期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 296, 期 4, 页码 G850-G859出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00071.2008
关键词
tumor necrosis factor-alpha; colitis-associated cancer; intestinal epithelial cells; carcinogenesis; TNFR2
资金
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Japanese Ministry of Health, Labor and Welfare
- Japan Medical Association
- Foundation for Advancement of International Science
- Terumo Life Science Foundation
- Ohyama Health Foundation
- Yakult Bio-Science Foundation
- Research Fund of Mitsukoshi Health and Welfare Foundation
- Japan Foundation for Applied Enzymology
- Memorial Fund of Nihon University Medical Alumni Association
- Abbott Japan Allergy Research Award
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [24659375] Funding Source: KAKEN
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-kappa B 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-kappa B activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-kappa B 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-kappa B 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.
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