Figure 9: Schematic model on the role of Wnt secretion in APC mutant cells.

(a) In normal colon cells, Wnt signalling gradients originating at the bottom of colonic crypts determine cell identity. Low amounts of Wnt signalling lead to differentiation of epithelial cells of the colon. Under these conditions, wild-type APC serves as a scaffold, binding β-catenin and catalytic components of the destruction complex, thus sequestering it in the cytoplasm and causing its degradation. (b) In colon cancer cells, APC is truncated but retains some ability to bind β-catenin and act as a scaffold for the destruction complex. However, the efficiency of β-catenin retention is reduced in a manner related to the length of the truncated APC protein. Thus, APC truncations sensitize to canonical Wnts, allowing cancer cells to be more sensitive to activation by Wnt ligands, while retaining regulatory activity throughout the signalling cascade. Further, colon cancer cells acquire the ability to secrete Wnts in an autocrine manner, rendering the tumour increasingly independent of the original Wnt sources of the colonic crypts.