National Cancer Institute®
Last Modified: May 1, 2002
UI - 11962511
AU - Talarico T; Cullinane C M; Gray P J; Webster L K; Deacon G B; Phillips D
TI - R Nuclear and mitochondrial distribution of organoamidoplatinum(II) lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.
SO - Anticancer Drug Des 2001 Apr-Jun;16(2-3):135-41
AD - Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Australia.
The DNA binding pattern of the organoamidoplatinum(II) compound 1a is of considerable interest because of its known activity against cisplatin-resistant cells. The activity of 1a appears to be due at least in part to a greater cellular uptake than cisplatin into cisplatin-resistant cells, but little is known of the DNA reactions of the organoamidoplatinum(II) compounds. In this study the level of DNA cross-linking and total DNA lesions formed by 1 a were measured by gene-specific Southern hybridization cross-linking assays and by quantitative PCR in cisplatin-sensitive (2008) and in cisplatin-resistant 2008/R human adenocarcinoma cell lines. The surprising result was that the major difference between cisplatin and 1a was that the number of interstrand cross-links induced by 1a were approximately 5-fold greater than that induced by cisplatin in the nuclear (but not mitochondrial) DNA of resistant cells, even though the total number of lesions were essentially the same in both sensitive and resistant cells. This result suggests that the extent of interstrand cross-linking is a critical determinant of the cellular response to 1a and that the enhanced uptake of 1a into resistant cells results in this elevated level of cross-linking, leading to good activity of 1a against cisplatin-resistant cells. It remains unclear as to why 1a exhibits such selective damage to nuclear DNA, and insight into the molecular aspects of this selectivity will provide new opportunities for the further development of new platinum-based agents with activity against cisplatin-resistant cells.
UI - 11606393
AU - Kumar A; Soprano DR; Parekh HK
TI - Cross-resistance to the synthetic retinoid CD437 in a paclitaxel-resistant human ovarian carcinoma cell line is independent of the overexpression of retinoic acid receptor-gamma.
SO - Cancer Res 2001 Oct 15;61(20):7552-5
AD - Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Treatment of ovarian carcinomas with the antimitotic antitumor drug paclitaxel is highly efficacious. However, development of drug resistance presents a major obstacle. The common cellular phenotypes associated with paclitaxel resistance are an increased expression of the drug transport protein P-glycoprotein (P-gp), an alteration in the levels of beta-tubulin isotypes, and/or changes in the drug binding affinity of the microtubules. We established two paclitaxel-resistant human ovarian carcinoma cell lines. The 2008/17/4 cells exhibited a "classic" multidrug-resistant phenotype (overexpression of P-gp associated with cross-resistance to natural product drugs), whereas the 2008/13/4 cells were an atypical multidrug-resistant subline (no overexpression of P-gp). In addition to being paclitaxel resistant (250-fold), the 2008/13/4 cells were also cross-resistant to etoposide (39-fold) and vincristine (460-fold). To identify the alterations in the gene expression profile associated with the development of atypical paclitaxel resistance, we used the Clontech Atlas Human Cancer cDNA Microarray (spotted with 588 genes). The expression of retinoic acid receptor (RAR)-gamma was significantly higher in the paclitaxel-resistant (2008/13/4 and 2008/17/4) cells than in the parental (2008) cells. Northern blotting analysis demonstrated that the expression of RAR-gamma was 7-fold higher in the 2008/13/4 and 2008/17/4 cells than in the 2008 cells, whereas the expression of RAR-alpha and RAR-beta was not observed in any cell line. Whereas the 2008, 2008/13/4, and 2008/17/4 cells were found to resist the antiproliferative effects of all-trans-retinoic acid, the paclitaxel-resistant cells were 6- to 7-fold cross-resistant to the antiproliferative effects of CD437 (a synthetic RAR-gamma-selective agonist; 6-[-(1-admantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid) compared with the sensitivity of the parental cells. To further understand the association of paclitaxel and CD437 resistance with the observed RAR-gamma overexpression, we transfected the 2008 cells with a full-length RAR-gamma cDNA construct. Two transfectants with increased expression of the RAR-gamma mRNA and protein were isolated and subjected to growth inhibition assays in the presence of various concentrations of paclitaxel, etoposide, vincristine, and CD437. The sensitivity of the 2008 transfected clones (displaying increased expression of RAR-gamma) to the cytotoxic effects of paclitaxel, etoposide, vincristine, and CD437 was similar to that observed in the parental 2008 cells. These results suggest that the overexpression of RAR-gamma (observed in the 2008/13/4 and 2008/17/4 cells) by itself is not capable of inducing paclitaxel and CD437 resistance (or resistance to etoposide and vincristine).
