Melanocyte-endothelial melanomas: Plasticity and transdifferentiation in melanomas

Abstract

Melanomas with extensive metastasis can rarely regress on the appearance of a halo nevus (HN). This study explores the possiblefactors involved. The component melanocytes of HN, flatten, depigment and line vascular spaces to replace and result in theinvolution of the nevus. This simulates vasculogenesis in amelanotic melanomas, malignant melanocytes differentiating intoendothelial cells. The reverse is seen in pigmented tumors. Nestin positive endothelial cells lining angiogenic tubes, enter thetumor margins, show glial differentiation and form transient tumor vascular complexes (TVC) with stepwise neural differentiationand pigment laden cells, suggesting transdifferentiation of endothelial cells to melanocytes. During development, a range ofmolecular tools are used by blood vessels as well as nerves, including ephrins/Eph, NP-I and Notch signalling. This is vindicatedby morphologic evidence of melanocyte/endothelial transdifferentiation as shown in this study. These observations, suggesta common multipotent stem cell, differentiating into vascular and melanocyte/neural stem cell depending on the surroundingmicroenviroment. Concurrent tumor regression may involve a rapid transdifferentiation triggered by a molecular switch or shutdown of the common stem cell and/or presence of circulating antibodies to melanomas released on the appearance of HN.