Medullary Thyroid Carcinomas Secrete a Noncalcitonin Peptide Corresponding to the Carboxyl-Terminal Region of Preprocalcitonin

The amino acid sequence of human preprocalcitonin predicted from complementary DNA analyses indicates that the 32-amino-acid sequence of calcitonin is internally situated. Extending beyond the carboxyl-terminal proline of the calcitonin sequence is a 25-amino-acid segment which contains the tetrapeptide Gly-Lys-Lys-Arg linking calcitonin to the remaining 21 amino acids. Our objective was to examine whether human medullary thyroid carcinomas (MTCs) elaborate a noncalcitonin peptide corresponding to the carboxyl terminus of human preprocalcitonin. An acidic peptide identical to the predicted terminal 21-amino-acid sequence of human preprocalcitonin was synthesized for establishing a RIA. We used gel filtration, isoelectric focusing, and high pressure liquid chromatography to demonstrate immunoreactive peptide(s) with size, charge, and hydrophobicity similar to the 21-amino-acid synthetic peptide in MTCs and nonneoplastic thyroid. The immunoreactive noncalcitonin peptide was present in these tissue extracts in amounts approximately equimolar to calcitonin. A similar immunoreactive noncalcitonin peptide was detected in hypercalcitoninemic plasmas from MTC patients; such circulating immunoreactivity was undetectable (<0.25 ng/ml) in thyroidectomized or normal persons. The circulating levels of immunoreactive noncalcitonin peptide and calcitonin in MTC patients were directly correlated, their ratio remaining nearly equal over a 30, 000-fold concentration range. Pentagastrin infusion of MTC patients concurrently raised circulating levels of calcitonin and noncalcitonin-peptide immunoreactivities. After curative thyroidectomy, serum levels of calcitonin and the noncalcitonin peptide were undetectable during pentagastrin infusion. Primary cultures of human MTC cells secreted approximately equal amounts of the immunoreactive noncalcitonin peptide and calcitonin. These results suggest that human MTCs and perhaps nonneoplastic human C cells cosecrete two peptides, calcitonin and a 21-amino-acid noncalcitonin peptide, which are probably derived from a common precursor.