Role of different inflammatory and tumor biomarkers in the development of ulcerative colitis‐associated carcinogenesis

• Published in: Inflammatory bowel diseases 2011-03, Vol.17 (3), p.696-710
• Main Authors: Talero, E., Sánchez‐Fidalgo, S., Villegas, I., de la Lastra, C. Alarcón, Illanes, M., Motilva, V.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adrenomedullin; Adrenomedullin - metabolism; Animals; beta Catenin - metabolism; biomarkers; Biomarkers, Tumor - metabolism; Blotting, Western; Carcinogenesis; Cell Transformation, Neoplastic - metabolism; Chronic Disease; chronic inflammation; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - metabolism; Colon cancer; colon carcinogenesis; Colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclooxygenase-2; cytokines; Cytokines - metabolism; Dextran sulfate; Dextran Sulfate - toxicity; Dysplasia; Female; Immunoenzyme Techniques; Inflammatory bowel diseases; iNOS; Interferon; Intestine; Mice; Mice, Inbred C57BL; Nitric-oxide synthase; Proliferating cell nuclear antigen; Prostaglandin-E synthase; Sodium; Tumor Necrosis Factor-alpha - metabolism; Tumors
• ISSN: 1078-0998; 1536-4844; 1536-4844
• DOI: 10.1002/ibd.21420

Background: Colorectal cancer (CRC) is the most severe complication in inflammatory bowel disease (IBD). In the present study we investigated different mechanistic links between chronic colonic inflammation and its progression to adenocarcinoma. Along these lines, given that adrenomedullin (AM) has been implicated in carcinogenesis, we also analyzed changes in its colonic expression. Methods: Mice were exposed to 5, 10, and 15 cycles of dextran sulfate sodium (DSS); each cycle consisted of 0.7% DSS for 1 week followed by distilled water for 10 days. After each period, macroscopic and histological studies, as well as characterization of inflammatory and tumor biomarkers, were carried out. Results: The disease activity index (DAI) showed that the disease was present from the third cycle and it gradually increased during the course of DSS treatment. Macroscopic tumors were only seen after 15 cycles, and microscopic study showed that inflammation, dysplasia, and adenocarcinomas correlated with DSS cycles. β‐Catenin and proliferating cell nuclear antigen expressions progressively increased in animals treated with the different cycles of DSS. TNF‐α and IFN‐γ showed the highest production at the tenth cycle. COX‐2, mPGES‐1, and iNOS levels were also appreciably higher at the fifth and tenth cycles. Moreover, we observed a progressive enhancement in AM expression and changes in its intracellular location during the progression of the disease. Conclusions: Our results show an early induction of proinflammatory factors, which may contribute to the development of colon cancer, as well as demonstrate, for the first time, the expression of AM in IBD‐derived CRC. Inflamm Bowel Dis 2011