Abstract
Glioblastoma (GBM) is a highly malignant primary tumor of the central nervous system originating in glial cells. GBM results in more years of life lost than any other cancer type. Low levels of Notch receptor expression correlates with prolonged survival in various high grade gliomas independent of other markers. Different downstream pathways of Notch receptors have been identified. We tested if the Notch/Deltex pathway, which is distinct from the canonical, CSL-mediated pathway, has a role in GBM. We show that the alternative or non-canonical Notch pathway functioning through Deltex1 (DTX1) mediates key features of glioblastoma cell aggressiveness. For example, DTX1 activates the RTK/PI3K/PKB and the MAPK/ERK mitotic pathways and induces anti-apoptotic Mcl-1. The clonogenic and growth potential of established glioma cells correlated with DTX1 levels. Microarray gene expression analysis further identified a DTX1-specific, MAML1-independent transcriptional program - including microRNA-21- which is functionally linked to the changes in tumor cell aggressiveness. Over-expression of DTX1 increased cell migration and invasion correlating to ERK activation, miR-21 levels and endogenous Notch levels. In contrast to high and intermediate expressors, patients with low DTX1 levels have a more favorable prognosis. The alternative Notch pathway via DTX1 appears to be an oncogenic factor in glioblastoma and these findings offer new potential therapeutic targets.
Highlights
Glioblastoma (GBM) is the most common primary tumor of the central nervous system
We performed semiquantitative RT-PCR with cDNA derived from established glioma cell lines, tumor biopsies directly derived from the operating room and with low passage ex vivo glioma cells generated in our laboratory
We found expression of DTX1 protein at varying levels in all glioma cell lines, tumor biopsies and ex vivo cell lines analyzed by immunoblotting (Figure 1, B), confirming the transcript analysis
Summary
Glioblastoma (GBM) is the most common primary tumor of the central nervous system. Despite continuing efforts to improve treatment over the last two decades and advances in microsurgery, radio- and chemotherapy, median survival of patients remained limited at ,14 months after diagnosis [1]. Notch activation has been implicated as a positive determinant of cancer formation in T cell acute lymphoblastic leukemia (T-ALL), primary melanomas, breast cancer and gliomas [3]. Previous studies have shown that loss of Notch positively predicts patient survival in subgroups of high grade glial brain tumors [10]. An additional mechanism by which Notch mediates tumor aggressiveness is by the induction of Tenascin-C – an extracellular glycoprotein which correlates with malignancy in glioblastoma and other cancers [11] – by the Notch canonical co-activator RBPJk [12,13]. The role of canonical Notch signaling in cancer development, progression and metastasis is intensively studied and evidence is pointing to an oncogenic role of Notch in glioblastoma. The role of the non-canonical signaling pathway via Deltex in these mechanisms is still ill defined
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