Article
Implications of Notch signaling in pediatric high grade glioma
Search Medline for
Authors
Published: | June 9, 2017 |
---|
Outline
Text
Objective: Malignant glioma (MG) are highly aggressive brain tumors, characterized by massive neovascularization, necrosis and therapy resistance. Many investigations report marked differences between adult and pediatric MG. Deregulated Notch signaling has been associated to different malignancies, comprising primary adult glioblastoma (GBM). Hitherto pediatric MG have not been investigated for deregulated Notch signaling. Hence our investigation aimed to reveal implications of Notch signaling in pediatric HG.
Methods: All children (age <=16 years) operated for MG in our department from 2008 to 2015 were included. Basic clinical parameters like age, gender, infra- and supratentorial location were assessed. Major components of Notch signaling (receptor: Notch1, Notch4; ligand: Dll4, Jagged1; effector: Hey1, Hey2) were examined by real-time reverse-transcription-polymerase chain reaction (PCR) and Western blotting (WB) in these children and compared to adult GBM (n=26) and control (n=11) brain tissue. Vascular pattern (VP) was analyzed after vessel staining with laminin.
Results: 12 children (5 boys, 7 girls) with a median age of 9.7 years were included. 4 (33%) children had a MG °III and 8 (67%) a MG °IV. The mRNA levels of Dll4, Jagged1, Notch1, Notch4, Hey1 and Hey2 were 55.7-, 13.3-, 2.2-, 138.6-, 7.9-, and 24.7-fold elevated, respectively, in pediatric MG, compared to control. Interestingly, the comparison of pediatric and adult MG revealed significant differences only for Dll4 (p=0.016) and Notch4 (p=0.015), implicated in angiogenesis. WB confirmed marked protein expression of Dll4 in pediatric cases (4.5 fold, p=0.002) and no significant difference between Notch1 protein expression compared to adult cases. There was no difference in mRNA expression between MG°III/°IV, as well as infra-/supratentorial location. Laminin staining revealed predominantly classic, effective vascularization pattern in pediatric MG.
Conclusion: According to our results, pediatric MG are different in comparison to adult MG. Major Notch signaling components are extremely upregulated in pediatric cases. Main differences in comparison to adult MG are upregulation of DLL4 and Notch4, which affect vascularization pattern. Further investigations are necessary to correlate our finding with clinical parameters, especially survival.