CD95 in cancer: tool or target?

• CD95 directly activates caspase-independent survival signaling pathways.
• CD95 triggers a cell death-inducing inflammatory response.
• In vivo data on CD95 contradicts in vitro findings in many mouse models of cancer.
• Blocking CD95 signaling in cancer patients is a safe and promising treatment option.

The role of CD95 (Fas/Apo1) in cancer has been a matter of debate for over 30 years. First discovered as an apoptosis-inducing molecule, CD95 soon emerged as a potential anticancer therapy. Yet accumulating evidence indicates a profound role for CD95 in alternative nonapoptotic signaling pathways that increase tumorigenesis. This fact challenges the initial clinical idea of using CD95 as a ‘tumor killer’ while setting the stage for clinical studies targeting the nonapoptotic signaling branch of CD95. This review summarizes the findings surrounding manipulation of the CD95 pathway for cancer therapy, considering how one receptor can both promote and prevent cell growth.