The canonical Wnt signalling pathway and its APC partner in colon cancer development

Abstract

he flat surface of the colon is covered by an epithelium composed of four differentiated cell types (enterocytes, enteroendocrine, goblet and Paneth cells) that invaginates at regular intervals to form crypts (fig 1).The bottom of the crypts is occupied by a few stem cells that give rise to actively dividing precursor cells that populate the bottom two-thirds of the crypts. 1 Proliferation occurs under the influence of growth factors from the Wnt family that may be produced by the underlying stromal cells underneath the stem cell compartment or by the epithelial cells themselves.The precursors migrate upward in an ordered fashion, which is also controlled by Wnt factors, 2 and they stop proliferation when they reach the top third of the crypt, probably because they are too far from the Wnt source.Meanwhile, they continue their migration movement and colonise the surface of the colon.After about a week, epithelial cells undergo apoptosis and are shed in the lumen of the gut.The Paneth cells constitute an exception, as they migrate downward and occupy the very bottom of the crypt.Thus, the epithelium of the colon is under perpetual renewal.Wnt growth factors activate a cascade of intracellular events, which is known as the canonical Wnt pathway that ultimately leads to the expression of a genetic program controlling the co-ordinated expansion, fate and sorting of the epithelial cell population.In colorectal cancer, epithelial cells initially proliferate inappropriately because they acquired mutations in components of the pathway, thereby mimicking the effect of a permanent Wnt stimulation.Thus, the mutated cell recapitulates a progenitor-like phenotype, independent of its position in the epithelium. 3Canonical Wnt signalling has received considerable attention from cancer researchers over the years, because of its essential role in the homeostasis of the colonic epithelium and its deregulation in colorectal cancer and other tumours.This review attempts to summarise briefly our current understanding of the pathway in relation to its role in colorectal cancer development and to introduce how current knowledge may be used for the development of new treatments against this disease.