Artikel
Activation of Dll4-Notch signalling in primary glioblastoma multiforme
Suche in Medline nach
Autoren
Veröffentlicht: | 4. Juni 2012 |
---|
Gliederung
Text
Objective: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, characterized by massive neovascularisation, necrosis and intense therapy resistance. Deregulated Notch signalling has been implicated in the formation and progression of different malignancies.
Methods: Patients with primary GBM (n = 26) were enrolled for real-time RT-PCR detection of Dll4, Jagged1, Notch1, Notch4 and Hey1. The surgical specimens of patients who underwent anterior temporal lobe resection due to temporal lobe epilepsy served as control (n = 11). Western Blot and immunostaining were performed to confirm the protein level of these components and to reveal the cellular localization of the immunoreactivity, respectively.
Results: The mRNA expression of Dll4, Jagged1, Notch1, Notch4 and Hey1 was significantly upregulated with mean fold expression of 3.12, 3.58, 3.37, 5.77 and 4.89 for Dll4, Jagged1, Notch1, Notch4, and Hey1, respectively. The upregulation of Dll4 and Notch1 was confirmed by Western blot. Immunostaining revealed the immunoreactivity for Dll4 and Notch1 in endothelial cells, tumor cells and microglia/macrophage. Moreover, activation status of Dll4-Notch signalling was positively associated with bizarre vascular pattern, microvascular density, tumor oedema and MGMT promoter methylation.
Conclusions: Activation of Dll4-Notch signalling is implicated in the majority of GBM and associated with clinical features. Targeting Dll4-Notch signalling may be a new therapeutic strategy for a subset of primary human GBM with hyper-activated Notch signalling.