Abstract
Inflammatory bowel disease (IBD) is a chronic illness caused by complex interactions between genetic and environmental factors that propagate inflammation and damage to the gastrointestinal epithelium. This state of chronic inflammation increases the risk for development of colitis-associated cancer in IBD patients. Thus, the development of targeted therapeutics that can disrupt the cycle of inflammation and epithelial injury is highly attractive. However, such biological therapies, including those targeting epidermal growth factor receptor pathways, pose a risk of increasing cancer rates. Using two mouse models of colitis-associated cancer, we found that epidermal growth factor receptor inactivation accelerated the incidence and progression of colorectal tumors. By modulating inflammation and epithelial regeneration, epidermal growth factor receptor optimized the response to chronic inflammation and limited subsequent tumorigenesis. These findings provide important insights into the pathogenesis of colitis-associated cancer and suggest that epidermal growth factor-based therapies for IBD may reduce long-term cancer risk.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Colitis / complications*
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Colitis / pathology
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Colitis / physiopathology*
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Colitis / prevention & control
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Colon / immunology
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Colon / physiopathology
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Colorectal Neoplasms / etiology
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Colorectal Neoplasms / physiopathology*
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Colorectal Neoplasms / prevention & control*
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Cytokines / genetics
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Disease Models, Animal
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Disease Progression
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / physiology*
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Gene Expression Profiling
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Humans
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Inflammatory Bowel Diseases / complications
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Inflammatory Bowel Diseases / pathology
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Inflammatory Bowel Diseases / physiopathology
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Inflammatory Bowel Diseases / therapy
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Interleukin-10 / deficiency
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Interleukin-10 / genetics
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Mice
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Mice, Knockout
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Mutation
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Proto-Oncogene Proteins B-raf / genetics
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Risk Factors
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Signal Transduction
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
Substances
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Cytokines
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IL10 protein, mouse
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Tumor Suppressor Proteins
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Interleukin-10
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ErbB Receptors
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Braf protein, mouse
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Proto-Oncogene Proteins B-raf