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Tumor Necrosis Factor-like weak inducer of apoptosis (TWEAK) is a newly identified member of the TNF superfamily. Due to its proinflammatory property, it has been suggested to play pivotal roles in various physiological and pathological conditions including autoimmune disorders, atherogenesis and chronic inflammation. The fibroblast growth-inducible 14 (Fn14) has been recently identified as a TWEAK receptor. Several studies have suggested that TWEAK-Fn14 interaction resulted in the promotion of apoptosis, cell growth as well as angiogenesis. Furthermore, recent studies have indicated that TWEAK is expressed in several tumor lines and tissues. They have also demonstrated that TWEAK can stimulate tumor cell apoptosis, proliferation, migration, survival and angiogenesis. In addition, it has been reported that the Fn14 gene is activated during tumorigenesis in several organs including liver, breast and brain. These studies have suggested that TWEAK/Fn14 pathway may be a critical regulator in tumorigenesis. In this study, we tried to clarify the importance of TWEAK/Fn14 pathway in human pancreatic cancer. First, we examined the expression of TWEAK and Fn14 in four human pancreatic cancer cell lines including CAPAN2, PK-8, PANC1 and MIAPaCa2 by RT-PCR analysis. TWEAK was expressed in three lines (CAPAN2, PANC1 and MIAPaCa2) and Fn14 was expressed in all four lines. Then, we examined the expression of TWEAK and Fn14 in human pancreatic cancer tissues. Fifty-one tissues were obtained from surgical cases in our department on patient consent. We performed immunohistochemical analysis on these samples using anti-human TWEAK mAb and anti-human Fn14 mAb. As a result, positive staining for TWEAK was detected in 15 (29%) and positive for Fn14 was detected in 31 (61%). These data suggested that TWEAK and Fn14 might play some role in human pancreatic cancer. Finally, we examined the antitumor effect of TWEAK and Fn14 mAb on tumor growth in vitro. Human pancreatic cancer cells were cocultured with anti-TWEAK mAb, anti-Fn14 mAb or control Ig. By 7 days after coculture, the significant inhibition of tumor growth was observed by mAb treatment. Coculture with anti-TWEAK mAb induced 47–53% cell growth inhibition compared to control Ig (CAPAN2, 47%, MIAPaCa, 53%, PANC1, 47%). Similarly, coculture with anti-Fn14 mAb induced 34–52% inhibition (CAPAN2, 45%, MIAPaCa, 34%, PANC1, 52%). Taken together, TWEAK/Fn14 pathway may be functional and important in pancreatic cancer. In conclusion, we have demonstrated for the first time that TWEAK and Fn14 was expressed in pancreatic cancer and mAb treatment significantly inhibited tumor cell growth in vitro. Thus, TWEAK and/or Fn14 could be novel molecular targets for anti-cancer therapy in human pancreatic cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]