Significance of TWEAK/Fn-14 pathway in human colorectal cancer

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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. 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. These studies have suggested that TWEAK/Fn14 pathway may be a critical regulator in tumorigenesis. In this study, we tried to examine the significance of TWEAK/Fn14 pathway in colorectal cancer. First, we examined the expression of TWEAK in 70 patients with colorectal cancer who underwent surgery by immunohistochemical analysis using anti-human TWEAK mAb. As a result, positive staining for TWEAK was detected in 28 (40%). Although no significant differences between TWEAK expression and clinicopathological factors of patients, there had a tendency toward strong expression in advanced or metastatic tumors. The ratio of positive staining for TWEAK was as follows: 0% in T1, 41.7% in T2, 42.0% in T3, 50.0% in T4; 38.4% in N0, 36.4% in N1, 52.6% in N2; 38.8% in M0, 42.9% in M1; 30.8% in Stage I, 38.5% in Stage II, 43.5 in Stage III, 42.9% in Stage IV. Then, toward developing novel therapy, we examined the antitumor effect of anti-TWEAK (MTW-1) and anti-Fn14 (ITEM-2) mAb on tumor growth in vivo. CT26, murine colon adenocarcinoma, was subcutaneously inoculated in the flank of syngeneic BALB/c mice. Each mAb was administrated intraperitoneally (0.3mg, every other day). Interestingly, both TWEAK and Fn14 blocking mAb treatment significantly inhibited tumor growth in vivo, suggesting that TWEAK/Fn14 pathway may be functionally important in colorectal cancer. Taken together, TWEAK/Fn14 pathway may be functional and critical for colorectal cancer. In conclusion, we have demonstrated for the first time that TWEAK was expressed in colorectal cancer. We also found that the blockade of TWEAK/Fn14 pathway significantly inhibited tumor growth of colon cancer in vivo. Thus, TWEAK and/or Fn14 could be novel molecular targets for anti-cancer therapy in human colorectal cancer.