Chronic Inflammation and Colorectal Cancer

Cancer is a disease that develops slowly. For most solid human tumors there is a 20 year interval between the carcinogen exposure and clinical detection of cancer. In ulcerative colitis, an idiopathic chronic inflammatory disease of the large intestine, colorectal cancer (CRC) development occurs at a higher rate and speed.The basic premise for the development of colorectal cancer is that cells accumulate millions of DNA mutations. The normal mutation rate, however, is insufficient to account for the multiple mutations observed in cancer cells. Therefore, changes that increase mutation rates are essential for tumor development. This so called "mutator phenotype" has been hypothesized for many years. It was first identified in tumors from patients with Lynch-syndrome (i.e. HNPCC or hereditary nonpolyposis colorectal cancer syndrome) in which multiple mutations within repetitive DNA-sequences (so called microsatellites) had been found. These multiple mutations in microsatellites are called microsatellite instability or MSI. In HNPCC, MSI is caused by germline mutations in DNA repair genes, the so called mismatch repair system (MMR). Indeed, MSI is regarded as fingerprint of inactivation of this DNA repair system that ensures DNA fidelity after each cell division. In ulcerative colitis, MSI is found in a minor form already in chronically inflamed mucosa suggesting that impairment of DNA fidelity during cell division is a key mechanism in the development of colitis-associated CRC. The reason for this is still unknown. Inhere we hypothesize that chronic inflammation in the colon creates an environment, which meets the criteria of a "mutator phenotype". We intend to simulate such an environment in cell culture and we will test its effect on the DNA mutation rate in a recently developed system. Thereby, we transfer the clinical situation into the laboratory and may proof the existence of an inflammation-associated "mutator phenotype". The model will be useful for studying molecular mechanisms in the development of cancer. In particular, we also intend to study the effects of certain drugs and natural compounds for its ability to improve DNA fidelity during cell division. The results of our tests can be transferred into the clinical situations and may be used for prevention of CRC in ulcerative colitis and eventually also for other inflammation-associated cancers within the digestive tract (such as esophageal cancer).

Cancer is a disease that develops slowly. For most solid human tumors there is a 20 year interval between the carcinogen exposure and clinical detection of cancer. In ulcerative colitis, an idiopathic chronic inflammatory disease of the large intestine, colorectal cancer (CRC) development occurs at a higher rate and speed.The basic premise for the development of colorectal cancer is that cells accumulate millions of DNA mutations. The normal mutation rate, however, is insufficient to account for the multiple mutations observed in cancer cells. Therefore, changes that increase mutation rates are essential for tumor development. This so called "mutator phenotype" has been hypothesized for many years. It was first identified in tumors from patients with Lynch-syndrome (i.e. HNPCC or hereditary nonpolyposis colorectal cancer syndrome) in which multiple mutations within repetitive DNA-sequences (so called microsatellites) had been found. These multiple mutations in microsatellites are called microsatellite instability or MSI. In HNPCC, MSI is caused by germline mutations in DNA repair genes, the so called mismatch repair system (MMR). Indeed, MSI is regarded as fingerprint of inactivation of this DNA repair system that ensures DNA fidelity after each cell division. In ulcerative colitis, MSI is found in a minor form already in chronically inflamed mucosa suggesting that impairment of DNA fidelity during cell division is a key mechanism in the development of colitis-associated CRC. The reason for this is still unknown. Inhere we hypothesize that chronic inflammation in the colon creates an environment, which meets the criteria of a "mutator phenotype". We intend to simulate such an environment in cell culture and we will test its effect on the DNA mutation rate in a recently developed system. Thereby, we transfer the clinical situation into the laboratory and may proof the existence of an inflammation-associated "mutator phenotype". The model will be useful for studying molecular mechanisms in the development of cancer. In particular, we also intend to study the effects of certain drugs and natural compounds for its ability to improve DNA fidelity during cell division. The results of our tests can be transferred into the clinical situations and may be used for prevention of CRC in ulcerative colitis and eventually also for other inflammation-associated cancers within the digestive tract (such as esophageal cancer).