Shifting the Focus of Signaling Abnormalities in Colon Cancer

Simple Summary: The major signaling pathways in colon cancer are WNT, RAS, and TGF-beta. Components of these pathways are mutated in the majority of colon cancers, resulting in aberrantly high or low activity of the pathway. The functional consequences of the mutations reflect the behavior of these signaling pathways in intestinal stem cells. To better understand the roles of each pathway, we cover the basic function as well as points of intersection between the different pathways, to describe how they function individually, as well as together, to regulate cell proliferation. Colon cancer tumorigenesis occurs incrementally. The process involves the acquisition of mutations which typically follow an established pattern: activation of WNT signaling, activation of RAS signaling, and inhibition of TGF-beta signaling. This arrangement recapitulates, to some degree, the stem cell niche of the intestinal epithelium, which maintains WNT and EGF activity while suppressing TGF-beta. The resemblance between the intestinal stem cell environment and colon cancer suggests that the concerted activity of these pathways generates and maintains a potent growth-inducing stimulus. However, each pathway has a myriad of downstream targets, making it difficult to identify which aspects of these pathways are drivers. To address this, we utilize the cell cycle, the ultimate regulator of cell proliferation, as a foundation for cross-pathway integration. We attempt to generate an overview of colon cancer signaling patterns by integrating the major colon cancer signaling pathways in the context of cell replication, specifically, the entrance from G(1) into S-phase.