Prevention of Colitis-Associated Carcinogenesis with Infliximab

Abstract

The emergence of infliximab was an epochal event in the treatment of inflammatory bowel disease (IBD). Because colitis-associated cancers arose in the setting of chronic inflammation, during which "inflammation-dysplasia-carcinoma sequence" prevails and anti-inflammatory agents can prevent carcinogenesis, we hypothesized whether infliximab can prevent colitic cancer in animal models for which C57BL/6 mice were exposed to 15 cycles of dextran sulfate sodium (DSS), with each cycle consisting of 0.7% DSS for 1 week followed by sterilized water for 10 days. Infliximab (4 mg/kg i.v.) was given on the 1st, 3rd, and 7th weeks or 25th, 27th, and 31st weeks of cycle according to "step-up" versus "top-down" strategy. Molecular change about inflammation and carcinogenesis was compared between groups. Multiple colorectal tumors developed in 75% to 80% of control mice, whereas only 16.7% of mice treated with infliximab on the 1st, 3rd, and 7th weeks developed colon tumors. Significant decreases in tumor necrosis factor-α level, mast cell number, and the expression of inflammatory cytokines were observed in top-down strategy using infliximab. The expression and activity of matrix metalloproteinase-9 (MMP-9) and MMP-11 were significantly decreased in mice treated with infliximab accompanied with attenuated numbers of "β-catenin-accumulated crypts." In animal group where infliximab was administered at later stage of 25th, 27th, and 31st weeks, no reduction in tumorigenesis was noted. These biological effects of infliximab were further explored in in vitro experiment using Raw264.7 and Jurkat T cells. Conclusively, earlier and intensive therapy with infliximab should be considered for either mitigating clinical course or preventing ultimate development of colitic cancer in high-risk IBD patients. Cancer Prev Res; 3(10); 1314-33. ©2010 AACR.

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

“…Although there are no data available whether IBD patients non-responding to IFX therapy are at an increased risk for colon cancer, an animal study indicated that IBD animals treated with IFX are protected from colon cancer [22][23][24][25][26][27][28][29]. Therefore, one may also speculate that patients having high Wnt5a gene expression may be subjected to IFX non-responsiveness and, also, are at a higher risk of cancer.…”

Mast Cell–Derived Prostaglandin D2 Inhibits Colitis and Colitis-Associated Colon Cancer in Mice

“…In the mouse colorectal cancer model, TNFa and one of the major prostaglandins, PGE 2 , induce tumorigenesis via an aberrant activation of NF-kB or Wnt/b-catenin signaling in epithelial cells (3,4). Consistently, clinical studies have shown that treatment with an anti-TNFa antibody or a COX inhibitor is effective against the development of human colorectal cancer (5,6). However, each COX metabolite PG or TNFainduced cytokine possesses a pro-or an anti-inflammatory role and acts coordinately to govern inflammatory responses, eliminate foreign objects, and remodel tissues.…”

Current overview of colitis-associated colorectal cancer

“…As shown in vivo on a mouse model of CACRC, only 16.7% of animals treated intravenously with infliximab at dose 4 mg kg -1 for 37 weeks developed tumors vs. 75-80% of control mice [57]. This suggests that the early and intensive therapy with infliximab may prevent the development of CACRC in high-risk IBD patients.…”