNA expression (>2-fold than that of benign tumor) were noted in 63% of the serous carcinomas (mean level: 17-fold, P = 0.032). Additionally, Notch 3 protein overexpression was significantly associated with advanced stage (P = 0.0008), lymph node (P = 0.001), and distant metastasis (P = 0.003). Notably, high Notch 3 mRNA and protein expressions were correlated with chemoresistance (P = 0.033) and poor overall survival (P = 0.027, P = 0.042) in these patients. Our results indicate that the Notch 3 signaling pathway is involved in the tumor progression of ovarian serous carcinoma, and higher Notch 3 expression may be an independent poor prognostic factor in this subset of tumors. (Cancer Sci 2010) [source] Rab5a overexpression promoting ovarian cancer cell proliferation may be associated with APPL1-related epidermal growth factor signaling pathwayCANCER SCIENCE, Issue 6 2010Zhen Zhao Rab5a is a regulatory guanosine triphosphatase that is associated with the transport and fusion of endocytic vesicles, and participates in regulation of intracellular signaling pathways embraced by cells to adapt to the specific environment. Rab5a is also correlated with lung, stomach, and hepatocellular carcinomas. Here, we detected Rab5a in paraffin-embedded samples of 20 ovarian cysts, 20 benign cystadenomas, and 39 ovarian cancers by immunohistochemistry, and observed that Rab5a expression was significantly higher in ovarian cancer (P = 0.0001). By setting up stable HO-8910 cell lines expressing Rab5a or dominant negative Rab5a (Rab5a:S34N), we found that Rab5a overexpression enhanced the cell growth by promoting G1 into S phase. In contrast, Rab5a:S34N inhibited this process. Additionally, APPL1 (adaptor protein containing PH domain, PTB domain, and Leucine zipper motif), a downstream effector of Rab5a, was also involved in promoting HO-8910 cell cycle progress. But this function was blocked by Rab5a:S34N. Laser scanning confocal microscopy represented the colocalization of APPL1 and Rab5a in the plasmolemma, which changed with the time of epidermal growth factor (EGF) stimulation. We also found APPL1 could transfer from the membranes into the nucleus where it interacted with NuRD/MeCP1 (the nucleosome remodeling and histone deacetylase multiprotein complex). NuRD is reported to be involved in the deacetylation of histone H3 and H4 to regulate nuclear transcription. So Rab5a promoted proliferation of ovarian cancer cells, which may be associated with the APPL1-related epidermal growth factor signaling pathway. (Cancer Sci 2010) [source] 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 growthCANCER SCIENCE, Issue 4 2010Ki-Yon Kim 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 [3H] 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. (Cancer Sci 2010; 101: 955,962) [source] Therapeutic antitumor efficacy of monoclonal antibody against Claudin-4 for pancreatic and ovarian cancersCANCER SCIENCE, Issue 9 2009Masayo Suzuki Claudin-4 (CLDN4) is a tetraspanin transmembrane protein of tight junction structure and is highly expressed in pancreatic and ovarian cancers. In this study, we aimed to generate an anti-Claudin-4 monoclonal antibody (mAb) and evaluate its antitumor efficacy in vitro and in vivo. To isolate specific mAb, we generated CLDN3, 4, 5, 6, and 9, expressing Chinese hamster ovary (CHO) cells, and then used them as positive and negative targets through cell-based screening. As a result, we succeeded in isolating KM3900 (IgG2a), which specifically bound to CLDN4, from BXSB mice immunized with pancreatic cancer cells. Immunoprecipitation and flow cytometry analysis revealed that KM3900 recognized the conformational structure and bound to extracellular loop 2 of CLDN4. Furthermore, binding of KM3900 was detected on CLDN4-expressing pancreatic and ovarian cancer cells, but not on negative cells. Next, we made the mouse,human chimeric IgG1 (KM3934) and evaluated its antitumor efficacy. KM3934 induced dose-dependent antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro, and significantly inhibited tumor growth in MCAS or CFPAC-1 xenograft SCID mice in vivo (P < 0.05). These results suggest that mAb therapy against CLDN4 is promising for pancreatic and ovarian cancers. (Cancer Sci 2009; 100: 1623,1630) [source] Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosisCANCER SCIENCE, Issue 8 2009Kosuke Yoshihara To elucidate the mechanisms of rapid progression of serous ovarian cancer, gene expression profiles from 43 ovarian cancer tissues