Subcellular distribution of somatostatin sst2A receptors in human tumors of the nervous and neuroendocrine systems: Membranous versus intracellular location

The distribution of the sst2A receptor was investigated, using immunohistoc hemistry, with the specific antipeptide antibody R2-88, in a total of 120 t umors of the nervous and the neuroendocrine systems, including small-cell l ung carcinomas, medulloblastomas, neuroblastomas, pheochromocytomas, and pa ragangliomas. The great majority of the tumor samples, frozen or formalin-f ixed, showed a positive immunohistochemical staining with R2-88, and an exc ellent correlation with receptor autoradiography using I-125[Tyr(3)]-oct- r eotide. Whereas small-cell lung carcinomas and medulloblastomas had a predo minantly plasma membrane staining, pheochromocytomas and neuroblastomas had variable ratios of cell surface and intracellular staining. Strikingly, a preferentially cytoplasmic staining was seen in tumors with a high level of somatostatin gene expression, whereas a more plasma membranous staining wa s seen in tumors lacking somatostatin messenger RNA. Specificity of both th e plasma membrane and the cytoplasmic staining pattern was confirmed in imm unoblots, which showed the immunoreactive receptor migrating as a character istic 70-kDa broad band. In both immunohistochemical and immunoblotting exp eriments, staining was abolished by antibody blockade with 100 nM antigen p eptide. These results describe, for the first time, the localization of the sst2A receptor protein in human small-cell lung carcinomas, medulloblastom as, neuroblastomas, and paragangliomas. Moreover, it is the first report in vestigating possible causes for distinct subcellular localizations of sst2A in human tissues. We show that the subcellular distribution of the recepto r may be dependent on the surrounding somatostatin concentration, consisten t with both the known effect of somatostatin to cause sst2A receptor intern alization and an autocrine regulation of tumors by the peptide they produce . Moreover, our demonstration that the sst2A receptor can be identified in this group of tumors using simple immunohistochemical methods in formalin-f ixed, paraffin-embedded material opens numerous diagnostic, therapeutic, an d prognostic opportunities.