Therapeutic potential of the TWEAK/FN14 pathway in intractable gastrointestinal cancer

Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily. It has been suggested that it plays a pivotal role in various physiological and pathological conditions due to its proinflam-matory properties. Fibroblast growth-inducible 14 (Fn14) has been identified as a TWEAK receptor. A number of studies have suggested that TWEAK-Fn14 interaction results in the promotion of apoptosis, cell growth as well as angiogenesis. Although recent studies have indicated that TWEAK and Fn14 are expressed in a number of tumor lines and tissues, the therapeutic potential of this pathway has yet to be elucidated. This study investigated the potential of TWEAK and Fn14 in esophageal and pancreatic cancer as novel molecular targets for anti-cancer therapy. TWEAK and Fn14 protein expression was evaluated in 43 patients with esophageal cancer and 51 patients with pancreatic cancer by immunohistochemistry. As a result, either TWEAK or Fn14 expression was observed in 58.1% of the cases with esophageal cancer and 74.5% of the cases with pancreatic cancer. Furthermore, TWEAK/Fn14 gene expression was identified in the majority of the human esophageal and pancreatic cancer cell lines. Therapeutic efficacies of blocking TWEAK and Fn14 were evaluated by tumor growth inhibition assay in TWEAK- and Fn14-expressing human esophageal and pancreatic cancer cell lines. Coculture with anti-TWEAK or -Fn14 mAb was found to induce a 22-65% cell growth inhibition of these cells. Finally, the significant therapeutic effect of targeting this pathway under in vivo physiological conditions was confirmed using a murine gastrointestinal cancer model. In conclusion, the TWEAK/Fn14 pathway may be functional and critical in intractable gastrointestinal cancers. Therefore, TWEAK and/or Fn14 may be novel molecular targets for anti-cancer therapy.