comprising eight early stage and 35 advanced stage tissues were carried out using oligonucleotide microarrays of 18 716 genes. By non-negative matrix factorization analysis using 178 genes, which were extracted as stage-specific genes, 35 advanced stage cases were classified into two subclasses with superior (n = 17) and poor (n = 18) outcome evaluated by progression-free survival (log rank test, P = 0.03). Of the 178 stage-specific genes, 112 genes were identified as showing different expression between the two subclasses. Of the 48 genes selected for biological function by gene ontology analysis or Ingenuity Pathway Analysis, five genes (ZEB2, CDH1, LTBP2, COL16A1, and ACTA2) were extracted as candidates for prognostic factors associated with progression-free survival. The relationship between high ZEB2 or low CDH1 expression and shorter progression-free survival was validated by real-time RT-PCR experiments of 37 independent advanced stage cancer samples. ZEB2 expression was negatively correlated with CDH1 expression in advanced stage samples, whereas ZEB2 knockdown in ovarian adenocarcinoma SKOV3 cells resulted in an increase in CDH1 expression. Multivariate analysis showed that high ZEB2 expression was independently associated with poor prognosis. Furthermore, the prognostic effect of E-cadherin encoded by CDH1 was verified using immunohistochemical analysis of an independent advanced stage cancer samples set (n = 74). These findings suggest that the expression of epithelial,mesenchymal transition-related genes such as ZEB2 and CDH1 may play important roles in the invasion process of advanced stage serous ovarian cancer. (Cancer Sci 2009) [source] Allelotype Analysis of Common Epithelial Ovarian Cancers with Special Reference to Comparison between Clear Cell Adenocarcinoma with Other Histological TypesCANCER SCIENCE, Issue 7 2002Satoshi Okada Determination of the histological type of epithelial ovarian cancer is clinically important to predict patient prognosis. To estimate accurately the chromosomal regions that frequently show loss of heterozygosity (LOH) in each histological type, LOH at 55 loci on 38 chromosomal arms was examined by means of laser capture microdissection and PCR-LOH analysis in 45 epithelial ovarian cancers composed of clear cell adenocarcinoma (CCA), serous adenocarcinoma (SEA), endometrioid adenocarcinoma (EMA) and mucinous adenocarcinoma (MUA). In addition, p53 (exons 5,8) gene mutations and the nuclear immunoreactivity of p53 proteins in these tumors were examined by PCR-SSCP and immunohistochemistry. In CCA, LOH was detected primarily on 1p (69%) followed by 19p (45%) and 11q (43%). On the other hand, in SEA, LOH was detected in at least 50% of cases on 1p, 4p, 5q, 6p, 8p, 9q, 12q, 13q, 15q, 16p, 17p, 17q, 18p, 18q, 19p, 20p and Xp. The incidences of LOH on 5q, 12q, 13q and 17p were significantly lower in CCA than in SEA (P=0.019, 0.031, 0.0035 and 0.012). EMA showed a tendency for frequent LOH on 7p, whereas MUA showed significantly high occurrence of LOH at 17p13.1. The incidences of p53 mutation and p53 nuclear immunoreactivity also differed between CCA and SEA: 0% and 7% in the former and 64% and 45% in the latter (P=0.0006 and 0.039). These findings clarify that there are differences in LOH distribution patterns among different histological subtypes of epithelial ovarian cancer. In CCA, p53 tumor-suppressor gene (TSG) is not involved in carcinogenesis and tumor-suppressor genes located on 1p are considered to play an important role in tumor development. [source] Increased MCL,1 Expression Is Associated with Poor Prognosis in Ovarian CarcinomasCANCER SCIENCE, Issue 5 2002Kazushi Shigemasa To investigate the potential role of the BCL,2 gene family (BAX, BCL,2, MCL,1, and BCL-XL) in ovarian cancer development and progression, mRNA expression levels of these genes were measured using semi-quantitative PCR in epithelial ovarian tumor tissues and normal ovaries. The immunohistochemical expression of MCL,1 in ovarian tumors was also examined. The expression levels of BAX and MCL,1 mRNA were significantly higher in ovarian cancers and in adenomas than in normal ovaries (P<0.05). In contrast, the BCL,2 mRNA expression level in ovarian cancers was significantly lower than in ovarian adenomas and in normal ovaries (P<0.05). Expression of BCL-XL mRNA was no different between normal ovaries and ovarian tumors. Log-rank testing showed that low BAX mRNA expression and high MCL,1 mRNA expression significantly correlate with