Insulin-Like Growth Factor Binding Protein-3 Inhibits Colitis-Induced Carcinogenesis

Abstract

Chronic inflammation in the setting of inflammatory bowel disease is thought to result in altered epithelial cell growth regulation and ultimately carcinogenesis. This loss in cell growth regulation may be partially caused by a decrease in circulating intact insulin-like growth factor binding protein-3 (IFGB-3) as a result of chronic inflammation. This study evaluates the effect of IFGB-3 on carcinogenesis in the setting of colitis. A previously described animal model for colitis-induced carcinogenesis was used. Colitis was induced in both wild-type and IFGB-3 transgenic CD1 mice with a one-week oral exposure to dextran sodium sulfate (2 percent in drinking water). All mice received a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic colonic carcinogen, azoxymethane. At Week 20, the animals were killed and their colons were excised. The colons were examined by a pathologist under blinded conditions. Criteria assessed included the severity of colitis, number of aberrant crypt foci per mouse colon, incidence of colonic adenomas, and mean size of colonic adenomas. A total of 20 mice (10 in each group) were included in the study. The severity of colitis was not significantly different between the two groups (mean colitis score wild-type = 13.2; IFGB-3 transgenic = 11; P = not significant). The average number of aberrant crypt foci per colon was significantly lower in the IFGB-3 transgenic mice compared with the wild-type mice (1.5 +/- 1.4 vs. 4.5 +/- 2.7, respectively; P < 0.0001). The number of adenomas per colon was significantly lower in IFGB-3 transgenic group (1.2 +/- 1.8) compared with the wild-type mice (3.7 +/- 2.7; P = 0.005). In addition the average size of adenomas was significantly smaller in IFGB-3 transgenic mice (1.4 +/- 1.3 mm) compared with the wild-type mice (2.6 +/- 2 mm; P = 0.013). IFGB-3 significantly reduces the development of colonic tumors and precursor lesions in the setting of induced murine colitis. It is possible that the loss of IFGB-3 as a result of chronic inflammation may be associated with an increased rate of carcinogenesis in the inflammatory bowel disease setting. Although further studies are necessary, in theory, inhibiting the depletion of IFGB-3 or replacement of IFGB-3 may serve as a novel treatment strategy to prevent the development of colitis-induced carcinogenesis.