Although a critical role of the endothelin (ET) system in differentiation of neural crest cells has been reported, implication of the ET system in human neuroblastic tumors has not been fully elucidated. We immunohistochemically examined for localization of ET-1, ET-3, ET-A receptor (ET-A), and ET-B receptor (ET-B) in 24 ganglioneuromas, 8 ganglioneuroblastomas, 37 neuroblastomas, 14 normal sympathetic ganglia, and 10 fetal adrenal glands with regard to neuroblastic cell differentiation. Neuroblasts in fetal adrenal glands expressed ET-B (100%) alone. Immature ganglionic cells in sympathetic ganglia of fetus frequently expressed ET-1 (86%) and ET-B (100%), while ET-A was occasionally detected (28%). Ganglionic cells of mature adult ganglia consistently harbored ET-1 (100%) and, infrequently, ET-3 (21%) or ET-B (29%). Expression of ET-1 and ET-B was closely associated with tumor cell differentiation: the expression frequency of ET-1 or ET-B was 16% or 46% in neuroblastomas; 100% or 88% in ganglioneuroblastomas; and 96% or 92% in ganglioneuromas. In contrast, ET-3 and ET-A showed no association with tumor cell differentiation: the expression frequency of ET-3 or ET-A was 26% or 14% in neuroblastomas; 63% or 13% in ganglioneuroblastomas; and 29% or 21% in ganglioneuromas. In conclusion, ET-1 and ET-B are expressed with differentiation of neuroblastic tumors.
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