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