In the Wnt-er of life: Wnt signalling in melanoma and ageing

Abstract

Although the clinical landscape of melanoma is improving rapidly, metastatic melanoma remains a deadly disease. Age remains one of the greatest risk factors for melanoma, and patients older than 55 have a much poorer prognosis than younger individuals, even when the data are controlled for grade and stage. The reasons for this disparity have not been fully uncovered, but there is some recent evidence that Wnt signalling may have a role. Wnt signalling is known to have roles both in cancer progression as well as in organismal ageing. In melanoma, the interplay of Wnt signalling pathways is complex, with different members of the Wnt family guiding different aspects of invasion and proliferation. Here, we will briefly review the current literature addressing the roles of different Wnt pathways in melanoma pathogenesis, provide an overview of Wnt signalling during ageing, and discuss the intersection between melanoma and ageing in terms of Wnt signalling.

Figure 1

Schematic representation of Wnt signalling in the aged microenvironment of melanoma. In melanoma cells, β-catenin signals to increase microphthalmia transcription factor (MITF), which in turn can signal to activate the base-excision repair endonuclease, APE1. This enzyme acts to protect the cells from ROS-induced DNA damage. MITF also signals to increase transcription of melanoma-associated antigens such as MART1, which is processed, presented on the surface of the cell and acts to increase the influx of cytotoxic T cells. During ageing, aged fibroblasts secrete sFRP2, which inhibits canonical Wnt signalling such as Wnt1 and Wnt3a. Inhibiting canonical Wnts inhibit β-catenin, resulting in an ablation of this protective signalling cascade. This allows the cells to accumulate DNA damage and become more genomically unstable. This also leads to less antigen presentation, and therefore, a decreased susceptibility to cytotoxic T cells.