The CD95/CD95L Signaling Pathway: A Role in Carcinogenesis

Apoptosis is a fundamental process contributing to tissue homeostasis, immune response, and development. CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNFR) superfamily. Its ligand, CD95L, was initially detected at the plasma membrane of activated T-lymphocytes and natural killer (NK) cells where it contributes to the elimination of transformed and infected cells. Given its implication in immune homeostasis and immune surveillance combined with the fact that various lineages of malignant cells exhibit loss-of-function mutations, CD95 was initially classified as a tumor suppressor gene. Nonetheless, in different pathophysiological contexts, this receptor is able to transmit non-apoptotic signals and promote inflammation and carcinogenesis. Although the different non-apoptotic signaling pathways (NF-κB, MAPK, and PI3K) triggered by CD95 are known, the initial molecular events leading to these signals, the mechanisms by which the receptor switches from an apoptotic function to an inflammatory role, and, more importantly, the biological functions of these signals remain elusive.