RESUMEN
The four and a half LIM domains 2 (FHL2) has been shown to play important roles in the regulation of cell proliferation, survival, adhesion, motility and signal transduction in a cell type and tissue-dependent manner. However, the function of FHL2 in ovarian physiology and pathology is unclear. The aim of this study was to determine the role and functional mechanism of FHL2 in the progression of ovarian granulosa cell tumors (GCTs). Immunohistochemical analysis indicated that FHL2 was overexpressed in GCT tissues. Cellular localization of FHL2 in GCT cells was cell cycle dependent. Knockdown of FHL2 suppressed GCT cell growth, reduced cell viability and inhibited cell migration. Consistently, ectopic expression of FHL2 in GCT cells with very low endogenous FHL2 promoted cell growth, improved cell viability and enhance cell migration. Importantly, overexpression of FHL2 promoted GCT progression in vivo. Mechanistic studies indicated that FHL2 regulates AKT1 gene expression in vitro and in vivo. Knockdown of FHL2 or AKT1 in GCT cell lines induced very similar phenotypes. Ectopic expression of constitutively active AKT1 rescued FHL2 knockdown-induced arrest of GCT cell growth and reduction of GCT cell viability, suggesting that FHL2 regulates GCT cell growth and viability through controlling AKT1 expression. Finally, co-immunoprecipitation and chromatin immunoprecipitation analyses indicated that FHL2 functions as a co-activator of NFκB and AP-1 to regulate AKT1 gene transcription. In conclusion, results from the present study indicate that FHL2 exerts its oncogenic action in GCT cells via controlling AKT1 gene expression. FHL2 is a promising target for the development of novel drugs against ovarian granulosa cell tumor.
Asunto(s)
Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Tumor de Células de la Granulosa/genética , Proteínas con Homeodominio LIM/genética , Proteínas Musculares/genética , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Factores de Transcripción/genética , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Genes Reporteros , Tumor de Células de la Granulosa/metabolismo , Tumor de Células de la Granulosa/patología , Humanos , Proteínas con Homeodominio LIM/antagonistas & inhibidores , Proteínas con Homeodominio LIM/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Ratones , Ratones Desnudos , Proteínas Musculares/antagonistas & inhibidores , Proteínas Musculares/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Trasplante de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
BACKGROUND: A long-standing hypothesis is that oxidative stress is a risk factor for cancer. Support for this hypothesis comes from observations of higher levels of oxidative damage in the DNA of WBC of cancer patients compared with healthy controls. METHODS: Two generally overlooked types of DNA damage, the formamide modification and the thymine glycol modification, both derived from pyrimidine bases, were assayed as markers of oxidative stress. Damage levels were measured in the DNA of WBC of ovarian cancer patients and of healthy controls. RESULTS: The levels of both modifications were higher in ovarian cancer patients than in healthy controls although in the case of the formamide modification age could not be ruled out as a factor. CONCLUSION: Our results in combination with other published measurements of oxidative DNA damage support the hypothesis that oxidative damage, on average, is higher in WBC of cancer patients than in healthy controls.
Asunto(s)
Daño del ADN , Neoplasias Ováricas/metabolismo , Estrés Oxidativo , Pirimidinas/metabolismo , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Leucocitos/metabolismo , Persona de Mediana Edad , Neoplasias Ováricas/genéticaAsunto(s)
Hibridación Genómica Comparativa , Neoplasias Primarias Múltiples/patología , Neoplasias Ováricas/patología , Neoplasias Uterinas/patología , Anciano , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/diagnóstico , Neoplasias Uterinas/diagnósticoRESUMEN
The goal of this study was to investigate the associations between ovarian cancer risk and usual consumption of black tea, regular coffee, or decaffeinated coffee. Using a hospital-based case-control design, participants included 414 women with primary epithelial ovarian, fallopian, or peritoneal cancer and 868 age- and region-matched women with nonneoplastic conditions. All participants completed a comprehensive epidemiologic questionnaire. Black tea consumption was associated with a linear decline in ovarian cancer risk (P for trend 0.03), with individuals consuming two or more cups daily experiencing a 30% decline in risk (adjusted OR 0.70, 95% CI 0.51-0.97). Similar declines were noted among individuals consuming two or more cups of decaffeinated coffee daily (adjusted OR 0.71, 95% CI 0.51-0.99; P for trend 0.002). However, no association was noted between any level of regular coffee consumption and risk of ovarian cancer. The chemoprotective effects of phytochemicals in black tea and decaffeinated coffee may be important, although the effects of phytochemicals in regular coffee may be counteracted by the elevated risk associated with its higher caffeine content.