UI - 11929819
AU - Hasumi Y; Mizukami H; Urabe M; Kohno T; Takeuchi K; Kume A; Momoeda M;
TI - Yoshikawa H; Tsuruo T; Shibuya M; Taketani Y; Ozawa K Soluble FLT-1 expression suppresses carcinomatous ascites in nude mice bearing ovarian cancer.
SO - Cancer Res 2002 Apr 1;62(7):2019-23
AD - Division of Genetic Therapeutics, Jichi Medical School, Tochigi 329-0498, Japan.
Vascular endothelial growth factor (VEGF), a bifunctional protein enhancing vascular permeability and stimulating endothelial growth, is thought to be responsible for fluid accumulation and angiogenesis in ascites tumors. To investigate the effects of stable expression of the soluble form of Flt-1 VEGF receptor (sFlt-1), a known endogenous inhibitor of VEGF, on the malignant ascites tumors, we cotransduced RMG-1 human ovarian cancer cells with adeno-associated virus vectors carrying the sFlt-1 cDNA and Neo gene or Neo gene alone and isolated both the sFlt-1-expressing clone and the Neo-expressing clone. In vitro growth characteristics were essentially the same. As expected, conditioned medium collected from the sFlt-1-expressing cells significantly inhibited the human umbilical vein endothelial cell proliferation in the presence of recombinant VEGF. Expression of sFlt-1 significantly suppressed RMG-1 cell-induced angiogenesis in vivo in the mouse dorsal air sac assay model. We then inoculated sFlt-1- or Neo alone-expressing cells i.p. into female BALB/c nude mice. The average volume of ascites fluid, number of leaked RBCs, and number of cancer cells were significantly lower in mice injected with sFlt-1-expressing cells than in the controls. Survival time was significantly prolonged in mice injected with sFlt-1-expressing cells. These results suggest that inhibition of VEGF activity by sFlt-1 expression may provide a means to control carcinomatous ascites and angiogenesis of malignant ascites tumors.
UI - 11765050
AU - Watson J; Taylor M; Pampiglione J; Rasbridge S; Armitage M
TI - An exception to the rule: ectopic ACTH production from functional neuroendocrine tissue in an ovarian dermoid cyst.
SO - J Endocrinol Invest 2001 Nov;24(10):802-5
AD - Bournemouth Diabetes and Endocrine Centre, Royal Bournemouth Hospital, UK.
Ectopic ACTH production accounts for 15% of Cushing's syndrome presentations and is characterized by the presence of an excess of ACTH precursors. However in the case presented here ectopic ACTH production was from functional pituitary tissue within an ovarian dermoid cyst. Endocrine investigations showed that the problem behaved more like pituitary-dependent Cushing's disease and this is discussed. Furthermore, this case is one of familial dermoid cysts, another unusual phenomenon.
UI - 11920956
AU - Bharaj BB; Luo LY; Jung K; Stephan C; Diamandis EP
TI - Identification of single nucleotide polymorphisms in the human kallikrein 10 (KLK10) gene and their association with prostate, breast, testicular, and ovarian cancers.
SO - Prostate 2002 Apr 1;51(1):35-41
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
BACKGROUND: The KLK10 gene (also known as the normal epithelial cell-specific 1 gene) is a member of the expanded human kallikrein gene family. Recently, it has been reported that KLK10 is a tumor suppressor gene and that its expression is downregulated in various forms of cancer and cancer cell lines. KLK10 is also upregulated in ovarian cancer. We thus hypothesized that the KLK10 gene may be a target for mutations in various cancers. METHODS: We sequenced the five coding exons of the KLK10 gene using genomic DNA from various tumors, normal tissues, and blood, by PCR amplification and automated sequencing. RESULTS: In none of the tumor-derived DNAs, we identified somatic mutations that could inactivate this gene. However, we identified a prevalent germline single nucleotide variation at codon 50 (exon 3) of this gene [GCC (alanine) to TCC (serine)]. The GCC genotype was less prevalent in prostatic cancer patients in comparison to control subjects (P = 0.027) but no differences were seen with testicular, ovarian, and breast cancer. We also identified four genetic variations in exon 4, at codons106 [GGC (glycine) to GGA (glycine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and at codon 149 [CCG (proline) to CTG (leucine)]. None of these variations was significantly different between normal subjects and cancer groups. CONCLUSIONS: We found no evidence for somatic mutations of the KLK10 gene in cancers of the prostate, breast, ovary, and testis. The single nucleotide variation at codon 50 appears to be associated with prostate cancer risk. Copyright 2002 Wiley-Liss, Inc.
