Expression of Nodal, a
Transforming Growth Factor-beta (TGF-β) related
growth factor, is associated with aggressive
melanoma. Nodal expression in adult
dysplastic nevi may predict the development of aggressive
melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital
melanocytic nevi (LCMN) has shown increased risk for development of
melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop
melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric
dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed
melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced
tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when
melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in
melanoma cells cultured with melanocyte
conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating
radical oxygen species, to investigate potential
anti-oxidant effect of MDM on Nodal expression and signaling in
melanoma,
melanoma cells were treated with either
N-acetyl-l-cysteine (NAC), a component of the
anti-oxidant glutathione or synthetic
melanin, which in addition to providing pigmentation can also exert
free radical scavenging activity.
Melanoma cells treated with NAC or synthetic
melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated
melanoma cells. Thus, the potential role for Nodal in
melanoma development in LCMN is less evident than in adult
dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro-
melanoma effects of Nodal via
anti-oxidant effects of MDM.