Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel disease

Abstract

Patients with ulcerative colitis and Crohn's disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflammation 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-kappaB and cyclooxygenase-2/prostaglandin pathways, release of proinflammatory mediators such as tumor necrosis factor-alpha 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 supports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observations in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients.

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease

“…COX-2 and iNOS are enzymes that play a pivotal role in mediating inflammation [2]. In this regard, COX-2 activation produces excessive PGE 2 and TXB 2 , which are important inflammatory mediators that contribute to the intestinal hyperemia, edema and even dysfunction, and iNOS activation leads to excessive production of NO which may be detrimental to the integrity of the colon based on the generation of reactive nitrogen species causing cellular degeneration in various tissues and contributing to the development of intestinal damage [42].…”

“…Furthermore, defects in the T-cellmediated regulatory processes have been suggested in prevention of inflammatory responses [1]. A complex system of intracellular signalling molecules such as mitogenactivated protein kinases (MAPKs) or the transcription factor nuclear factor B (NF-B), influences this uncontrolled immune system activation and inflammation by ultimately modulating gene transcription [2].…”

Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia

“…Hence, the chronic inflammatory load seems to be the central element for an increased risk of UC-associated CRC. 10,11 Furthermore, a range of epidemiological studies have repeatedly recognized pancolitis to be an independent risk factor for CRC compared with less widespread colonic inflammation, e.g., left-sided UC. 12,13 However, it is unknown why the inflammatory process in pancolitis leads to a higher risk of CRC compared with left-sided UC.…”

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

“…colon cancer | receptor splice variants | substance P | IBD C hronic inflammation is associated with a higher rate of cancer development in various organs (1). More specifically, patients with ulcerative colitis (UC) are at high risk for developing colorectal cancer (2); both extent and duration of intestinal inflammation further increase risk (3,4).…”