UI - 11873549
AU - Fries MH; Holt C; Carpenter I; Carter CL; Daniels J; Flanagan J; Murphy
TI - K; Hailey BJ; Martin L; Hume R; Hudson G; Cadman M; Weatherly R; Nunes ME Guidelines for evaluation of patients at risk for inherited breast and ovarian cancer: recommendations of the Department of Defense Familial Breast/Ovarian Cancer Research Project.
SO - Mil Med 2002 Feb;167(2):93-8
AD - Air Force Medical Genetics Center, Keesler Air Force Base, MS 39534, USA.
Patients at high risk for inherited breast and/or ovarian cancer are frequently encountered in all medical specialties. Department of Defense, Health Affairs funding as part of the Breast Cancer Education and Awareness Program was used to develop a comprehensive program for the identification, counseling, genetic testing, and long-term follow-up of such high-risk patients. This article reports the recommendations for high-risk patient management based on 4 years of evaluation and care, including discussions of the approach to counseling, indications for genetic testing, post-testing counseling, patient surveillance with examination, imagining, and laboratory testing, and suggested options for surgical and chemoprophylaxis as well as lifestyle modifications.
UI - 11873550
AU - Fries MH; Holt C; Carpenter I; Carter CL; Daniels J; Flanagan J; Murphy
TI - K; Hailey BJ; Martin L; Hume R; Hudson G; Cadman M; Weatherly R; Nunes ME Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of the Department of Defense Familial Breast/Ovarian Cancer Research Project.
SO - Mil Med 2002 Feb;167(2):99-103
AD - Air Force Medical Genetics Center, Keesler Air Force Base, MS 39534, USA.
The Department of Defense Familial Breast/Ovarian Cancer Research Project has offered genetic counseling and testing for BRCA1 and BRCA2 on a research basis to patients meeting specific diagnostic criteria, with risk for BRCA1 and BRCA2 mutations calculated based on the Couch model. In 2.5 years, 250 patients were evaluated and 101 patients met criteria requirements, including 33 who met criteria in more than one category. Ninety patients elected to undergo DNA testing. In this group of 90 patients, 14 mutations (15.5%) and 16 unclassified variants (17.7%) were identified. The most common inclusion criteria were onset of breast/ovarian cancer before age 45 years (n = 32) and onset of breast/ovarian cancer before age 45 years with strong family history (n = 21). However, when number of mutations and unclassified variants found were compared separately across all diagnostic criteria (including those of more than one capacity) using the chi 2 statistic, no significant differences were seen among the categories to suggest that one criterion was more predictive of mutations or variants than another. Couch risk values for patients with mutations showed a mean of 14% and ranged from 3.2 to 43.5% (range for all patients, 1.2-69.7%). These findings emphasize the importance of using multiple diagnostic criteria and suggest that a Couch risk value of > 3% may be useful in selecting patients for testing. The data also underscore the necessity of genetic counseling in the testing process, particularly given the large number of unclassified variants diagnosed and their uncertain status for disease predisposition.
UI - 11883288
AU - Waksmanski B; Dudkiewicz J; Srebrniak M
TI - [Chromosome instability in women with genital organs carcinoma]
SO - Ginekol Pol 2001 Dec;72(12A):1411-7
AD - II Katedry i Kliniki Poloznictwa i Ginekologii SlAM w Zabrzu.
OBJECTIVES: The aim of the current work was the assessment of the mutagen susceptibility of chromosomes of patients with carcinomas in comparison to healthy volunteers. It was interesting whether the bleomycin assay can be useful for searching for more susceptible to cancer disease individuals. MATERIALS AND METHODS: There were 4 groups of patients analysed: controls and three test groups (patients with uterine cervix carcinoma, endometrium carcinoma and ovarian carcinoma). In total 108 female patients were examined by use of bleomycin assay. Lymphocytes were cultured in vitro and treated with bleomycin. The b/c (breaks per cell) index was evaluated by use of light microscopy. RESULTS: Statistically significant increased test values were found in patients with uterine cervix carcinoma, endometrium carcinoma and ovarian carcinoma. CONCLUSIONS: The assessment of chromosome instability could be a useful prognostic test in the diagnosis of carcinoma of female genital organs. The bleomycin assay is useful for searching subpopulations with higher chromosome instability and more susceptible to cancer disease.
