Chronic Inflammation and Gastrointestinal Cancer

Erwin Schrödinger Fellowship J 1702 Chronic Inflammation and Gastrointestinal Cancer Christoph GASCHE 08.05.2000 Cancer often occurs in the setting of chronic inflammation. This is particularly true in the gastrointestinal tract (e.g. colon cancer in inflammatory bowel disease). It has been commonly assumed that since chronic inflammation generates free radicals and causes mutations that cancer is the unavoidable consequence. However, the human genome is well protected by mechanisms that repair mutations, and there is little quantitative evidence that the mutagenic milieu created by the inflammatory cells is sufficient to produce cancer. Many gastrointestinal cancers associated with chronic inflammation are characterized by "microsatellite instability", a feature that suggests inactivation of the DNA mismatch repair system. However, investigators have been unable to find evidence for inactivation of DNA mismatch repair genes in these tumors. Perhaps the mechanism responsible for inflammation-associated carcinogenesis is complex and involves a combined increase in the concentration of mutagens together with a relaxation of the DNA repair apparatus. This proposal will present evidence to suggest that partial or temporary inactivation of the DNA mismatch repair system occurs in some tumors that evolve in the setting of chronic inflammation. A proper understanding of the mechanisms by which these tumors develop might open new avenues for the primary prevention of cancer.