Role of the NOTCH Signaling Pathway in Head and Neck Cancer

The NOTCH signaling cascade has been implicated in multiple cellular functions, such as cell proliferation, differentiation, and survival. Dysregulation of the NOTCH pathway is associated with the progression of several types of malignant tumors, including head and neck squamous cell carcinoma (HNSCC). Accumulating data suggest that NOTCH is one of the most frequently altered pathways in HNSCC. Given the importance of NOTCH signaling in regulating tumor cell behavior, several NOTCH-targeted strategies are currently being developed and tested in preclinical and clinical settings. However, the precise role of the NOTCH pathway in head and neck malignancies remains incompletely defined and controversial. In most tumor types, NOTCH1 has been reported as an oncogene. However, early characterization of the genomic landscape found that inactivating mutations of NOTCH1 frequently occur in HNSCC, suggesting that NOTCH1 is a tumor suppressor. More recent evidence indicates that NOTCH signaling may be activated in a subset of HNSCC tumors, similar to other tumor types, indicating a more complex function in HNSCC. This overview will summarize the evidence for oncogenic and tumor suppressor roles of the NOTCH signaling pathway in HNSCC, discuss recent studies that aid in interpretation of these contradictory findings, and describe potential therapeutic opportunities and future directions.