UI - 11925118
AU - Fei R; Shaoyang L
TI - Combination antigene therapy targeting c-myc and c-erbB(2) in the ovarian cancer COC(1) cell line.
SO - Gynecol Oncol 2002 Apr;85(1):40-4
AD - Department of Gynecologic Oncology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, 430071, People's Republic of China.
OBJECTIVE: Antigene therapy targeting only one oncogene in ovarian cancer has made much progress, although it still has some limitations. To explore the potential for combination antigene therapy in ovarian cancer, we examined the in vitro effects of liposmal antisense phosphorothioate oligodeoxynucleotides targeting c-erbB(2) and c-myc (LF-c-erbB(2)/c-myc AS-ODNs) in the human ovarian cancer COC(1) cell line. METHODS: COC(1) cells were treated differently as follows: group A with single LF-c-erbB(2) AS-ODNs; group B with single LF-c-myc AS-ODNs; group C with combination LF-c-erbB(2)/c-myc AS-ODNs; and group D as untreated control. Cell proliferation was studied by MTT assay and clonal cultures. RT-PCR was used to measure gene expression of c-erbB(2) and c-myc before and after transfection. Morphologic changes in the COC(1) cells were observed with the electron microscope. RESULTS: Single antigene therapy targeting c-erbB(2) or c-myc could reduce target gene expression and inhibit COC(1) cell growth by 61.9 +/- 9.3 and 64.5 +/- 11.2%, respectively. However, combination antigene therapy could not only suppress expression of c-erbB(2) and c-myc simultaneously, but also inhibit COC(1) cell proliferation with a higher inhibitory rate of 82.6 +/- 12.1%. Apart from that, the combination agents could induce COC(1) cell apoptosis. CONCLUSIONS: Our study suggests that combination antigene therapy targeting c-erbB(2) and c-myc can inhibit COC(1) cell proliferation and gene expression of c-erbB(2) and c-myc. Furthermore, its effectiveness is much higher than that of individual antigene therapy.
UI - 11925114
AU - Piver MS
TI - Hereditary ovarian cancer. Lessons from the first twenty years of the Gilda Radner Familial Ovarian Cancer Registry.
SO - Gynecol Oncol 2002 Apr;85(1):9-17
AD - Founder and Director of the Gilda Radner Familial Ovarian Cancer Registry, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. email@example.com
UI - 11717538
AU - Davidson B; Risberg B; Goldberg I; Nesland JM; Berner A; Trope CG;
TI - Kristensen GB; Bryne M; Reich R Ets-1 mRNA expression in effusions of serous ovarian carcinoma patients is a marker of poor outcome.
SO - Am J Surg Pathol 2001 Dec;25(12):1493-500
AD - Department of Pathology, the Norwegian Radium Hospital, Oslo, Norway. firstname.lastname@example.org
Ets-1 proto-oncogene is a transcription factor with a role in the activation of metastasis-associated molecules. We recently found that Ets-1 mRNA expression in solid tumors is a marker of poor prognosis in ovarian carcinoma. The objective of this study was to compare the expression of Ets-1 mRNA in effusions and primary and metastatic tumors of serous ovarian carcinoma patients and to evaluate its prognostic role in effusions. Sections from 67 malignant effusions and 90 primary and metastatic lesions were evaluated for expression of Ets-1 using mRNA in situ hybridization. Expression of Ets-1 mRNA was detected in carcinoma cells in 24 of 67 (36%) effusions. Expression in cancer cells was similar in peritoneal and pleural effusions. In solid lesions Ets-1 expression was detected in both tumor cells and stromal cells in 34 of 90 (38%) lesions. Ets-1 expression in tumor cells showed a strong association with that of stromal cells (p <0.001). Ets-1 expression in effusions showed an association with mRNA expression of basic fibroblast growth factor, previously studied in this patient cohort (p = 0.019). Ets-1 expression in solid lesions showed an association with mRNA expression of vascular endothelial growth factor (p <0.001 for both carcinoma and stromal cells), basic fibroblast growth factor (p = 0.007 for carcinoma cells, p = 0.006 for stromal cells), and interleukin-8 (IL-8) (p = 0.001 for tumor cells). Ets-1 mRNA showed upregulation in metastases when compared with effusion specimens (p = 0.028). In univariate survival analysis Ets-1 expression in carcinoma cells in effusions correlated with poor survival (p = 0.003). Our findings confirm the role of Ets-1 as a novel prognostic marker in advanced-stage ovarian carcinoma and extend it to effusion specimens. The elevated expression in solid metastases supports a central role in tumor progression as well. The association between Ets-1 mRNA expression and the expression of angiogenic genes, documented also in our previous study, points to the close link between these molecules, in agreement with the role of angiogenic genes in the transcriptional activation of Ets-1. The identical phenotype of carcinoma cells in pleural and peritoneal effusions provides further evidence for our theory that cells at these sites share similar genotypic and phenotypic profiles.
