RESUMO
Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.
Assuntos
Proteína 4 Semelhante a Angiopoietina/genética , Carcinoma de Células de Transição/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica/genética , Microambiente Tumoral , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Proteína 4 Semelhante a Angiopoietina/sangue , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Carcinogênese/genética , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cistectomia , Metilação de DNA/genética , Regulação para Baixo , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Oncogenes/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report an extremely rare case of Ewing's sarcoma (ES) of the humerus in a Chinese neonate. Plain radiography and magnetic resonance imaging showed extensive neoplastic involvement of the humeral diaphysis and adjacent soft tissues, confirmed on histology and immunohistochemistry as being due to ES. This is the first report of congenital ES in a long bone. Since ultrasound at 20 weeks gestation showed a normal fetal skeleton, the ES may have begun to develop in the late middle or third trimester.
Assuntos
Neoplasias Ósseas/congênito , Úmero , Sarcoma de Ewing/congênito , Neoplasias Ósseas/diagnóstico , Feminino , Seguimentos , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Sarcoma de Ewing/diagnósticoRESUMO
BACKGROUND AND STUDY AIMS: The aim of the present study was to review endoscopic findings, treatment, and clinical outcomes in patients with severe upper gastrointestinal bleeding due to tumors. PATIENTS AND METHODS: A retrospective analysis was made of prospectively gathered data on all patients with severe upper gastrointestinal bleeding who were admitted to two large referral centers during a 45-month period. RESULTS: Nine hundred thirty-five patients had severe upper gastrointestinal bleeding, of whom 42 (5%) were found to have tumors. Histologically, nearly all of the tumors were of a malignant type. Fifty-two percent of the patients had acute severe upper gastrointestinal bleeding as the initial presentation of their tumor. The most common tumor was gastric adenocarcinoma, and all of these cases were at advanced stages. Endoscopic hemostasis with thermal probes or epinephrine injection, or both, was carried out in seven patients (17%), with successful hemostasis in all of the tumors. Regardless of the treatment given, patients with upper gastrointestinal tumor bleeding, had a 30-day surgery rate of 43%, a 30-day rebleed rate of 33%, a 30-day mortality rate of 10%, and a 1-year mortality rate of 89%. CONCLUSIONS: Most tumors that cause severe upper gastrointestinal bleeding are of a malignant histologic type and are already at an advanced stage. Endoscopic hemostasis of bleeding upper gastrointestinal tumors is safe and initially effective, and may provide time for elective surgical palliation. Regardless of therapy, upper gastrointestinal tumors with severe bleeding have a poor one-year survival.