Wnt Signaling in Cancer: Not a Binary ON:OFF Switch

Abstract

In the March 1 issue of Cancer Research, we identified the Wnt receptor Fzd7 as an attractive therapeutic target for the treatment of gastric cancer. In summary, we showed that pharmacological inhibition of Wnt receptors, or genetic deletion of Fzd7, blocks the initiation and growth of gastric tumors. Inhibiting Fzd receptors, specifically Fzd7, inhibits the growth of gastric cancer cells even in the presence of adenomatous polyposis coli (Apc) mutation. Apc is located in the cytoplasm downstream of Fzd7 in the Wnt signaling cascade and APC mutations activate Wnt/β-catenin signaling, therefore, this result seems counterintuitive. Here, we analyze this result in greater detail in the context of current knowledge of Wnt signaling and discuss the wider implications of this aspect of Wnt signaling in other cancers.

Figure 1. Wnt signalling with mutant Apc.

A. The levels of cytoplasmic β-catenin are regulated by the degradation complex which is inhibited when Wnt signalling is active (left hand panel). In Apc mutant cells it is often misconceived that Apc is completely deleted and therefore the degradation complex is non-functional and Wnt signalling cannot be regulated upstream of the degradation complex at the level of the receptor/ligand (illustration faded out, central panel). However mutant Apc is transcribed and translated resulting in a compromised, yet functional, β-catenin degradation complex which explains how upstream factors including sFRP, Dkk and Fzd inhibitors can still modulate Wnt signal activity (right hand panel). B. Immunohistochemistry for β-catenin in a human colorectal carcinoma showing increased nuclear localisation, as a surrogate marker of active Wnt, in the invasive front compared to the tumour center (from Brabletz et al. Pathol Res Pract. 1998;194:701-4).

Figure 2. Alteration of Wnt pathway components in epithelial cancers.

Analysis of selected datasets from The Cancer Genome Atlas (TCGA) for mutations, amplifications and deletions of either intracellular (APC, β-catenin, Axin2 and Dvl) or receptor (e.g. WNTs, FZDs, RNF43, sFRP) pathway components. Relative frequency of genetic alterations shown as percentages. NSCLC = Non small cell lung cancer; CRC = Colorectal cancer; GBM = Glioblastoma. This figure was generated using data available at www.cbioportal.org.