EXPRESSION AND PROCESSING OF PARATHYROID HORMONE-RELATED PROTEIN IN A PANCREATIC ENDOCRINE CELL TUMOR-ASSOCIATED WITH HYPERCALCEMIA

We describe a patient with a neuroendocrine tumour of the pancreas associated with hypercalcaemia which was attributed to production of parathyroid hormone-related protein (PTHrP) by the tumour. Plasma PTHrP 1-86 was significantly raised, and fell following surgical resection of the tumour. PTHrP mRNA and peptide were identified in tumour tissue by in-situ hybridization and immunohistochemistry respectively. PTHrP was quantitated in an extract of tumour tissue by three region-specific immunoassays (PTHrP 1-34 45.2 pmol/g, PTHrP 37-67 81.7 pmol/g, PTHrP 1-86 27.3 pmol/g) and suggested the presence of excess of amino-terminal and mid-region immunoreactivity. On chromatography of the tumour extract the first peak eluted as 22 kDa and comprised approximately equimolar 1-34, 37-67 and 1-86 activities. The second and major peak of 16 kDa contained only 37-67 activity, while the third peak of 6 kDa contained only 1-34 activity. This suggested that the tumour contained a native or intact form of PTHrP together with two major sub-fragments containing 37-67 and 1-34 activity respectively. Thus chromatographic separation and quantitation of PTHrP by region-specific immunoassays have provided new information on in-vivo proteolytic processing by tumour tissue by indicating that a site of cleavage is located between residues 17 and 61. Our findings are compatible with cleavage at residue 37, a site previously indicated from in-vitro studies.