Signaling by cell surface death receptors: Alterations in head and neck cancer

Cell surface death receptors are members of the tumor necrosis factor receptor (TNFR) superfamily and mediate signals leading to the induction of apoptosis or necroptosis, as well as NF-κB-mediated cell survival. These biochemical processes play key roles in cell growth, development, tissue homeostasis, and immune responses. The downstream signaling complexes activated by different death receptors can differ significantly and are subject to multiple, distinct regulatory mechanisms. Dysregulation of signaling by the TNFR superfamily contributes to a variety of pathologic conditions, including defective immune responses and cancer. Caspase-8 signaling is important for mediating death receptor signals leading to either apoptosis or NF-κB activation. By contrast, inactivation of caspase-8 or loss of caspase-8 expression shifts death receptor signaling to the necroptosis pathway. Notably, the gene encoding caspase-8 is mutated in roughly ten percent of head and neck cancers. These findings support the hypothesis that alterations in the biochemical pathways mediated by death receptors have important consequences for the development of head and neck, and possibly other, cancers.