Tumor stem cells, notch, and the news

As we prepared to put this issue of Neuro-Oncology to bed, we noted with interest that the topic of our review article this month, Notch signaling in human gliomas, is also in the news. In our case, we are running a review titled “The functional role of Notch signaling in human gliomas,” by Stockhausen et al. (see page 199–211).¹ In this review, the authors look at the “interplay” between Notch signaling in normal glial development and processes known to be involved in the development of malignant tumors (for instance, hypoxia and angiogenesis). In particular, they look at the roles of Notch in normal neural stem cells and brain cancer stem cells, the latter of which represent a formidable therapeutic challenge (as stem cells do in all cancers²).

As Stockhausen et al. point out, therapies that can act at the stem cell level may offer the promise of overcoming gliomas' characteristic resistance to therapy and the consequently poor outcomes the patients face. The authors discuss several approaches of recent interest, including the use of gamma-secretase inhibitors to overcome the Notch signal. In the news, meanwhile, appeared an announcement from Duke University that the journal Stem Cells had posted a prepublication version of an article detailing Notch's contribution to the radioresistance of glioma stem cells and the use of gamma-secretase inhibitors to overcome that problem.³ This example demonstrates the complexity of tumor progression and tumor cell differentiation and the necessity to better understand the multiple molecular signaling networks that exert control in this process.

A Picture of the Whole Emerges from the Parts

Although the existence of Notch has been known for decades and Notch signaling has long been known to be involved in normal cellular development and cell–cell interactions, evidence for a role in the proliferation of cancer is of more recent vintage. Gaining an understanding of the complexity of Notch functionality has grown in importance as it has become clear, particularly within the last 10 years or so, that the Notch pathway is involved in normal and cancer stem cell proliferation. The potential value of targeting cancer stem cells therapeutically has grown at the same time, energizing investigations into pathways whose full functionality may have gone unexplored (and certainly unexploited) until we could begin to understand them.

It is particularly important to those of us in the brain tumor community to begin to piece together the disparate evidence that will help us improve the effectiveness of not just single therapies but also multimodality treatments. Targets like Notch represent an opportunity to find synergy between chemotherapy and radiotherapy, for instance, and may ultimately lead to better survival and quality of life for those who develop brain (and other) tumors.