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

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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.

Section snippets

Evidence of inflammation and cancer

Chronic inflammation is characterized by persistently activated immune cells in which there is a vicious cycle of tissue destruction and repair due to either irremovable injurious stimuli or a dysfunction in any component of the normal inflammatory response. Sources of chronic inflammation include infectious agents, physical and chemical agents such as environmental exposures and dietary carcinogens, sustained wounds or trauma, gastric fluids, bile acids, or urine reflux, and dysfunctions of

Overview of mechanisms in inflammation-associated carcinogenesis

Mechanisms involved in the progression of chronic inflammation to cancer, as well as the role of inflammation in cancer and cancer-related inflammation have been scrutinized extensively, leading to the acceptance of several paradigms. Not only can processes involved in chronic inflammation promote malignant transformation of tissue, termed the extrinsic pathway, but tissues “initiated” by a series of genomic mutations such as in oncogenes can also change the transcriptome of cells to express an

Chronic intestinal inflammation

Chronic inflammatory diseases of the intestinal tract include IBDs and celiac disease, which account for the majority of known cases. The most common forms of IBDs include ulcerative colitis and Crohn's disease. Clinically, intestinal inflammation in ulcerative colitis is limited most commonly to the colon, whereas Crohn's disease and celiac disease encompass both the small and large intestinal tract. The GI tract is a very complicated system to study because billions of microbes reside in both

Mouse models of intestinal inflammation and cancer

A plethora of mouse models are now available to study an aspect of chronic inflammation thought to play an important role in the pathogenesis of IBDs and in inflammation-associated carcinogenesis. Most mechanistic studies of celiac disease involve the use of human biopsies, and the use of mouse models to study pathogenesis is limited. However, new transgenic mouse models mimicking the HLA-DQ variants and celiac disease progression are emerging. Though no single model captures all of the

Pathogenesis of inflammatory bowel diseases

Animal models of intestinal inflammation mimicking IBDs have allowed for examination of multiple aspects of acute and chronic inflammation and its progression to dysplasia and cancer, as well as the evaluation of novel therapeutic regimens. From these studies, it is generally accepted that strong immune responses driven by pathogenic effector CD4+ T cells against the commensal luminal bacteria are due to multiple defects resulting in immune-mediated tissue damage. These defects encompass innate

Conclusion

Although the correlation between chronic inflammation and cancer has been recognized for over a century, mechanisms involved in the pathogenesis of chronic inflammation itself, as well as the sequence of events thought to be involved in the progression to cancer, are still actively being investigated. Numerous studies have been and will continue to be carried out targeting components of the inflammatory response and its associated effects in an effort to abrogate inflammation-associated

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported in part by NIH grant ES09519 (RS), the Jonsson Comprehensive Cancer Foundation (RS), a TRP grant (L618-B11) from the FWF (AS and RS) and a UCLA-NIEHS training grant in Molecular Toxicology (AW).

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