Peptide Products of the Neurotrophin-Inducible Gene vgf Are Produced in Human Neuroendocrine Cells from Early Development and Increase in Hyperplasia and Neoplasia

Abstract

Although the neurotrophin-inducible gene vgf is expressed in mammalian neurons and endocrine cells, limited data is available in man. The objective of the study was to map proVGF peptides in human endocrine cells during development, adulthood, hyperplasia, and tumors. Antisera were generated against peptides related to internal cleavage or cleavage-amidation sites (rat proVGF(422-430) and human proVGF(298-306)-NH2) and the proVGF C-terminal ending (human proVGF(607-615)). Developing and normal adult endocrine cells, hyperplastic endocrine lesions (thyroid, parathyroid, lung, and stomach), and 120 tumors (102 endocrine) were studied. Immunogold electron microscopy was performed on normal adult pancreas and gut, and Western blotting was performed on extracts of control tissues and endocrine tumors. proVGF fragments were revealed in developing pituitary, gut, pancreas, and adrenal medulla from 10 gestational weeks, in normal adult pituitary and adrenal medulla, pancreatic glucagon, and insulin cells and gut serotonin cells, in hyperplastic thyroid calcitonin cells, lung P cells, gastric enterochromaffin-like cells, and gastrin cells, and in 88 of 102 endocrine tumors. At electron microscopy proVGF immunoreactivity was restricted to electron-dense granules. Western blotting revealed large molecular weight forms and cleavage fragments in both control tissues and tumor extracts. proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.