Abstract 2058: Colorectal cancer in the setting of inflammatory bowel disease: role of hemoglobin

Abstract

Abstract Colorectal carcinoma (CRC) is a serious complication of inflammatory bowel disease (IBD) and accounts for approximately 15% of all IBD-associated deaths. The likelihood of IBD-related carcinoma is greater than that of sporadic CRC. Over one half are diagnosed at stage III or IV. During the last few years we have worked on mining colon mucosal and submucosal layers for discovery of biomarkers that differentiate ulcerative colitis (UC) from Crohn's colitis (CC). Using LC-MS/MS, we examined signals found to be significantly different between CC and UC samples. We found a signal at m/z 5045 which was more intense in UC samples. The MALDI spectrum did not identify an intact protein entity but did identify hemoglobin chains. Macrophages are highly versatile phagocytes active in multiple roles in the immune system and key players in the inflammatory response. The microenvironment of most inflammation is filled with a large population of macrophages. In IBD, studies have found that macrophages can count for more than 50% of the exudative mass. Their presence within the inflammatory microenvironment, in some cases, has been proven to increase transformation, angiogenesis, and immunosuppression. In hemorrhagic situations (as in UC) macrophages engulf erythrocytes and as a result release free heme iron (heFe). Earlier studies observed that heFe has cellular proliferation effects on colon cancer cells. Recently, the potential carcinogenic effects of heFe were documented when it was shown that heFe increases the number of aberrant crypt foci in colon mucosa. In the colon, iron is expected to increase the production of reactive oxygen (O2) species (ROS) from peroxides via the Fenton reaction, which may be the cause of cellular toxicity and even pro-mutagenic lesions. Intracellular reactions with active O2 can result in the initiation and progression of carcinogenesis by induction of gene mutations, chromosomal damage and cytotoxic effects. We hypothesize that elevated expression of mucosal free heFe would be associated with an increased risk of UC-associated CRC. To validate this will require investigating whether hemoglobin could be classified as a proliferative or transforming agent for colon cancer cells by causing reactive oxygen species release. For this purpose, we plan to study the cellular viability of differentiated colon cell line (cancer: CCL 224, CCL 227 and normal: NCM 356 and NCM 460) after administration of hemoglobin at different concentrations. ROS production will be investigated in each step. Additionally, we intend to examine the potential cytotoxicity of hemoglobin. Supported: MMC-VICC Cancer Partnership Grant # 3U54CA091408-09S 1 (SEA & HLM); MeTRC grant # 5U54RR026140-03 (SEA), and Vanderbilt SPORE in GI Cancer Grant # P50CA095103 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2058. doi:1538-7445.AM2012-2058