UI - 11965534
AU - Mirza A; McGuirk M; Hockenberry TN; Wu Q; Ashar H; Black S; Wen SF; Wang
TI - L; Kirschmeier P; Bishop WR; Nielsen LL; Pickett CB; Liu S Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway.
SO - Oncogene 2002 Apr 18;21(17):2613-22
AD - Tumor Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, NJ 07033, USA.
Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.
UI - 11965550
AU - Bingle L; Singleton V; Bingle CD
TI - The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms.
SO - Oncogene 2002 Apr 18;21(17):2768-73
AD - Respiratory Medicine Unit, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield S10 2RX, UK.
The whey acidic protein (WAP) domain is a conserved motif, containing eight cysteines found in a characteristic 4-disulphide core arrangement, that is present in a number of otherwise unrelated proteins. WAP motifs are present in SLPI and elafin, two antiproteinases located on chromosome 20q12-13, in a locus rich in poorly characterized WAP domain proteins. One of these proteins, which contains two WAP domains, is HE4 (also known as WFDC2), originally described as an epididymis specific protein but more recently suggested to be a putative serum tumour marker for ovarian cancer. We have shown that HE4 is expressed in a number of normal human tissues outside of the male reproductive system, including regions of the respiratory tract and nasopharynx, as well as in a subset of lung tumour cell lines. Comparison of multiple HE4 cDNAs and RT-PCR products with genomic sequence allowed the elucidation of the genomic organization. These studies revealed that HE4 can undergo a complex series of alternative splicing events that can potentially yield five distinct WAP domain containing protein isoforms. These results cast doubt on the potential role of HE4 as a serum tumour marker specific for ovarian cancer and open the door to understanding the function of multiple WAP domain containing protein isoforms arising from a single gene.
UI - 11809533
AU - Baxter SW; Choong DY; Campbell IG
TI - Microsomal epoxide hydrolase polymorphism and susceptibility to ovarian cancer.
SO - Cancer Lett 2002 Mar 8;177(1):75-81
AD - VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Institute, Locked Bag No. 1 A'Beckett Street, Melbourne, Victoria, 8006, Australia.
Polymorphic variants of microsomal epoxide hydrolase (mEPHX) with altered enzyme activity have been associated with an increased risk for ovarian cancer. We assessed the frequency of exon 3 and exon 4 variants of mEPHX among 291 ovarian cancers and 257 controls from a UK-based population. The distribution of the exon 3 alleles among both the cancer and control groups was significantly different from that expected under Hardy-Weinberg equilibrium suggesting that the PCR restriction fragment length polymorphism (PCR-RFLP) genotyping assay might be flawed. The codon 113 polymorphism was reassessed using a two-color allele-specific PCR-based assay. We found that a codon 119 G>A polymorphism, present in 20% of the British population and linked to the wild-type exon 3 allele, resulted in some Tyr113/His113 heterozygotes being falsely classified as His113/His113 homozygotes when using the PCR-RFLP assay. Consequently, we reassessed all our codon 113 data using the new allele-specific assay. We found no evidence of an association of ovarian cancer risk with the exon 3 Tyr113>His113 variant. Similarly the frequencies of the exon 4 His139>Arg139 genotypes were not significantly different between cases and controls. Stratifying the genotyping data according to the predicted mEPHX activity revealed a highly significant decrease in high mEPHX activity among the serous ovarian cancers (P=0.01) suggesting that high mEPHX activity may be protective for this histological sub-type. Furthermore previous disease association studies of exon 3 alleles which utilized the PCR-RFLP assay may be compromised by the existence of a codon 119 G>A polymorphism which may be common in Caucasian populations.
UI - 11977628
AU - Yan C; Tian F; Xiao F; Li K; Li C
TI - [Adhesion induces matrix metalloproteinase-9 gene expression in ovarian cancer cells]
SO - Zhonghua Zhong Liu Za Zhi 2002 Jan;24(1):17-9
AD - Department of Tumor Molecular Biology, Reseach Clinic, Academy of Military Medical Sciences, Beijing 100039, China.
