Notch signaling in glioblastoma: a developmental drug target?

Abstract

Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM) features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.

Figure 1

Ligands, structure and processing of Notch1 receptor. Left: the Delta-like ligand (Dll) and Serrate-Jagged ligand (Jag) structural subsets of Notch ligands. Right: structure of Notch1 receptor resulting from post-translational cleavage at site S1 and heterodimerization of the cleaved parts. Ligand-dependent cleavages at sites S2 and S3 generate soluble Notch extracellular truncation (NEXT) and cytosolic Notch intracellular domain (N-IC) forms, respectively. Notch1 and Notch2 are highly similar. Notch3 and Notch4 contain 34 and 29 epidermal growth factor (EGF)-like repeats, and are devoid of trans-activation domain (TAD) domains.

Figure 2

Sequential events and control of Notch signaling. Activating and inhibitory mechanisms are depicted in red and blue, respectively.