Mechanisms of intestinal inflammation and development of associated cancers: lessons learned from mouse models

Abstract

Chronic inflammation is strongly associated with approximately 1/5th of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With regards to extraintestinal manifestations such as lymphoma, however, more suitable models are required to further investigate the complex and heterogeneous mechanisms that may be at play.

Figure 1

Mechanisms of intestinal inflammation-mediated carcinogenesis. Persistent antigenic stimulation in the intestinal tract through a permeabilized epithelial barrier results in chronic inflammation. Dysfunctions of the epithelial barrier itself, the innate and adaptive immune responses, DNA repair and stress responses, as well as related downstream signaling pathways can result in transcriptional changes promoting malignant transformation of the tissue, as well as extraintestinal manifestations.

Figure 2

Systemic genotoxicity of intestinal inflammation (Adapted from [251]). Tissue atrophy from persistent inflammation results in genotoxicity to surface epithelial cells as well as to infiltrating leukocytes. Damaged resident leukocytes may then migrate into the peripheral circulation through the lymph nodes, or circulating activated effector cells may cause genotoxicity to proximal circulating leukocytes through oxidative burst.