During embryonic development, melanoblasts, the precursors of melanocytes, emerge from a subpopulation of the neural crest stem cells and migrate to colonize skin.
Melanomas arise during melanoblast differentiation into melanocytes and from young proliferating melanocytes through somatic mutagenesis and epigenetic regulations. In the present study, we used several human
melanoma cell lines from the sequential phases of
melanoma development (radial growth phase, vertical growth phase and metastatic phase) to compare: (i) the frequency and efficiency of the induction of cell death via apoptosis and necroptosis; (ii) the presence of neural and cancer stem cell
biomarkers as well as
death receptors, DR5 and FAS, in both adherent and spheroid cultures of
melanoma cells; (iii) anti-apoptotic effects of the endogenous production of
cytokines and (iv) the ability of
melanoma cells to perform neural trans-differentiation. We demonstrated that programed
necrosis or necroptosis, could be induced in two metastatic
melanoma lines, FEMX and OM431, while the mitochondrial pathway of apoptosis was prevalent in a vast majority of
melanoma lines. All
melanoma lines used in the current study expressed substantial levels of pluripotency markers, SOX2 and NANOG. There was a trend for increasing expression of
Nestin, an early neuroprogenitor marker, during
melanoma progression. Most of the
melanoma lines, including WM35, FEMX and A375, can grow as a spheroid culture in
serum-free media with supplements. It was possible to induce neural trans-differentiation of 1205Lu and OM431
melanoma cells in
serum-free media supplemented with
insulin. This was confirmed by the expression of neuronal markers, doublecortin and β3-Tubulin, by significant growth of neurites and by the negative regulation of this process by a dominant-negative Rac1N17. These results suggest a relative plasticity of differentiated
melanoma cells and a possibility for their neural trans-differentiation without the necessity for preliminary dedifferentiation.