Therapeutic targeting of TWEAK/Fnl4 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway.

TNF-like weak inducer of apoptosis (TWEAK) and FGF-inducible molecule 14 (Fn14) are a TNF superfamily ligand-receptor pair. Initially identified as an inducer of tumor cell killing, TWEAK has pleiotropic effects, mediating proinflammatory and pro-angiogenic activity as well as stimulation of invasion, migration, and survival through its widely recognized receptor, Fn14. Fn14 is expressed at relatively low levels in normal tissues, but is dramatically elevated locally in injured and diseased tissues, where it plays a role in tissue remodeling. Herein we review the link between the TWEAK/Fn14 pathway and cancer as well as discuss potential therapeutic strategies targeting this pathway for cancer treatment. Many of the activities associated with the TWEAK/Fn14 pathway are linked with tumorigenesis and could thereby provide a growth advantage to tumors, suggesting that inhibition of the pathway may be beneficial in the treatment of cancer. At the same time, the elevated expression of Fn14 by tumor cells as well as the intrinsic tumor cell killing capacity of this receptor represents a promising alternative of harnessing the intrinsic tumor cell killing capacity of Fn14 to treat cancer.