Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development

Abstract

Interleukin-10-deficient mice develop colitis and colorectal cancer similar to the inflammatory bowel disease associated cancer in humans. The aim of this study was to identify possible mutations of oncogenes and tumour suppressor genes involved in tumorigenesis in Interleukin-10 (IL-10)-deficient mice. Twenty colon carcinomas from IL-10-deficient mice were screened for mutations in the K-ras and p53 genes by 'cold' single-strand-conformation polymorphism. Immunohistochemical staining was performed to detect mutations in the proteins P53, APC and MSH2, and the transforming growth factor beta type II receptor. Microsatellite instability was analysed at eight chromosomal loci and plasma levels of transforming growth factor beta1 (TGF-beta1) were also measured. At 9 weeks, 14% of the animals developed colorectal cancer, and at 10-31 weeks the incidence of carcinoma was 65%. No mutations were detected in the analysed oncogene and tumour suppressor genes. Plasma TGF-beta1 levels in IL-10-deficient mice 10-31 weeks old were higher than in wild-type littermates e.g. 45.7 +/- 4.6 ng/ml versus 19.8 +/- 4.5 ng/ml (P<0.01). No alterations in K-ras, p53, APC: and Msh2 genes suggests that other genes are involved in the development of these tumours. Elevated TGF-beta1 plasma levels correspond to the high incidence of dysplasia and cancer. Normal expression of the TGF-beta II receptors hints at genetic alterations in other members of the TGF-beta receptor signal transduction pathway.

Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

“…A recent genetic-linkage analysis of patients with IBD revealed that loss-of function mutations in genes encoding the IL-10 receptor proteins are associated with severe, early-onset enterocolitis, a finding that underscores the pivotal role of IL-10 in mediating the signals that control inflammation in the human gut (Glocker et al, 2009). Consistent with the clinical finding, a mouse model with targeted disruption of the IL-10 gene invariably develops enterocolitis that eventually progresses to colon cancer under conventional housing conditions; this mouse model is thus extremely useful as a disease model of human IBD (Kuhn et al, 1993;Berg et al, 1996;Sturlan et al, 2001). In the present study, expression of AID was most prominent in the inflamed cecal mucosa of IL-10…”

Inflammatory Cytokine Gene Polymorphisms, Nonsteroidal Anti-Inflammatory Drug Use, and Risk of Adenoma Polyp Recurrence in the Polyp Prevention Trial

“…These differences in results may reflect real differences in the gene-drug association and their effect at different stages of disease (i.e., adenoma recurrence versus invasive colorectal cancer), or may be due to limited sample size, differences in aspirin/NSAID exposure categorization, or due to chance. However, our data mimic IL-10-deficient mice that develop spontaneous chronic inflammatory bowel disease, a known risk factor for colorectal cancer (49,54). IL-10-deficient mice have increased production of proinflammatory cytokines and several studies report that IL-10À/À mice treated with NSAIDs develop progressive, severe colitis much faster than IL-10À/À mice not treated with NSAIDs (49).…”

Meta-analysis of epidemiological studies of association of two polymorphisms in the interleukin-10 gene promoter and colorectal cancer risk

“…A zoological study conducted by Sturlan et al (2001) indicated that IL-10-deficient mice can develop chronic enterocolitis and CRC. Moreover, a statistically significant decrease in IL-10 mRNA expression in tumor tissue of patients with colon cancer compared to normal mucous tissue was observed (Cacev et al, 2008).…”