poor survival for patients with stage III ovarian carcinomas (BAX, P=0.05; MCL,1, P=0.02). Immunohistochemical analysis showed that diffuse-positive expression of MCL,1 protein in mucinous carcinomas was significantly higher than in mucinous low malignant potential (LMP) tumors (P=0.03). In ovarian cancer cases, diffuse-positive expression of MCL,1 protein significantly correlates with advanced clinical stage, high histologic grade, and poor survival (stage, P<0.01; grade, P=0.01; survival, P=0.01). These results suggest that increased MCL,1 expression may play an important role in replacing the functions of increased BAX and decreased BCL,2 in ovarian carcinoma cells, thereby promoting cell survival, and resulting in a poor prognosis for patients with ovarian cancer. [source] In vitro three-dimensional modelling of human ovarian surface epithelial cellsCELL PROLIFERATION, Issue 3 2009K. Lawrenson Objectives:, Ninety percent of malignant ovarian cancers are epithelial and thought to arise from the ovarian surface epithelium (OSE). We hypothesized that biological characteristics of primary OSE cells would more closely resemble OSE in vivo if established as three-dimensional (3D) cultures. Materials and methods:, OSE cells were cultured as multicellular spheroids (MCS) (i) in a rotary cell culture system (RCCS) and (ii) on polyHEMA-coated plastics. The MCSs were examined by electron microscopy and compared to OSE from primary tissues and cells grown in 2D. Annexin V FACS analysis was used to evaluate apoptosis and expression of extracellular matrix (ECM) proteins was analysed by immunohistochemical staining. Results:, On polyHEMA-coated plates, OSE spheroids had defined internal architecture. RCCS MCSs had disorganized structure and higher proportion of apoptotic cells than polyHEMA MCSs and the same cells grown in 2D culture. In 2D, widespread expression of AE1/AE3, laminin and vimentin were undetectable by immunohistochemistry, whereas strong expression of these proteins was observed in the same cells grown in 3D culture and in OSE on primary tissues. Conclusions:, Physiological and biological features of OSE cells grown in 3D culture more closely resemble characteristics of OSE cells in vivo than when grown by classical 2D approaches. It is likely that establishing in vitro 3D OSE models will lead to greater understanding of the mechanisms of neoplastic transformation in epithelial ovarian cancers. [source] Apoptosis-Inducing High .CHEMMEDCHEM, Issue 10 2008NO Concentrations Are Not Sustained Either in Nascent or in Developed Cancers Abstract Nitric oxide (.NO) induces apoptosis at high concentrations by S-nitrosating proteins such as glyceraldehyde-3-phosphate dehydrogenase. This literature analysis revealed that failure to sustain high . NO concentrations is common to all cancers. In cervical, gastric, colorectal, breast, and lung cancer, the cause of this failure is the inadequate expression of inducible nitric oxide synthase (iNOS), resulting from the inhibition of iNOS expression by TGF-,1 at the mRNA level. In bladder, renal, and prostate cancer, the reason for the insufficient . NO levels is the depletion of arginine, resulting from arginase overexpression. Arginase competes with iNOS for arginine, catalyzing its hydrolysis to ornithine and urea. In gliomas and ovarian sarcomas, low . NO levels are caused by inhibition of iNOS by N -chlorotaurine, produced by infiltrating neutrophils. Stimulated neutrophils express myeloperoxidase, catalyzing H2O2 oxidation of Cl, to HOCl, which N-chlorinates taurine at its concentration of 19,mM in neutrophils. In squamous cell carcinomas of the skin, ovarian cancers, lymphomas, Hodgkin's disease, and breast cancers, low . NO concentrations arise from the inhibition of iNOS by N -bromotaurine, produced by eosinophil-peroxidase-expressing infiltrating eosinophils. Eosinophil peroxidase catalyzes the H2O2 oxidation of Br, to HOBr, which N-brominates taurine to N -bromotaurine at its concentration of 15,mM in eosinophils. In microvascularized tumors, the . NO concentration is further depleted; . NO is rapidly consumed by red blood cells (RBCs) through S-nitrosation of RBC glutathione and hemoglobin, and by oxidation to nitrate by RBC oxyhemoglobin. Angiogenesis-inhibiting antibodies are currently used to treat cancers; their mode of action is not, as previously thought, reduction of the tumor O2 or nutrient supply. They actually decrease the loss of . NO to RBCs. [source] | |||||||||||||||||||||||||