Abstract
Chronic inflammation has long been implicated as a predisposition for cancer, but the underlying mechanism for how this occurs has remained obscure. Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine which is known to be highly linked to colorectal cancer. During chronic inflammation the intestinal mucosa is in a constant cycle of injury and repair resulting in aberrant epithelial proliferation, a process that increases the risk of neoplastic transformation. In particular, the coexistence of commensal flora in the intestine plays an important role in the regulation of mucosal restitution after epithelial injury. It has become apparent that signaling through toll-like receptors (TLRs), the receptor family recognizing pathogen-associated molecular patterns, is crucial to intestinal epithelial proliferation and mucosal restitution. We have recently described two important downstream pathways underlying TLR4-mediated epithelial proliferation in a mouse model of colitis-associated cancer; i.e., cyclooxygenase 2 (COX-2)-mediated production of prostaglandin E2 (PGE2), and induction of specific ligands for epidermal growth factor receptor (EGFR). These two pathways are closely involved with mucosal levels of PGE2 and other prostanoids such as 15-deoxy-delta 12,14-prostaglandin-J2 (15d-PGJ2). Understanding the fine interplay between the TLR signaling and intestinal tumorigenesis in the setting of chronic inflammation can contribute to establishing a novel treatment strategy for inflammation-associated cancers.
Highlights
Chronic inflammation has been implicated in the development of cancer in many organs including the gastrointestinal tract
Using the AOM-DSS model, we have previously described that mice deficient in toll-like receptor 4 (TLR4), a pathogen recognition receptor specific for gram-negative bacteria, are resistant to the development of colitis-associated tumors due to decreased expression levels of mucosal cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR)
Two types of prostaglandins can be induced by cyclooxygenase 2 (COX-2) expression, i.e., PGE2 and 15d-PGJ2, which trigger epithelial proliferation and apoptosis, respectively balancing mucosal integrity during inflammation
Summary
Chronic inflammation has been implicated in the development of cancer in many organs including the gastrointestinal tract. The intestinal mucosa is in continuous contact with a diverse array of dietary antigens and luminal microbes to which the host maintains a silent state of inflammation Disruption of this mucosal integrity has been thought to be the central pathogenesis of uncontrolled inflammation in patients with UC. The underlying mechanism is that chronic induction of mucosal PGE2 forms a positive feedback loop leading to sustained up-regulation of COX-2 in macrophages and AR release from epithelial cells. Both PGE2 and AR induce epithelial cell proliferation through EGFR activation and uncontrolled activation of this pathway is known to result in the development of cancer. Elucidating how TLR4-mediated regulation of epithelial proliferation leads to cancer will provide a novel insight into the pathogenesis of inflammationinduced tumorigenesis in the intestine
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