Superficial spreading melanoma is the most common histologic subtype in Caucasians, accounting for around 70% of newly diagnosed disease. It generally follows a radial growth phase, beginning in the epidermis (melanoma in situ), and spreading laterally with minimal extension into the dermis. The presence of atypical MCs, either as single cells or nests at all levels of a usually slightly thickened epidermis, essentially defines SSM (Smoller, 2006). Over time, vertical growth can be initiated, with melanoma cells extending, usually in dense sheets, throughout the dermis. Clinically, the depth of extension into the dermis, and rarely into the subcutis, is highly predictive of outcome (Balch et al., 2001). Hence, it is critical to understand how melanoma cells behave in the dermis, where they are totally separated from any possible restraining influence of keratinocytes. Superficial spreading melanoma can arise from a pre-existing common or atypical naevus (in about 35% of cases), or de novo, skipping a premalignant naevus phase altogether (Bevona et al., 2003).
As BRAFV600E is the predominant oncogenic event in SSM (Table 2, Lee et al., 2011), to recapitulate SSM, we might begin by expressing this mutation in mice. Several such models have been generated. Two transgenic mouse lines expressing BrafV600E constitutively in MCs have been created by Goel et al. (2009). The higher expressing line developed senescent naevi, and melanoma, whereas the low expressing line had naevi and only few melanomas. In addition, ‘knock-in’ models that enable conditional expression of BrafV600E under control of its endogenous promoter have been reported. One model, from Martin McMahon’s laboratory, had hyperpigmentation and naevi with heterozygous and homozygous expression of BrafV600E and no melanomas. Deletion of Pten was required for overt neoplasia (Dankort et al., 2009). The second model, utilized by Richard Marais’ group, also developed naevi, with melanomas appearing in approximately 50% of heterozygous BrafV600E mice by 1 yr of age (Dhomen et al., 2009). Disparities between these two studies could pertain to BrafV600E expression level or genetic background differences. Interestingly, increased copy numbers of mutant BRAFV600E may be found in a proportion of human lesions showing that variation in mutant BRAF expression level is important in human melanomagenesis (e.g. Willmore-Payne et al., 2006). Despite some differences between these models, they both confirm the role of BrafV600E as a melanoma initiator.
Nonetheless, mouse BrafV600E lesions are located almost totally within the dermis, and therefore like most other models, they do not recapitulate some of the key features of human SSM. For example, a radial growth phase is absent prior to tumour extension into the dermis. This is likely related to the underlying absence of epidermal MCs, at least in hair-covered mouse skin, and the fact that in virtually all mouse models, the introduction of mutations into MCs, by genetic engineering (Damsky and Bosenberg, 2010), or via carcinogen treatment (Shapiro et al., 1996), results in the appearance of melanocytic proliferations in the interfollicular dermis, apparently the preferred location of ‘initiated’ MCs in mouse skin. However, it should be noted that some epidermal involvement does occur, particularly in the ear, tail and footpads, when mutant Braf MCs are further destabilized by concomitant deletion of Pten (Dankort et al., 2009). One potentially very good murine model for SSM is the Mt-Hgf transgenic, in which melanomas often exhibit pagetoid spread (Noonan et al., 2001). After neonatal UVR exposure, these mice tend to develop epidermal lesions (Noonan et al., 2001), suggesting that the Mt-Hgf mice may model SSM arising after intermittent sun exposure. K14-Kitlg mice, which have epidermal MCs throughout life (Kunisada et al., 1998), may represent another. When combined with Tyr-NrasQ61K::Arf−/− mice that had only dermal lesions (Figure 1A), Tyr-NrasQ61K::Arf−/−::K14-Kitlg mice developed epidermal lesions reminiscent of SSM (Figure 1B), characterized by atypical MCs within all levels of the epidermis. Atypical MCs were to some extent also present beneath the epidermis in the papillary dermis. In addition, we have generated Tyr-NrasQ61K::Cdk4R24C/R24C::K14-Kitlg mice (G. Walker, unpublished) and found that lesions once more exhibit significant epidermal involvement (Figure 1C) and are evocative of human SSM (Figure 1D). In these models, the localization of the murine lesions is totally controlled by only one keratinocyte cytokine, Kitlg. The presentation of melanomas in the epidermis of K14-Kitlg and Mt-Hgf mice suggests that dermal location of melanoma no longer presents an insurmountable barrier for mouse models to recapitulate key features of human melanoma. As reproducing SSM in mice is in its infancy, modelling of the vertical growth phase has not yet been performed. Interestingly, mice carrying K14-Kitlg along with MC-specific Grm1 activation (Abdel-Daim et al., 2010) developed melanomas earlier than MC-specific Grm1 alone, but all lesions were dermal. Why this is different from the above models is unknown, but genetic modification design differences and strain background differences must be examined. One important complication is that in the Tyr-NrasQ61K model, all MCs express the mutation developmentally, whereas in the Grm1 model, the oncogene is only activated in adult mice. However, it is tempting to consider that Grm1 activation may override the effects of K14-Kitlg, again underlining the idea that particular genes specify either dermal or epidermal location of MCs and lesions. Notably, Gnaq and Gna11, which act in the same signalling pathway as Grm1, seem to confer dermal location of both murine and human melanocytic lesions (Van Raamsdonk et al., 2010).