Molecular mechanisms involved in colorectal cancer initiation and progression

118 WNT signalling and the initiation of CRC Around 70% of sporadic colorectal tumours show biallelic inactivation of the APC gene (Adenomatous polyposis Coli). A high percentage of remaining tumours show activating mutations in beta-catenin or axin. These molecules are components of the Wnt signalling pathway. Activating mutations of the Wntsignalling pathway are the only known genetic alterations present in early premalignant lesions in the intestine, such as aberrant crypt foci and small adenomas. In various animal models, activating mutations in this pathway effectively initiate tumorogenesis in the intestine in a process characterised by the formation of dysplastic crypts and adenomas similar to those found in humans. Therefore, it is widely accepted that constitutive activation of Wnt signalling caused by mutations in components of the pathway is responsible for the initiation of CRC (reviewed in Sancho et al, 2004; Figure 1).