In situ analyses of molecular mechanisms of colorectal carcinogenesis

The main signaling pathways of colorectal carcinogenesis encompass the classical adenoma-carcinoma sequence and the serrated route. In the classical adenoma-carcinoma sequence there are initially frequent mutations of the APC gene which lead to an activation of the WNT signaling pathway. When the WNT signaling pathway is activated beta-catenin mediates the transcription of diverse factors which cause migration, invasion and proliferation of cells. Although APC mutations occur in all tumor cells, a heterogeneous distribution pattern of beta-catenin is found in tumors and beta-catenin also represents an important prognostic marker. A similar picture is found for gamma-catenin which is expressed independently from beta-catenin. Clearly more homogeneous is the expression of TCF4 and LEF1 which are the main binding partners of beta-catenin and gamma-catenin and are likewise important prognostic markers. The TRAIL signaling pathway is therapeutically interesting and within this pathway loss of the main receptors TRAIL-R1 and TRAIL-R2 is frequently found. Furthermore, the membranous localization of both factors correlates with a better overall survival. These results might be therapeutically relevant with respect to therapy with recombinant TRAIL molecules binding to TRAIL-R1 and TRAIL-R2. In the serrated route oncogen-induced senescence caused by mutations of the KRAS and BRAF oncogenes initially plays an important role. This senescence blockade is overcome by hypermethylation of the p16(INK4a) promoter and leads to the development of invasive tumors. The SIRT1 and c-Myc genes also contribute to progression of lesions in the serrated route and are activated through the RAS/RAF/MAPK-kinase signaling pathway as well as the WNT/beta-catenin signaling pathway.