BASIC SCIENCE REVIEW Mechanisms by Which Inflammation May Increase Intestinal Cancer Risk in Inflammatory Bowel Disease Pamela M. O’Connor, PhD,* Tamia K. Lapointe, PhD,* Paul L. Beck, MD, † and Andre G. Buret, PhD* Patients with ulcerative colitis and Crohn’s disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflamma- tion and repeated events of inflammatory relapse in inflammatory bowel disease (IBD) expose these patients to a number of signals known to have tumorigenic effects including persistent activation of the nuclear factor-jB and cyclooxygenase-2/prostaglandin path- ways, release of proinflammatory mediators such as tumor necro- sis factor-a and interleukin-6, and enhanced local levels of reactive oxygen and nitrogen species. These inflammatory signals can contribute to carcinogenesis via 3 major processes: 1) by increasing oxidative stress, which promotes DNA mutagenesis thus contributing to tumor initiation; 2) by activating prosurvival and antiapoptotic pathways in epithelial cells, thereby contributing to tumor promotion; and 3) by creating an environment that sup- ports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observa- tions in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients. (Inflamm Bowel Dis 2010;16:1411–1420) Key Words: Crohn’s disease, ulcerative colitis, colorectal cancer, inflammation, nuclear factor-jB P atients with both ulcerative colitis (UC) and Crohn’s disease (CD) are at increased risk of developing colo- rectal cancers. 1–5 Unlike the hereditary colorectal cancer syn- dromes, familial adenomatous polyposis and hereditary non- polyposis colorectal cancer, which have clear-cut genetic etiologies, a well-defined genetic basis for colitis-associated cancer has not been identified. Instead, the increased risk of colorectal cancer in inflammatory bowel disease (IBD) patients is thought to be due to the chronic inflammatory conditions in the intestinal mucosa. Lending support to this hypothesis is the fact that colon cancer risk correlates with the degree, 6 duration, 4 and anatomical extent 7 of colonic inflammation. Furthermore, there is evidence that antiinflam- matory medications can reduce the risk of developing both IBD-associated and sporadic colorectal cancer. 8,9 The idea that inflammation may contribute to carcino- genesis is not new. In 1863 Virchow observed a ‘‘lymphore- ticular infiltrate’’ in neoplastic tissues and hypothesized that cancer originates at sites of chronic inflammation. 10 There are now several known instances where chronic inflammation of both infectious and noninfectious etiologies is thought to contribute to the development of neoplasia (Table 1). For example, there are strong associations between chronic gastri- tis and hepatitis and the development of cancer in the stom- ach and liver, respectively. 11–13 Given the considerable bur- den of IBD on society and the fact that colorectal cancer accounts for increased morbidity and mortality in these dis- eases, the questions of whether and how inflammation con- tributes to colorectal carcinogenesis in IBD have recently gained more attention. Using the data from the clinical and the basic research literature, the present article discusses the major cellular and molecular mechanisms whereby inflamma- tory processes may increase the risk of developing intestinal cancer in patients with IBD. DOES CHRONIC INTESTINAL INFLAMMATION INCREASE CANCER RISK? INSIGHTS FROM THE CLINICAL LITERATURE Although there is a very clear association between UC and elevated risk for colorectal cancer, 2 there has been some debate about whether CD poses a similar risk. Earlier studies from Israel, 14 Copenhagen, 15 and Minnesota 16 did not find that CD significantly increased the risk of intesti- nal cancers. This may argue for the point that chronic in- testinal inflammation does not necessarily predispose one to cancer. However, if the data from these studies are cor- rected to assess those patients with longstanding, extensive, unresected colonic disease there is an 10-fold increased cancer risk. 5 Moreover, several other studies support the association between CD and cancer, 17,18 including a Received for publication November 30, 2009; Accepted November 30, 2009. From the *Department of Biological Sciences and Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada, † Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada. Reprints: Andre G. Buret, PhD, Department of Biological Sciences and Inflammation Research Network, University of Calgary, 2500 University Dr., N.W., Calgary, Alberta, T2N 1N4, Canada (e-mail: aburet@ucalgary.ca) Copyright V C 2010 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21217 Published online 12 February 2010 in Wiley InterScience (www. interscience.wiley.com). Inflamm Bowel Dis  Volume 16, Number 8, August 2010 1411