Asunto(s)
Café , Neoplasias Ováricas/epidemiología , Té , Cafeína , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana EdadRESUMEN
INTRODUCTION: Primary fallopian tube carcinoma is a rare tumor. The aim of this study was to evaluate clinical characteristics and management of fallopian tube malignancies at a large tertiary care cancer institute. METHODS: A retrospective review of the Tumor Registry was conducted to identify all primary fallopian tube carcinomas between 1980 and 2001. Medical charts were retrospectively reviewed. Primary endpoints were overall survival and disease recurrence. RESULTS: Thirty-five patients had histology consistent with fallopian tube carcinoma. The median age at diagnosis was 56 years. The most common signs or symptoms were abnormal vaginal bleeding (29%) and abdominal/pelvic mass (26%). The most common histology was adenocarcinoma in 16 (46%) patients. Five patients (14%) were Stage I, seven patients (20%) Stage II, 17 patients (49%) Stage III and six patients (17%) Stage IV. Thirty-two (91%) patients received adjuvant chemotherapy and 77% received platinum-based chemotherapy. Twenty-seven (77%) patients underwent second-look surgery, of which 17 patients (63%) were positive for disease. The 5-year survival rate was 64% for Stage I, 42% for Stage II, 32% for Stage III, and 17% for Stage IV. CONCLUSIONS: Fallopian tube malignancies are rare and carry a poor prognosis. More extensive research needs to be performed to have definitive etiologic, diagnostic and treatment guidelines.
Asunto(s)
Carcinoma/mortalidad , Carcinoma/patología , Causas de Muerte , Neoplasias de las Trompas Uterinas/mortalidad , Neoplasias de las Trompas Uterinas/patología , Segunda Cirugía/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Carcinoma/terapia , Terapia Combinada , Neoplasias de las Trompas Uterinas/terapia , Femenino , Procedimientos Quirúrgicos Ginecológicos/métodos , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Probabilidad , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
It is unclear whether smoking is a risk factor for epithelial ovarian cancer, although some studies have suggested that it may be associated with an increased risk of mucinous tumors. This study investigated the effect of smoking and environmental tobacco smoke (ETS) on ovarian cancer risk among 434 women with primary epithelial ovarian, peritoneal, or fallopian cancers and 868 age- and region-matched hospital controls with nonneoplastic conditions. All participants completed a comprehensive epidemiologic questionnaire. Results indicate that decreased risk of ovarian cancer was associated with being a nonsmoker exposed to ETS (adjusted odds ratio [aOR] 0.68, 95% confidence interval [CI] 0.46-0.99), a former smoker (aOR 0.76, 95% CI 0.53-1.10), or a current smoker (aOR 0.53, 95% CI 0.32-0.88). A similar protective effect was noted for smokers with moderate or high exposure based on smoking intensity, duration, and cumulative exposure, as well as for never smokers exposed to ETS. Results did not differ substantially by histologic subtype. Although prevailing theories of ovarian cancer etiology implicate incessant ovulation, characteristics of the study population suggest that anovulation was not the protective mechanism in this study. Immunosuppression by nicotine or upregulation of enzymes that metabolize carcinogens may be responsible for the effects observed.
Asunto(s)
Neoplasias Glandulares y Epiteliales/etiología , Neoplasias Ováricas/etiología , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
With rising numbers of single-parent families, a phenomenon becoming increasingly prevalent is the child orphaned by cancer. We sought to examine issues related to custody planning addressed prior to the patient's death. Ten deceased patients with minor children were identified. The contact person was administered a brief questionnaire regarding the minor children and custody issues. The study involved twenty children, ages ranging from 3-20, mean age 9.8. Only five of the ten families developed custody plans that were ultimately successful. One-half of the families reported the patient had suffered with this issue and almost one-half of the children were not aware of the custody plans that had been arranged for them. In 40% of the cases, the children ultimately went to people to whom the deceased parents were opposed. It is our belief that if we can improve these statistics, we might improve the quality of life of these families.
Asunto(s)
Cuidado en Custodia , Neoplasias/tratamiento farmacológico , Padres Solteros/estadística & datos numéricos , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Detailed deletion mapping of chromosome 6q has shown that the highest percentage of loss of heterozygosity (LOH) is located at 6q25-q27 and suggested that an ovarian cancer associated tumor suppressor gene may reside in this region. To further define the smallest region of common loss, we used 12 tandem repeat markers spanning a region no more than 18 cM, located between 6q25.1 and 6q26, to examine allelic loss in 54 fresh and paraffin embedded invasive ovarian epithelial tumor tissues. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). Detailed mapping of chromosome 6q25-q26 in these tumor samples identified a 4 cM minimal region of LOH between markers D6S473 and D6S448 (6q25.1-q25.2). Loss of heterozygosity at D6S473 correlated significantly both with serous versus non-serous ovarian tumors (P=0.040) and with high grade versus low grade specimens (P=0.023). The results suggest that a 4 cM deletion unit located at 6q25.1-q25.2 may contain the putative tumor suppressor gene which may play a role in the development and progression of human invasive epithelial ovarian carcinomas (IEOC).
