RESUMEN
Ovarian granulosa cell tumors (GCTs) represent 3%-5% of all ovarian malignancies. Treatments have limited proven efficacy and biologically targeted treatment is lacking. The aim of this study was to investigate the role of Notch signaling in the proliferation, steroidogenesis, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in a FOXL2-mutated granulosa tumor cell line (KGN) representative of the adult form of GCTs. When Notch signaling is initiated, the receptors expose a cleavage site in the extracellular domain to the metalloproteinase TACE and, following this cleavage, Notch undergoes another cleavage mediated by the presenilin-gamma-secretase complex. To achieve our goal, DAPT, an inhibitor of the gamma-secretase complex, was used to investigate the role of the Notch system in parameters associated with cell growth and death, using a human granulosa cell tumor line (KGN) as an experimental model. We observed that JAGGED1, DLL4, NOTCH1, and NOTCH4 were highly expressed in KGN cells as compared to granulosa-lutein cells obtained from assisted reproductive techniques patients. The proliferation and viability of KGN cells, as well as progesterone and estradiol production, decreased in the presence of 20 µM DAPT. Apoptotic parameters like PARP and caspase 8 cleavages, BAX, and BCLXs increased in KGN cells cultured with DAPT, whereas others such as BCL2, BCLXl, FAS, and FAS ligand did not change. AKT phosphorylation decreased and PTEN protein increased when Notch signaling was inhibited in KGN cells. We conclude that the Notch system acts as a survival pathway in KGN cells, and might be interacting with the PI3K/AKT pathway.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factores de Transcripción Forkhead/genética , Tumor de Células de la Granulosa/metabolismo , Neoplasias Ováricas/metabolismo , Receptores Notch/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Dipéptidos , Femenino , Proteína Forkhead Box L2 , Hormonas Esteroides Gonadales/biosíntesis , Tumor de Células de la Granulosa/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Jagged-1 , Proteínas de la Membrana/metabolismo , Mutación , Neoplasias Ováricas/genética , Receptores Notch/antagonistas & inhibidores , Proteínas Serrate-JaggedRESUMEN
BACKGROUND: In Mexico, ovarian cancer represents 5.3% of cancer diagnoses in all age groups and 21% of gynecologic cancers. The states with the highest incidence of this disease Nuevo León, Mexico State and Federal District. OBJECTIVE: To determine the epidemiological profile of ovarian cancer. PATIENTS AND METHODS: A retrospective cross-sectional study that included all patients with complete records, diagnosed with ovarian cancer treated at the Oncology department UMAE Monterrey No. 23, January 2009 to 31 December 2009. RESULTS: We identified 40 patients with ovarian cancer. The average age of menarche was 12.7 years, 40% were of reproductive age, 25% were nulliparous, 15% had a pregnancy and 37.5% had two pregnancies. Of the total patients, 17% had a history of breast cancer, 40% used a contraceptive method, 37% used oral contraceptives. The tumor marker CA 125 was found in 40% of patients, 63.1% had ultrasound markers for cancer. The most frequent clinical stage 1A in which they found 32% of cases. Papillary serous adenocarcinoma was diagnosed in 25% of patients, endometroid adenocarcinoma and mucinous tumor of low malignant potential was diagnosed borderline at 20%, poorly differentiated adenocarcinoma in 18% tumor granulosa cells in 7% and papillary adenocarcinoma ring cell adenocarcinoma in 5%. In total, 43% of patients received chemotherapy. CONCLUSION: The majority of cases tenia50 years or more. The background was the most frequent hereditary breast cancer. There were no deaths during the study.
Asunto(s)
Adenocarcinoma/epidemiología , Neoplasias Ováricas/epidemiología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Adulto , Factores de Edad , Anciano , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Antígeno Ca-125/sangre , Anticoncepción/métodos , Anticoncepción/estadística & datos numéricos , Estudios Transversales , Femenino , Neoplasias Gastrointestinales/epidemiología , Neoplasias Gastrointestinales/genética , Tumor de Células de la Granulosa/tratamiento farmacológico , Tumor de Células de la Granulosa/epidemiología , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/cirugía , Terapia de Reemplazo de Hormonas/estadística & datos numéricos , Humanos , Incidencia , México/epidemiología , Persona de Mediana Edad , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Paridad , Embarazo , Historia Reproductiva , Estudios RetrospectivosRESUMEN
The purpose of this study is to investigate the expression of p53, c-erbB-2, Ki-67, and angiogenic activity and their correlation with the clinicopathologic characteristics in a series of granulosa cell tumors of the ovary (GCTO). Eighteen GCTO cases assisted at the Department of Obstetrics and Gynecology, School of Medical Science, UNICAMP, after diagnostic confirmation by three pathologists, were submitted to immunohistochemistry for assessment of p53, c-erbB-2, Ki-67, and CD34 expressions. The mean tumor size was 13 cm (range: 4-30 cm). Six (33%) cases presented with extraovarian disease. Thirteen (72%) cases presented some solid diffuse or sarcomatoid pattern and six (33%) moderate or strong atypia. Fourteen cases presented