RESUMO
This corrects the article DOI: 10.1038/onc.2011.466.
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Glioblastomas (GBMs) are the most common and aggressive type of brain tumor. GBMs usually show hyperactivation of the PI3K-Akt pathway, a pro-tumorigenic signaling cascade that contributes to pathogenesis. Girdin, an actin-binding protein identified as a novel substrate of Akt, regulates the sprouting of axons and the migration of neural progenitor cells during early postnatal-stage neurogenesis in the hippocampus. Here, we show that Girdin is highly expressed in human glioblastoma (GBM). Stable Girdin knockdown in isolated GBM stem cells resulted in decreased expression of stem cell markers, including CD133, induced multilineage neural differentiation, and inhibited in vitro cell motility, ex vivo invasion, sphere-forming capacity and in vivo tumor formation. Furthermore, exogenous expression of the Akt-binding domain of Girdin, which competitively inhibits its Akt-mediated phosphorylation, diminished the expression of stem cell markers, SOX2 and nestin, and migration on the brain slice and induced the expression of neural differentiation markers glial fibrillary acidic protein/ßIII Tubulin. Our results reveal that Girdin is required for GBM-initiating stem cells to sustain the stemness and invasive properties.
Assuntos
Neoplasias Encefálicas/patologia , Diferenciação Celular , Movimento Celular , Glioblastoma/patologia , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas de Transporte Vesicular/metabolismo , Antígeno AC133 , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas dos Microfilamentos/genética , Gradação de Tumores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina , Peptídeos/genética , Peptídeos/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Proteínas de Transporte Vesicular/antagonistas & inibidores , Proteínas de Transporte Vesicular/genéticaRESUMO
Previously, we have shown that the genetically modified human neural stem cells (NSCs) show remarkable migratory and tumor-tropic capability to track down brain tumor cells and deliver therapeutic agents with significant therapeutic benefit. Human NSCs that were retrovirally transduced with cytosine deaminase (CD) gene showed remarkable 'bystander killer effect' on the glioma cells after application of the prodrug, 5-fluorocytosine (5-FC). Interferon-beta (IFN-beta) is known for its antiproliferative effects in a variety of cancers. In our pilot clinical trial in glioma, the IFN-beta gene has shown potent antitumor activity in patients with malignant glioma. In the present study, we sought to examine whether human NSCs genetically modified to express both CD and IFN-beta genes intensified antitumor effect on experimental glioma. In vitro studies showed that CD/IFN-beta-expressing NSCs exerted a remarkable bystander effect on human glioma cells after the application of 5-FC, as compared with parental NSCs and CD-expressing NSCs. In animal models with human glioma orthotopic xenograft, intravenously infused CD/IFN-beta-expressing NSCs produced striking antitumor effect after administration of the prodrug 5-FC. Furthermore, the same gene therapy regimen prolonged survival periods significantly in the experimental animals. The results of the present study indicate that the multimodal NSC-based treatment strategy might have therapeutic potential against gliomas.
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Citosina Desaminase/fisiologia , Terapia Genética/métodos , Glioma/tratamento farmacológico , Glioma/terapia , Interferon beta/fisiologia , Animais , Efeito Espectador , Linhagem Celular Tumoral , Citosina Desaminase/genética , Modelos Animais de Doenças , Feminino , Flucitosina/uso terapêutico , Humanos , Interferon beta/genética , Camundongos , Camundongos NusRESUMO
Medulloblastomas are highly malignant neuroectodermal cerebellar tumors of children. One of the reasons for the difficulty for the treatment of medulloblastomas is their inherent tendency to metastasize through the cerebrospinal fluid (CSF) pathway leading to leptomeningeal dissemination. Recently, genetically modified neural stem cells (NSCs) were shown to have the capability of selectively migrating into glioma mass and delivering therapeutic agents with significant therapeutic benefits. In the present study, we applied the NSC strategy to target medulloblastomas, particularly their leptomeningeal dissemination. We used NSCs that were retrovirally transduced with the cytosine deaminase gene (CD-NSCs). In vitro studies demonstrated that CD-NSCs had sufficient migratory activity toward medulloblastoma cells and exerted a remarkable bystander effect on these cells following the application of 5-fluorocytosine (5-FC). It is noteworthy that neutralization of the hepatocyte growth factor blocked their migration In animal studies using our leptomeningeal dissemination model, CD-NSCs implanted directly into CSF space were shown to distribute diffusely within the disseminated tumor cells and could provide remarkable antitumor effect after intraperitoneal administration of 5-FC. Furthermore, CD-NSC treatment followed by 5-FC administration prolonged survival periods significantly in experimental animals. Our data suggest that the CD-NSC strategy can also be applied to target leptomeningeal dissemination of medulloblastomas.
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Citosina Desaminase/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Meduloblastoma/terapia , Neoplasias Meníngeas/terapia , Transplante de Células-Tronco/métodos , Animais , Antimetabólitos/uso terapêutico , Efeito Espectador , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Cisterna Magna , Feminino , Flucitosina/uso terapêutico , Glioma/terapia , Humanos , Marcação In Situ das Extremidades Cortadas , Injeções , Meninges/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neurônios/enzimologia , Neurônios/transplanteRESUMO
In present study, in two cases with hepatocellular carcinoma and cholangioma associated with hypercalcemia, the accumulations of 99mTc labeled phosphorous compound in the primary lesion were demonstrated and its mechanism was discussed.