Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed.
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