The role of chronic inflammation in the pathogenesis of sporadic colorectal cancer

The adenoma-carcinoma sequence is well established and describes the sequential change from normal colonic mucosa to pre-malignant benign adenoma to overt adenocarcinoma. Each stage is associated with well defined genetic mutations. Adenomas are subjected to persistent traumatic influences, including physical, chemical and microbial insults. We hypothesise that this creates a focus of chronic inflammatory activity within the polyp and that this is a key to carcinogenesis. The concept that development of sporadic colorectal cancer is an inflammatory linked process is novel. This thesis explores this hypothesis by investigating inflammatory activity within adenomatous polyps compared to adjacent normal mucosa. We have shown that inflammatory cell infiltrate is a key feature of adenomas, with a predominant neutrophil and Thelper cell infiltrate within the stroma of small polyps less than or equal to 1 cm in size, and a predominant macrophage and CD25+ T cell infiltration in larger lesions. This inflammatory infiltrate increases along with increasing degree of cell dysplasia towards malignancy and furthermore, our data suggests that macrophage function with the adenomas is predominantly pro-inflammatory in nature. Expression of cyclo-oxygenase 2, a key inflammatory mediator, is increased in adenomas and is linked to adenoma characteristics associated with malignant potential. We have also shown that inflammatory cytokine gene expression is dysregulated in polyps.EThOS - Electronic Theses Online ServiceGBUnited Kingdo