Wnt pathway and its involvement in oncogenesis

   Wnt proteins are cysteine-rich secreted ligands, involved in development control in organisms ranging from worm to mammals. 19 Wnt members are expressed in mammals and are classified in two distinct groups based upon their ability to induce transformation in mouse mammary epithelial cell line C57MG. The highly transforming group includes Wnt1, Wnt3, Wnt7a, while the intermediately or non transforming members are Wnt2, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7b, Wnt11. The two classes of Wnts signal through different pathways and lead to different developmental outcomes. In the “canonical pathway” activation of beta-catenin mediates signal transduction.

   Briefly, in absence of Wnt ligands, cytoplasmatic beta-catenin is phosphorylated by a destruction complex composed of Axin, Adenomatous polyposis coli protein (APC) and glycogen synthase kinase 3B. Phosphorylated beta catenin is also ubiquitinated and degraded in proteosoma. In contrast, when Wnt interacts with Frizzled serpentine receptors and their co-receptors LRP5 and/or 6, the destruction complex is inhibited. Indeed, axin is relocated to the membrane where is inactive. Thus, beta-catenin accumulates in the cytoplasm and after its translocation into the nucleus forms a complex with TCF/LEF family proteins. This interaction allows the specific activation of gene expression. Some Wnt proteins can activate a beta-catenin independent signalling, namely the “non canonical pathway”. This activation occurs via three different mechanisms. Specific Wnts and Fz receptors can increase the intracellular calcium concentration through trimeric GTP-binding proteins and activate calcium/calmodulin-dependent protein kinase II and protein kinase C (PKC). Otherwise, Wnt-Fz complexes act through heterotrimeric G proteins to activate phospholipase C and phosphodiesterase. Lastly, Fz mediates the planar cell polarity pathway which activates small G proteins, including Rac and Rho, c-Jun N-terminal kinase (JNK) and Rho-associated kinase. Even if two classes of Wnt proteins have been proposed, is not totally clear which pathways are activated by each Wnt. It seems that the receptor context determines Wnt signalling output, suggesting a major complexity in the Wnt cascade control with relevant implications in development and disease, such as cancer. Indeed, Wnts are, for instance, genetically altered in MMTV-induced tumour or overexpressed in many breast cancer cell lines.

   Over-expression of WNT3a, WNT4, WNT6, WNT8b, WNT9a, WNT10b that signal through the canonical pathway correlates with a poor prognosis. Colon cancer seems also affected and caused by alteration of Wnt canonical pathway. Several studies are publishing on this topic because it’s very interesting and important and recently, the evidence that cancer stem cells use Wnt pathway to maintain their stemness has made this pathway much more crucial. Further works will clarify the role of each Wnt pathway component in order to figure out how this pathway works. Moreover, Wnt pathway will be a possible therapeutic target and each protein will be validated and inhibited. The opportunity to attack cancer against multiple sides is largely accepted by the scientific community. In this vision, the inhibition of Wnt pathway could give a significant contribution.