Literature ReviewTherapeutic Targeting of the Notch Pathway in Glioblastoma Multiforme
Introduction
Glioblastoma (GBM) is the most common and lethal form of brain tumor. In the United States, GBM incidence is approximately 3 cases per 100,000 people. The prognosis for this disease continues to be bleak, with a mean survival of only 12–15 months after diagnosis. In patients who receive the standard treatment of resection, radiation therapy, and chemotherapy, the mean 5-year survival is <5%.1, 2, 3, 4 It is therefore imperative for new treatments to be developed to increase the survival and quality of life for patients with GBM. Research in recent years has found several potential chemotherapeutic targets for GBM within the Notch receptor–mediated signaling pathway.
The Notch pathway is involved in a diverse array of cellular activities, including differentiation, proliferation, apoptosis, and cell survival. In mammals, the Notch pathway provides intercellular communication via direct cell-to-cell contact between 2 neighboring cells, which are called the signal-sending cell and the signal-receiving cell (Figure 1). The signal-sending cell expresses δ-like or Jagged ligands on its cell membrane surface, and the signal-receiving cell expresses Notch receptors on its cell membrane surface. In mammals, the Notch receptor has 4 isoforms (Notch1–4).5 Each Notch receptor is a 300-kD single-pass transmembrane protein with an intracellular domain (NICD) and an extracellular domain (NECD).6
Notch signaling is initiated by binding of one of its ligands to the NECD. On binding, the Notch receptor undergoes a conformational change that exposes site 2 of the NECD, enabling it to be cleaved by a member of the ADAM-family of metalloproteases. Cleavage of site 2 releases the NECD-ligand complex, which is endocytosed and degraded by the signal-sending cell. In the signal-receiving cell, the enzyme γ-secretase (comprised of subunits presenilin, nicastrin, PEN2, and APH1) cleaves the Notch receptor at exposed sites 3 and 4 (S3/S4) to release the NICD. The NICD then translocates to the nucleus and associates with the DNA-binding protein CSL (comprising subunits CBF1, Su(H), and LAG-1). Binding of NICD to CSL results in an NICD-CSL complex that displaces transcriptional repressors. In addition, the transcriptional coactivator, Mastermind (MAM), recognizes the NICD-CSL complex and activates the expression of several target genes, especially the hairy and enhancer-of-split (HES) and the hairy/enhancer-of-split related with YRPW motif protein (HEY) families. The HES and HEY families are transcriptional repressors deeply implicated in neurodevelopment and carcinogenesis.7, 8
Notch signaling is involved in many cellular processes, and dysregulation of the Notch gene or its signaling cascades can lead to neoplasms. Dysregulation of Notch signaling has been observed in bone marrow, lymphatic, lung, skin, breast, pancreatic, prostate, ovarian, and liver cancers.9, 10, 11, 12, 13 Aberrant Notch signaling has also been recently observed in GBM cells and is the focus of this review.
The goal of this systematic review is to determine if there is a correlation of Notch pathway activation with the development and progression of GBM and to identify possible candidate molecular targets for pharmacologic therapies in patients with GBM. We hope that the information found in this article will assist clinicians and scientists in the development of clinical trials and basic science projects targeting the Notch signaling cascade. We found that most of the literature supports the hypothesis that Notch signaling is increased in GBM and may lead to GBM neoplasia and aggressiveness.
Section snippets
Study Selection
Using the MeSH (Medical Subject Heading) database system of PubMed, a literature search was performed between 2003 and July 2015 for all articles containing the terms “glioblastoma” and “receptors, notch((“Glioblastoma”[Mesh]) AND “Receptors, notch”[Mesh])”. The articles were limited to humans as the only study species; reviews were excluded. A total of 62 articles were found from the initial screen. Nine articles were identified through additional sources. None of these were found to be
GBM Cell Types Used
Of 55 articles reviewed, 35 used only established human GBM cell lines,14, 15, 16, 17, 18, 22, 23, 25, 26, 27, 28, 30, 31, 35, 37, 38, 44, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 63, 64, 65, 66, 67, 68 7 used only human GBM surgical samples,19, 24, 29, 34, 43, 47, 59 10 used a combination of established human GBM cell lines and human GBM surgical samples,20, 21, 36, 39, 40, 41, 42, 45, 46, 48 2 used a rat GBM cell line along with established human GBM cell lines,32, 62 and 1 did not
Discussion
The findings of our literature review suggest that Notch pathway activation is a characteristic of GBM. This finding is consistent with previous studies that showed increased Notch activation in primary GBM compared with low-grade gliomas, secondary GBM, and normal brain tissue.40, 59, 72 Increased Notch activity was found to be associated with many of the malignant hallmarks of cancer such as self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis,
Conclusions
The research discussed in this article suggests that Notch pathway activation is a characteristic of GBM. GBM is the most common and most aggressive primary central nervous system malignancy, with a dismal survival average of 12–15 months.2 A multitude of recent and ongoing research shows the connection between Notch signaling activation and the pathophysiology of GBM. Four clinical trials (NCT01122901, NCT01119599, NCT01269411, and NCT01189240) exploring the relationship of the Notch pathway
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.