OBJECTIVE: This work was conducted to investigate the expression of matrix metalloproteinase 9 (MMP 9) gene in cancer cells by fibronectin adhesion and the underlying mechanism of cell invasion. METHODS: Following adhesion of ovarian cancer cells A2780 to fibronectin, mRNA expression of MMP cells were assayed by reverse transcription-polymerase chain reaction (RT-PCR). MMP9 promoter was cloned from genomic DNA of HT1080 cells with PCR. The MMP-9-pGL2 reporter gene vector was constructed and then transiently transfected into A2780 cells. RESULTS: Adhesion induced the increase of cellular MMP9 mRNA content in A2780 cells, not affecting the expression of MMP2 or TIMP-1 gene. The stimulation was enhanced with the increase adhesion time. When the transfected cells were allowed to adhere and spread on FN-coated surface, the promoter activity of MMP9 gene was also enhanced dramatically. CONCLUSION: Cell-ECM adhesion may stimulate the expression of MMP9 gene through stimulating the promoter activity, thereby enhancing cancer cell invasion and metastasis.
UI - 11964077
AU - Davidson B; Reich R; Kopolovic J; Berner A; Nesland JM; Kristensen GB;
TI - Trope CG; Bryne M; Risberg B; van de Putte G; Goldberg I Interleukin-8 and vascular endothelial growth factor mRNA and protein levels are down-regulated in ovarian carcinoma cells in serous effusions.
SO - Clin Exp Metastasis 2002;19(2):135-44
AD - Department of Pathology, The Norwegian Radium Hospital, University of Oslo. email@example.com
Angiogenic factors are involved in tumor growth and spread. The aim of this study was to evaluate the expression of angiogenesis-related genes in malignant serous effusions of patients with advanced-stage (FIGO stage III and IV) ovarian carcinoma. In addition, to compare the results for carcinoma cells in effusions with corresponding primary tumors and metastatic lesions, and analyze their prognostic role. Sections from 66 effusions and 90 primary and metastatic lesions from 62 ovarian and primary peritoneal carcinoma patients, were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA in situ hybridization (ISH). Protein expression was evaluated in a subset of specimens using immunohistochemistry (IHC). ISH results were correlated with clinical parameters. In both effusions and solid tumors, bFGF mRNA was the most commonly expressed factor (93% of effusions and 95% of solid tumors) followed by IL-8, while VEGF was expressed in a minority of the specimens (P < 0.001 for bFGF vs. IL-8 and VEGF). In solid tumors, angiogenic mRNA expression was seen in both tumor and stromal cells in the majority of positive cases. ISH results did not differ in primary and metastatic tumors. However, carcinoma cells in effusions showed down-regulated expression of VEGF, when compared with both primary tumors (P = 0.029) and metastases (P = 0.015). IL-8 showed a similar down-regulation in effusions, when compared with metastases (P = 0.005). IHC showed excellent agreement with mRNA findings on protein level. In the study of clinico-pathologic parameters, IL-8 mRNA expression in effusions was associated with higher tumor grade (P = 0.044). Angiogenic gene expression in effusions showed no correlation with patient age, previous treatment, residual tumor size, FIGO stage or disease outcome in survival analysis (P > 0.05). Peritoneal and pleural effusions showed similar expression patterns. In conclusion, bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. It is highly expressed in both solid tumors and serous effusions, while IL-8 and VEGF are down regulated in carcinoma cells in effusions, possibly due to the lack of interaction with stromal cells. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma. Carcinoma cells in pleural and peritoneal effusions show a similar metastatic expression profile, in agreement with our previous findings, supporting the true metastatic nature of ovarian carcinoma cells in ascites.
UI - 11774353
AU - Smith DI
TI - Transcriptional profiling develops molecular signatures for ovarian tumors.
