Intestinal Inflammation and Cancer
Section snippets
Clinical and Pathologic Features of Colitis-Associated Cancer
Several lines of evidence indicate that chronic inflammation is a key risk factor for CRC in patients with IBD.1, 2 The risk for developing CRC increases with longer duration of colitis. CRC is rarely encountered in patients who have had colitis for less than 7 years; thereafter the risk increases at a rate of approximately 0.5%–1.0% per year. The extent of colitis is another important risk factor; the more colonic surface that is involved with colitis, the greater the risk for colon cancer.
Anti-inflammatory Medications
If chronic inflammation is the main cause of CRC in patients with IBD, then suppressing inflammation should lower the risk for colitis-associated cancer. However, studies have not established that the anti-inflammatory agents most commonly used to treat IBD have chemopreventive effects against cancer (reviewed in reference 1). The chemopreventive effects of mesalamine compounds (eg, sulfasalazine and mesalamine) have been investigated in mainly post-hoc, secondary analyses, and produced
Pathogenesis
Colitis-associated cancers develop in chronically inflamed mucosa and are believed to develop in a sequence of no dysplasia–indefinite dysplasia–low-grade dysplasia–high-grade dysplasia–carcinoma (Figure 2). Tumor progression in patients can skip one or more of these steps.1 Like sporadic CRC, colon carcinogenesis in patients with IBD occurs through a sequence of events, such as mutations in somatic cells followed by their clonal expansion. However, unlike sporadic CRC, which develops from
Oxidative Stress
In addition to promoting chromosomal and microsatellite instability and CpG island methylation (Figure 2), inflammation contributes to colon carcinogenesis by producing oxidative stress. IBD has been considered to be an “oxyradical overload” disease, in which chronic inflammation increases the risk for cancer.39 Oxidative stress causes cellular damage that contributes to pathogenesis of the colitis itself and to colon carcinogenesis (Figure 3). The initiation of tumor formation in chronically
The Immune Response
Proinflammatory factors of the innate and adaptive immune systems contribute to development and growth of colon neoplasia. Although a detailed description of all mediators and cell types is beyond the scope of this review, there are some important components to cover here. Most of what we have learned about the role of the immune response in colon neoplasia has come from studies of animal models. In comparing results from animal models of colitis-associated cancer, it is important to remember
Gastrointestinal Microflora
The intestinal microbiota makes a significant contribution to the development of not only colitis, but also neoplasia. In several different rodent models of IBD, commensal bacteria or specific bacteria (such as H hepaticus) are required to initiate inflammation and for development of dysplasia or cancer.2 Without these bacteria, neither colitis nor neoplasia develops.
Under conventional conditions, IL-10–null mice develop spontaneous, generalized enterocolitis that requires IL-12 and the
Conclusions
There is a close relationship between colonic inflammation and neoplasia. Although there is little doubt that chronic inflammation promotes colon cancer, the cellular and microbial mechanisms involved are not clear. Experimental evidence indicates that the innate and adaptive immune systems each have a role in pathogenesis of colitis-associated cancer, and that the bacterial flora also contributes. It will be important to determine how specific immune cells, cytokines, chemokines, and the
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Conflicts of interest The authors disclose the following: Dr Ullman has served as a consultant and received research support from Procter and Gamble, Shire, and Warner-Chilcott. Dr Itzkowitz has received research support from Exact Sciences Corporation.
Funding Funded in part by grant KO8 DK069393.