RESUMO
Glia maturation factor-ß (GMF-ß) has been reported to promote glial differentiation, and act as a negative prognostic indicator in certain cancers. However, its roles in glioma progression remain unclear. Since neurogenesis and vasculogenesis were proved to share some common regulators during gliomagenesis, we aim to explore the potential impact of GMF-ß on tumor neovascularization and patient survival in glioma. In this study, we first detected GMF-ß expression not only in tumor cells but also in microvascular endothelia by double immunohistochemical staining. Both tumoral and endothelial GMF-ß expression levels were positively correlated with tumor grade and microvessel density (MVD), while negatively associated with poor prognoses of the patients. Interestingly, multivariate analysis demonstrated that endothelial GMF-ß expression level was the only independent predictor of progression-free and overall survival of glioma patients. The results of in vitro angiogenesis assay showed that GMF-ß knockdown significantly inhibited tubulogenesis of human U87 glioblastoma cells. Furthermore, GMF-ß knockdown suppressed tumor growth and the formation of human-CD31 positive (glioma cell-derived) microvessels in a mouse orthotopic U87 glioma model. Our results demonstrated that GMF-ß is an important player in glioma progression via promoting neovascularization. GMF-ß may therefore be a novel prognostic marker as well as a potential therapeutic target for glioma.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Endotélio Vascular/fisiologia , Fator de Maturação da Glia/fisiologia , Glioma/irrigação sanguínea , Neovascularização Patológica/etiologia , Adulto , Idoso , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proliferação de Células , Feminino , Fator de Maturação da Glia/análise , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análiseRESUMO
AIMS: To investigate whether Glia maturation factor-beta (GMFB) is expressed in thymomas and is associated with T-cell development. METHODS AND RESULTS: We investigated the expression of GMFB by immunohistochemistry in 86 cases of thymoma classified into five type A, 35 type AB, 11 type B1, 26 type B2, and nine type B3 thymomas according to the World Health Organization classification system. Immunoblotting and in situ hybridization (ISH) studies were also performed in selected cases. The results of the immunoblot analysis were in accordance with those of immunohistochemical scoring. The ISH study ascertained the tumour cells producing the protein. Immunohistochemically, GMFB expression was observed in one (20%) of type A, 32 (80%) of type AB, all (100%) of type B1 and B2, and eight (89%) of type B3 thymoma with statistically significant differences between type A and type AB, type B1, or type B2 thymoma, and between type B3 and type AB or type B2 thymoma. There was a significant correlation between GMFB expression and the amount of accompanying non-neoplastic T cells. GMFB promoted T-cell differentiation into CD4-/CD8+ cells when analysed by two-colour flow cytometry. CONCLUSIONS: The present study suggests that T-cell development in thymoma may be maintained partly by GMFB produced by the tumour cells.
Assuntos
Diferenciação Celular , Fator de Maturação da Glia/análise , Linfócitos T/patologia , Timoma/patologia , Neoplasias do Timo/patologia , Adulto , Idoso , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Citometria de Fluxo/métodos , Fator de Maturação da Glia/genética , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/imunologia , Timoma/genética , Timoma/metabolismo , Neoplasias do Timo/metabolismoRESUMO
We developed sensitive and specific two-site enzyme immunoassays (EIA) for glia maturation factor beta (GMFB) and gamma (GMFG) using specific antibodies raised in rabbits. These assay systems enabled us to identify GMFB and GMFG (GMFs) in both human and rat samples and they were used to investigate the tissue distribution and serum concentrations of human and rat GMFs. In the case of rat, relatively high levels of GMFB were found in the central nervous system, except for the spinal cord, and in thymus and colon. Higher levels of GMFG were found in the thymus, spleen and colon. The distribution of GMFs in human was similar to that in rat. In the rat, the maximum serum concentration of GMFG was at 4 weeks of age. The decrease in its level was rapid for the first 30 days of life in both sexes. On the other hand, the concentration of GMFB in serum did not change significantly with age. Similarly, in human, the concentration of GMFG in serum was highest in the 21-30-year-old group and began to decrease rapidly in the 30-year-old group. In contrast, the concentration of GMFB did not change significantly during this period. No significant sex differences in the serum levels of GMFs were observed in human and rat. The present EIA systems are sufficiently sensitive for studying GMFs in human and rat organs.
