Role of different inflammatory and tumor biomarkers in the development of ulcerative colitis-associated carcinogenesis.
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.
Talero
E
E
Department of Pharmacology, School of Pharmacy, University of Seville, Seville, Spain. etalero@us.es
Sánchez-Fidalgo
S
S
Villegas
I
I
de la Lastra
C Alarcón
CA
Illanes
M
M
Motilva
V
V
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D053607:Adrenomedullin / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D014408:Biomarkers, Tumor; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D053607:Adrenomedullin; D016264:Dextran Sulfate