Cancer initiation and progression are fuelled by cells with both stem cell and mesenchymal properties. The Wnt/β-catenin signal transduction pathway plays critical roles in these processes in colon cancer and in other Wnt-driven gastrointestinal cancers. Our aim is to understand how Wnt governs these properties.
The intestinal epithelium is a self-renewing tissue with a high turnover rate that is maintained by Lgr5 stem cells that reside at the base of glands (called crypts). Wnt/β-catenin signalling is crucial for normal Lgr5+ stem cell function, while aberrant activation of Wnt/β-catenin signalling in the Lgr5+ stem cells leads to the initiation of colon cancer. More specifically, Wnt3 or Wnt2b signalling is necessary for the maintenance and function of Lgr5+ stem cells. Recently we demonstrated that Fzd7 functions as a Wnt receptor in intestinal stem cells. Fzd7 expression is enriched in the Lgr5+ stem cells, and Wnt-dependent stem cell function is compromised in the absence of Fzd7. Furthermore, Fzd7 binds the stem cell Wnts, namely Wnt2b and Wnt3 (Flanagan et al., Stem Cell Reports, 2015). Intriguingly, the same FZDs and Wnts might also orchestrate transitions between epithelial and mesenchymal states during tumour invasion and metastasis. FZD7 is necessary for mesenchymal to epithelial transition (MET) to re-establish tumour formation from a dormant mesenchymal state (Vincan et al., Oncogene 2007). These roles that we have identified for FZD7 in stem cell function and MET, and our more recent studies in other Wnt-driven gastrointestinal cancers, make FZD7 an attractive therapeutic target that has the potential to impact on metastatic disease, which is the cause of death in most cancer patients (Phesse, Flanagan & Vincan, 2016).