SO - Cytometry 2002 Jan 1;47(1):60-2
AD - Mayo Clinic Cancer Center, Rochester, Minnesota 55905, USA. firstname.lastname@example.org
Of the cancers unique to women, ovarian cancer has the highest mortality rate. Over 26,000 women are diagnosed with this disease in the U.S. annually, and 60% of those diagnosed will die of the disease. One of the greatest problems with this disease is the lack of strong early warning signs or symptoms resulting in advanced stage at presentation in most women, followed by the outgrowth of chemotherapy-resistant disease in the majority of patients. The 5-year survival for patients with early stage disease ranges from 50-90%, but it is less than 25% for advanced-stage disease. In collaboration with researchers at Millennium Predictive Medicine (Cambridge, MA), the Ovarian Cancer Program of the Mayo Clinic Cancer Center analyzed gene expression in over 50 primary ovarian tumors, as compared with normal ovarian epithelial cells. The technologies utilized included microarray analysis with nitrocellulose filters containing 25,000 arrayed human cDNAs, as well as the construction of subtraction suppression hybridization cDNA libraries and their subsequent sequencing. Our specific focus has been on genes that are underexpressed during the development of ovarian cancer, although this analysis has revealed a large number of consistently up- and down-regulated genes. There were more down-regulated genes in ovarian tumors than up-regulated genes. In addition, the number of genes that had altered expression levels was quite large. For example, we found 409 genes down-regulated at least 5-fold, and 72 genes up-regulated at least 5-fold in 33% of the tumors analyzed. We also observed that most of the expression alterations observed in later stage (Stages III/IV) tumors were also observed in early-stage tumors (Stages I/II). This was corroborated using comparative genomic hybridization analysis on the same tumors that were expression profiled. This analysis revealed that the late-stage tumors had more gene amplification than early-stage tumors, but most regions of change (either increases or decreases) were in common between different stage tumors. We also have verified the altered expression levels of several of these genes using several complementary strategies. Finally, we are taking top candidate genes that are consistently under-expressed in ovarian tumors and attempting to determine their functional role in the development of ovarian cancer. Copyright 2001 Wiley-Liss, Inc.
UI - 11836606
AU - Furui T; Imai A; Tamaya T
TI - Intratumoral level of gonadotropin-releasing hormone in ovarian and endometrial cancers.
SO - Oncol Rep 2002 Mar-Apr;9(2):349-52
AD - Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu 500-8705, Japan.
Gonadotropin-releasing hormone (GnRH) produced within ovarian cancers and endometrial cancers acts as a negative autocrine regulator in their growth. To provide a potential association of GnRH content with the presence of GnRH receptor, we have evaluated GnRH levels in human gynecologic carcinomas and compared them to those in normal tissues. Surgically removed tumors and normal tissues had been screened for GnRH receptor expression before analysis. GnRH was determined by a radioimmunoassay and a high-performance liquid chromatography in peptide extracts. GnRH levels for ovarian cancers (n=25, range 0.01- 0.99 pg/mg protein, with a mean +/- SD of 0.37 +/- 0.28 pg/mg protein) and for endometrial cancers (n=12, range 0.01-0.19, 0.13 +/- 0.074 pg/mg protein) were significantly higher than those for normal ovaries (n=11, range 0.007-0.195, 0.10 +/- 0.06 pg/mg protein) (P=0.003) and endometria (n=7, range 0.01-0.09, 0.049 +/- 0.029 pg/mg protein) (P=0.014), respectively. The GnRH levels in these cancers were not different between GnRH receptor-positive specimens (20 ovarian cancers and 9 endometrial cancers) and -negative specimens (5 ovarian cancers and 3 endometrial cancers). In contrast, GnRH was <0.001 pg/mg protein in all 13 uterine cervical carcinomas bearing no GnRH receptor. These data demonstrate that the neoplastic ovaries and endometria that frequently express GnRH receptor have the capacity to produce excessive amount of GnRH regardless of whether GnRH receptor is evident.
UI - 11393611
AU - Paterson AG; Trask PC; Schwartz SM; Deaner SL; Riba M; Holland J;
TI - Fleishman SB; Breitbart W Screening and treatment of distress.
SO - J Consult Clin Psychol 2001 Apr;69(2):339
UI - 11860053
AU - Benazon NR; Coyne JC; Calzone KA; Weber BL
TI - Why not to screen high-risk women anticipating BRCA1/BRCA2 testing for psychological distress.
SO - J Consult Clin Psychol 2002 Feb;70(1):258
UI - 11932746
AU - Judson H; Hayward BE; Sheridan E; Bonthron DT
TI - A global disorder of imprinting in the human female germ line.
SO - Nature 2002 Apr 4;416(6880):539-42
AD - University of Leeds, Molecular Medicine Unit, St. James's University Hospital, UK.
Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment.
UI - 11982262
AU - Cummings S
TI - Weighing the risks. Genetic counseling for hereditary breast and ovarian cancer.
