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. AGE IS A PROGNOSTIC FACTOR FOR MELANOMAAs human lifespan increases, there is a growing concern over the availability of treatments to manage the increasing incidence of cancer in aged individuals. Recently, comparison of melanoma incidence and mortality rates across different age groups indicated a worse prognosis with increasing age (Macdonald et al, 2011). Aged populations (those 470 years at the time of diagnosis) tend to have deeper primary melanomas as well as a higher number of metastasis than younger populations. Consequently, these aged patients are generally identified in the T3 or T4 stages of melanomas, where the primary lesion depth is 42 mm (T3) and 44 mm (T4). Aged patients also have a greater chance of recurrence (14.9% vs 3.4-6%, Po0.001, within 5 years of surgery) and higher mortality from the disease (29.8% vs 12.3%, Po0.001, 5 years after surgery; Macdonald et al, 2011). These data suggest it is critical to identify the molecular mechanisms for these variations in disease outcome.Factors such as changes in adaptive immunity, chronic inflammation and the accumulation of genetic damage over time have all been proposed as potential age-related factors in the ageinduced increase in cancer incidence and progression (Wolters and Schumacher, 2013;Zanussi et al, 2013). However, other data suggest that secreted factors in the aged microenvironment may also contribute to the age-induced progression of cancer. For example, it has long been proposed that the ageing stroma contributes to cancer progression, based on the studies using senescence as an artificial model of ageing (Campisi, 2013;Campisi and Robert, 2014). Senescent dermal fibroblasts have been shown to support the growth and invasion of melanoma cells in co-culture models (Kim et al, 2013), suggesting that naturally aged fibroblasts may have similar roles. This studies provide further insight into the age-related progression observed in melanoma and other cancers, and suggest that the microenvironment may have a dominant role in age-induced melanoma progression. It has been recently shown that Yu...

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