PROPROTEIN CONVERTASES (PC1 PC3 AND PC2) IN NORMAL AND NEOPLASTIC HUMAN TISSUES - THEIR USE AS MARKERS OF NEUROENDOCRINE DIFFERENTIATION/

By immunocytochemistry and immunoblotting, we examined normal and neop lastic human tissues with polyclonal antibodies raised against selecte d peptide regions of proprotein convertase-2 and -3 (PC2 and PC3), two proteases that have been shown to selectively cleave neuroendocrine p recursor molecules at pairs of basic residues. Immunoreactivity for bo th enzymes was detected in neuroendocrine cells of pituitary, gut, pan creas, thyroid, and adrenals and in tumors thereof, but was absent in thyroid follicular cells, parathyroids, adrenal cortex, testes, and a number of nonneuroendocrine tissues, both normal and tumorous. Althoug h both PCs were virtually universal concomitants of the neuroendocrine system, cells with a neural phenotype (e.g. pheochromocytes and Merke l cells) predominantly contained PC2, whereas classic endocrine cells contained mostly PC3. PC3 immunoreactive cells were abundant all along the gastrointestinal tract, whereas PC2 was highly expressed only in the pyloric antrum and proximal third of duodenum. Double immunostaini ng experiments revealed colocalization of PC3 with virtually all gastr ointestinal peptides, whereas PC2 immunoreactivity was mostly expresse d in gastrin, cholecystokinin, and somatostatin cells. Noticeably, the proportion of glucagon-producing cells immunoreactive for PC3 was hig h in the gut and low in pancreatic islets and glucagonomas, whereas th e reverse occurred for PC2. At the ultrastructural level, immunostaini ng was confined to the mature dense core granules, the site of storage of granins and peptide hormones. With the exception of parathyroid ce lls, PC2 and/or PC3 expression correlated with the occurrence of grani ns, canonical markers of the secretory granules. Immunoblotting experi ments confirmed the identity of the immunocytochemical reactivities. I t is concluded that PC2 and PC3 are highly sensitive markers of neuroe ndocrine differentiation and have distinct distribution patterns, and that antibodies to these enzymes may play an important role in the ana lysis of tumors.