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

Abstract

Chronic inflammation is strongly associated with approximately 1/5 th 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.

Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review

“…More recent evidence, however, indicates that also in other forms of sporadic as well as heritable CRC, inflammation is likely to be involved (Terzic et al, 2010). Considering the large number of pathways disturbed (Westbrook et al, 2010), chronic inflammation has been proposed to affect the three stages of cancer: tumor initiation, tumor promotion and tumor progression.…”

“…Tumor initiation, the process by which a normal cell starts to become malignant, is associated with accumulation of genetic alterations Westbrook et al, 2010). Research data indicate that inflammation can induce genetic alterations through several mechanisms.…”

“…However, in sporadic CRC, most intratumoral immune cells are only recruited after the tumor is formed indicating that chronic inflammation does not precede but follows tumor development. Inflammation is thus probably not involved in tumor initiation in sporadic CRC although after tumor formation, the localized inflammatory microenvironment can promote accumulation of additional mutations and epigenetic changes (Meira et al, 2008;Terzic et al, 2010;Westbrook et al, 2010). Furthermore, cytokines released by activated immune cells can play a role during tumor promotion and progression by stimulating angiogenesis and suppressing immune-mediated tumor elimination (Karin, 2006;Yu et al, 2009;Grivennikov et al, 2010).…”

Epithelial-mesenchymal Transition and Its Role in the Pathogenesis of Colorectal Cancer

“…In addition, DNA methylation and histone modification could also affect intestinal epithelium during development (Colotta et al, 2009). Colitis-associated cancer has been investigated in mouse models (Westbrook et al, 2010). These studies have highlighted the role of toll-like receptors (TLR) and tumor necrosis factor-α (TNF-α) in the activation of nuclear factor kB (NFkB), which induces transcription of genes involved in tumorogenesis, including COX-2.…”

Hypoxic Inflammation, a Deadly Bridge to Malignant Transformation and a Fertile Soil for Cancer Prevention

“…Despite the fact that it has been known for a long time that chronic inflammation in the mucosa and sub mucosa of patients with inflammatory bowel disease, as well as mouse models such as Gia2 KO mouse act as harbingers for malignant transformation, until this writing, no one has been able to connect the pieces together and describe the mechanism by which malignancy arises in real life IBD patients and Gia2 KO mouse (Triantafillidis, 2009;O'Connor et al, 2010;Westbrook et al, 2010).…”