Fig. 7.

Proposed model for the chemical heterogeneity of eumelanin in the progression of melanoma and its relation to the pump-probe signal. Eumelanin formed by aggregation of thick oligomer stacks is primarily distributed in normal melanocytes. In this stage, the pump-probe signal of normal melanocyte is dominated by GSB. With the development of melanoma, the pigment experiences structural dissociation in lysosomal compartments such as autophagosomes and heterophagosomes. The structural alteration leads to small subunit fragments and makes the pump-probe signal heterogeneous, but this process is not effective because of its low susceptibility to oxidative degradation in the lysosomal compartments. On the other hand, population of eumelanin formed by aggregation of thin oligomer stacks (DHICA-derived eumelanin) increases with high level of DCT in melanoma. Because eumelanin composed of thin oligomer stacks is very susceptible to oxidative degradation, a large portion of newly generated eumelanin in melanoma undergoes structural dissociation. Small eumelanin fragments are shown to have a high capability to generate ROS. Thus, the structural dissociation of eumelanin leads to an increase in ROS levels, serving as signaling molecules for the promotion of melanoma proliferation and metastasis. In this phase, ESA signal is highly increased because of the generation of eumelanin formed by aggregate of thin oligomer stacks and small fragments. In metastatic melanoma, the high level of autophagy and eumelanin sensitive to oxidative degradation allows most of the pigmentation to be dissociated into small subunit fragments. Thus, pump-probe signals of metastatic melanomas are dominated by ESA.