38: The function of ADAM17 in colitis-associated cancer

Abstract

The protease ADAM17 ( A D isintegrin and M etalloprotease 17) cleaves TNF- α , L-selectin, and EGF-R ligands from the plasma membrane. ADAM17 is expressed in immune cells and strongly up-regulated during inflammation and cancer. To study ADAM17 biology in vivo we generated hypomorphic mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17 ex / ex were viable, and showed compromised shedding of ADAM17 substrates. To investigate ADAM17 activity during inflammation we performed a mouse model of inflammatory bowel disease by administration of dextran sodium sulphate (DSS). Unexpectedly, although the intestine of unchallenged homozygous ADAM17 ex / ex mice was normal, ADAM17 ex / ex mice showed substantially increased susceptibility to inflammation in DSS colitis. This was due to impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and consequently in defective regeneration of epithelial cells and breakdown of the intestinal barrier. In recent experiments we investigated the function of ADAM17 in a model of colitis associated cancer (CAC) induced by the intraperitoneal injection of the carcinogen azoxymethane (AOM), followed by multiple rounds of inflammation and leukocyte infiltration caused by administration of DSS. We found a moderate decrease in tumor formation in the ADAM17 ex / ex mice coupled with increased intestinal inflammation. In wild-type mice, 11 ± 6 tumor nodules were found compared with 7 ± 4 in ADAM17 ex / ex mice. In addition ADAM17 ex / ex mice developed smaller adenomas than wild-type mice indicating that depletion of ADAM17 interferes with tumor progression rather than tumor initiation. In further experiments we will reveal the molecular pathways which are governed by ADAM17 during CAC.