To uncover molecular mechanisms specifically involved in the pathogenesis of colitis-associated colon cancer (CAC), we studied tumorigenesis in experimental models of CAC and sporadic CRC that mimic characteristics of human CRC. Using comparative whole genome expression profiling, we observed differential expression of epiregulin (Ereg) in mouse models of colitis-associated, but not sporadic colorectal cancer. Similarly, highly significant upregulation of Ereg expression was found in cohorts of patients with colitis-associated cancer in inflammatory bowel disease but not in sporadic colorectal cancer. Furthermore, tumor-associated fibroblasts were identified as major source of Ereg in colitis-associated neoplasias. Functional studies showed that Ereg-deficient mice, although more prone to colitis, are strongly protected from colitis-associated tumors, and data from serial endoscopic studies revealed that Ereg promotes growth rather than initiation of tumors. 4 samples of individual distal colitis-associated tumors (CAC) from 4 mice, 2 samples of tumor-free distal colon epithelium with a pool of 5 mice per sample (CAC contr), 5 samples of individual Apcmin/+ tumors from the distal colorectum of 5 mice (sporCRC) and 3 samples of tumor-free distal colon epithelium (pool of 4 mice per sample) (sporCRC contr). Colitis-associated tumorigenesis was performed by intraperitoneal injection of Azoxymethane (10mg/kg) (Sigma) into C57BL/6J wildtype mice followed by 3 cycles of Dextran Sodium Sulfate (DSS) in drinking water. Each DSS-cycle was composed of DSS (2.5% (w/v) (MP Biomedicals) in drinking water for 7 days, followed by a recovery phase with regular drinking water for 14 days. Sporadic tumors were from C57BL/6J-ApcMin/+/J mice. All tumors were obtained from the from the lower 6th of the large intestine and they had the same size covering between ¼ and up to ½ of the colonic circumferenc as evaluated by mini-endoscopy.