Notch signaling: a hero or villain in the war against cancer?

The Notch signal transduction pathway regulates cell fate decisions throughout embryonic development. The mechanisms through which Notch signaling maintains cellular integrity are well understood. However, Notch signaling is more complex than previously thought as Notch is also involved in cancer where it functions as both an oncogene and tumor suppressor depending on the cellular context. Aberrant activation of oncogenic Notch is found in various cancers prompting the search for therapeutic agents to attenuate constitutively active Notch. However, there is also substantial evidence that Notch signaling suppresses tumor growth and progression, suggesting that Notch activators might be of therapeutic benefit in other cancers. This editorial describes the dual role of Notch signaling observed within and across multiple cancers. We highlight a study in non-small cell lung cancer cells (NSCLC) revealing a tumor suppressive role for endothelial cell Dll4-activated Notch1 and the underlying molecular mechanism involving suppression of PI3K signaling.