Localization and Characterization of Endothelin Receptors in Human Gliomas: A Growth Factor?

Localization and characterization of endothelin receptors in surgical specimens of human gliomas (6 benign astrocytomas and 7 glioblastomas multiforme) and in normal human cortices were studied using quantitative receptor autoradiographic methods. Low numbers of [125 I]endothelin-1 ([125I] ET-1) binding sites were detected in the gray matter of the human frontal cortex, with little binding in the white matter. Conversely, relatively high numbers of [125I]ET-1 binding sites were homogeneously present in tissue sections derived from astrocytomas, whereas higher numbers of [125I]ET-1 binding sites were heterogeneously located on groups of cells with a pseudopalisading appearance and pleomorphic astrocytes in glioblastoma multiforme. Necrotic areas within the tissue sections derived from glioblastoma were devoid of binding. Binding of [125I]ET-1 to gliomas and normal gray matter was specific. Unlabeled ET-1 and its natural analogs (ET-2 and ET-3) inhibited the binding of [125I]ET-1 to these lesions in a concentration-dependent manner and with similar high potencies. Possibly related substances, such as ion channel regulators (w-conotoxin. apamin. and tetrodotoxin). a Ca2+channel blocker (nicardipine). and growth factors (epidermal growth factor and insulin-like growth factor I). did not affect the binding to tissue sections derived from gliomas or from normal frontal cortices. Scatchard analysis revealed the presence of a single class and high-affinity binding sites for endothelin in normal cortex and in gliomas. There was no significant difference in the binding affinities: dissociation constants (Kd) were 2.1 ± 0.5 nM in 6 astrocytomas, 2.5 ± 0.4 nM in 7 glioblastomas. and 1.4 and 1.5 nM in two normal cortices. The concentrations of [125I]ET-1 binding sites were significantly higher in glioblastomas than in astrocytomas: the maximum number of binding sites (Bmax) was 30 ± 6 fmol/mg in 6 astrocytomas and 60 ± 11 fmol/mg in 7 glioblastomas (P < 0.05. F= 5.61), and 14 and 16 fmol/mg in two normal cortices. These observations suggest the presence of a specific receptor for endothelin in human gliomas. Endothelin may be involved in the modulation of growth in gliomas.