Asunto(s)
Carcinoma/genética , Cromosomas Humanos Par 6/genética , Eliminación de Gen , Genes Supresores de Tumor/genética , Neoplasias Ováricas/genética , Adenocarcinoma Mucinoso/genética , Carcinoma/patología , Carcinoma Endometrioide/genética , Mapeo Cromosómico , Cistadenocarcinoma Seroso/genética , Femenino , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite/genética , Neoplasias Ováricas/patologíaRESUMEN
OBJECTIVE: To review the 32-year experience of the New England Trophoblastic Disease Center (NETDC) with choriocarcinoma occurring after a term gestation and to evaluate potential prognostic factors using the World Health Organization (WHO) prognostic score. STUDY DESIGN: The charts of 44 women who were treated for postterm choriocarcinoma at the NETDC from August 1964 to January 1996 were retrospectively reviewed. Demographic data and details of the clinical course were determined. Potential risk factors, including disease duration, pretreatment human chorionic gonadotropin (hCG) level, sites of metastases and stage, as well as data regarding the infants and previous and subsequent pregnancies, were evaluated. RESULTS: Five (11%) of the infants suffered significant complications secondary to maternal choriocarcinoma. The time interval from delivery to diagnosis, pretreatment hCG level and sites of metastatic disease were all significant risk factors in predicting outcome. All 31 patients with a WHO score < or = 8 survived, and 6/13 (46%) patients with a WHO score > 8 died. CONCLUSION: Disease duration greater than four months from delivery, pretreatment hCG level > 100,000 mIU/mL, presence of liver or brain metastases, and a WHO score > 8 were all important predictors of outcome in patients with postterm choriocarcinoma.
Asunto(s)
Coriocarcinoma , Gonadotropina Coriónica/uso terapéutico , Periodo Posparto , Neoplasias Uterinas , Adolescente , Adulto , Coriocarcinoma/diagnóstico , Coriocarcinoma/tratamiento farmacológico , Coriocarcinoma/patología , Gonadotropina Coriónica/administración & dosificación , Femenino , Humanos , Recién Nacido , Estadificación de Neoplasias , Embarazo , Resultado del Embarazo , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/patologíaRESUMEN
We used PCR amplification of tandem repeats to study the pattern of allelic loss in borderline and invasive ovarian epithelial tumors using 12 primer pairs to generate a detailed deletion map of chromosome 9p. In the invasive ovarian carcinomas, there were three regions displaying high frequency of loss of heterozygosity (LOH) ranging from 31-38%. In contrast, LOH was a rare event among the borderline ovarian tumors, with one region revealing a rate of 20% and the remaining regions only 0-8% LOH. Therefore, allelic loss does not seem to be important for the development of borderline ovarian tumors. We also examined p16 gene expression and mutations in ovarian cancer cell lines and invasive and borderline ovarian tumor tissues. Southern blot analysis revealed no losses of the p16 gene in either the invasive or borderline ovarian tumors. However, the ovarian carcinoma cell lines showed a 50% homozygous deletion rate. SSCP analysis detected a mobility shift in only one (borderline) tumor. Since the primary invasive ovarian tumors did not show any deletions or mutations, it appears that p16 does not play a role in the pathogenesis of these tumors.
Asunto(s)
Proteínas Portadoras/genética , Deleción Cromosómica , Cromosomas Humanos Par 9 , Invasividad Neoplásica/genética , Neoplasias Ováricas/genética , Línea Celular Transformada , Células Cultivadas , Mapeo Cromosómico , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Femenino , Heterocigoto , Humanos , Neoplasias Ováricas/patología , Ovario/citología , Ovario/metabolismo , Reacción en Cadena de la PolimerasaRESUMEN
We have used PCR amplification of tandem repeats and Southern blot analysis to study the pattern of allelic loss at chromosome 6q in borderline ovarian tumors and compared that with invasive ovarian carcinomas. DNA from 46 borderline ovarian tissues, 20 invasive ovarian tumor tissues, together with corresponding uninvolved (control) tissues was used. The invasive tumors demonstrated the highest percentage of loss of heterozygosity (13 of 45 informative cases, 29%) at the 6q25-27 locus site. In contrast, the borderline ovarian tumors showed only an 11% frequency of loss of heterozygosity (3 of 26). Our results display a sharp contrast in the pattern of loss of heterozygosity between invasive and borderline ovarian tumors and suggest that allelic loss at chromosome 6q may not be involved in the development of borderline ovarian tumors.
Asunto(s)
Alelos , Cromosomas Humanos Par 6/genética , Eliminación de Gen , Neoplasias Ováricas/genética , Southern Blotting , Femenino , Humanos , Neoplasias Ováricas/patología , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells. STUDY DESIGN: Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test. RESULTS: Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies. CONCLUSIONS: Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.