SO - AWHONN Lifelines 2001 Jun-Jul;5(3):42-7
AD - Cancer Risk Clinic, University of Chicago, Chicago, IL, USA.
UI - 12023992
AU - Kauff ND; Satagopan JM; Robson ME; Scheuer L; Hensley M; Hudis CA; Ellis
TI - NA; Boyd J; Borgen PI; Barakat RR; Norton L; Castiel M; Nafa K; Offit K Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.
SO - N Engl J Med 2002 May 23;346(21):1609-15
AD - Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
BACKGROUND: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. METHODS: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan-Meier analysis and a Cox proportional-hazards model. RESULTS: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). CONCLUSIONS: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer.
UI - 12023993
AU - Rebbeck TR; Lynch HT; Neuhausen SL; Narod SA; Van't Veer L; Garber JE;
TI - Evans G; Isaacs C; Daly MB; Matloff E; Olopade OI; Weber BL; The Prevention and Observation of Surgical End Points Study Group Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.
SO - N Engl J Med 2002 May 23;346(21):1616-22
AD - Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA. email@example.com
BACKGROUND: Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. METHODS: A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. RESULTS: Six women who underwent prophylactic oophorectomy (2.3 percent) received a diagnosis of stage I ovarian cancer at the time of the procedure; two women (0.8 percent) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9 percent) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95 percent confidence interval, 0.01 to 0.16). Of 99 women who underwent bilateral prophylactic oophorectomy and who were studied to determine the risk of breast cancer, breast cancer developed in 21 (21.2 percent), as compared with 60 (42.3 percent) in the control group (hazard ratio, 0.47; 95 percent confidence interval, 0.29 to 0.77). CONCLUSIONS: Bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations.
UI - 12014223
AU - Rudzki Z; Zazula M; Bialas M; Klimek M; Stachura J
TI - Synchronous serrated adenoma of the appendix and high-grade ovarian carcinoma: a case demonstrating different origin of the two neoplasms.
SO - Pol J Pathol 2002;53(1):29-34
AD - Department of Pathomorphology, Collegium Medicum, Jagiellonian University, Krakow.
Association of mucinous adenomas of the appendix and mucinous ovarian tumors is well known. The origin of the ovarian tumor (metastasis from the appendix vs independent primary) is still debated. Serrated adenoma is a rare neoplasm of the distal gastrointestinal tract, and its precancerous role in the colorectum was recently postulated. A 74-year-old patient was subjected to hysterectomy with routine appendectomy due to a 17-cm tumor of her right ovary. Histological examination revealed a high-grade ovarian adenocarcinoma with peritoneal involvement. The appendix, grossly unremarkable, harbored a serrated adenoma with no evidence of invasion or malignant transformation. Immunohistochemical examination revealed CD7+, CK20-phenotype of the ovarian and reverse (CK7-, CK20+) phenotype of the appendiceal tumor. Microsatellite analysis demonstrated microsatellite instability (MSI-high) within the serrated adenoma (4/5 markers with positive amplification) and no MSI (0/6 amplified markers) in the samples from the ovarian carcinoma, its metastases and the uninvolved uterine cervix. There were also differences in LOH pattern between the ovarian adenocarcinoma and the serrated adenoma. The findings suggest two independent primaries with profound differences in tumorigenetic pathways of both lesions. To the best of our knowledge this is the first report of synchronous serrated adenoma of the appendix and ovarian carcinoma.
UI - 11980661
AU - Xiang R; Davalos AR; Hensel CH; Zhou XJ; Tse C; Naylor SL
TI - Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice.
SO - Cancer Res 2002 May 1;62(9):2637-43
AD - Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Loss of heterozygosity on human chromosome 3p21.3 is a frequent occurrence in many tumor types. In a previous study, our laboratory demonstrated that an 80-kb P1 clone from chromosome 3 suppresses the tumorigenicity of the mouse fibrosarcoma cell line A9. Two cDNAs corresponding to genes encoded on this P1 clone, semaphorin 3F (SEMA3F) and N23, were tested for their effects on in vitro and in vivo growth characteristics after transfection into mouse A9 cells. Transfection of SEMA3F cDNA resulted in complete loss of tumorigenicity in nude mice, whereas transfection of N23 had no effect. Moreover, SEMA3F also functioned to block apoptosis of transfected A9 cells treated with Taxol or Adriamycin. The human ovarian adenocarcinoma cell line HEY showed a similar result as A9 cells, but the small cell lung cancer line GLC45 was unaffected by expression of SEMA3F.
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