title: Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.
abstract: Treatment with anti-TNF-alpha MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-alpha signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-alpha MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-kappaB pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-kappaB activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-kappaB activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-alpha MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-kappaB inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-alpha MAb may prevent the development of CAC in patients with long-standing IBD.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Onizawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagaishi
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nagano
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oshima
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nemoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshioka
authors.forename: Teruji
authors.initials: T
authors.lastname: Totsuka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohya
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D002277:Carcinoma; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003110:Colonic Neoplasms / Q000150:complications*; D016264:Dextran Sulfate / Q000633:toxicity; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate