corticotropin-like-intermediate-lobe-peptide and Thymus-Neoplasms

POMC processing is frequently altered in ACTH-secreting nonpituitary tumors in which intermediate lobe-like peptides such as corticotropin-like intermediate lobe peptide (CLIP) are occasionally generated. In rodent pituitaries, the exclusive presence of prohormone convertase PC2 in the melanotrophs of the intermediate lobe is responsible for the specific conversion of ACTH to alpha MSH and CLIP, by contrast with corticotrophs of the anterior lobe, which do not contain PC2 and, therefore, only produce ACTH. The goal of our study was to look for PC2 expression in ACTH-secreting nonpituitary tumors in man. Using Northern blot analysis, PC2 transcripts were detected in five nonpituitary tumors that contained large proportions of CLIP (from 40-95% of the total C-terminal immunoreactive ACTH). A predominant PC2 messenger ribonucleic acid migrated with an apparent mol wt of 5 kilobases, and a minor signal at 3 kilobases was also detected. No PC2 messenger ribonucleic acid could be detected in the small cell carcinoma of the lung-derived DMS-79 human cell line, which produces unprocessed POMC, or in three pituitary tumors responsible for Cushing's disease or Nelson's syndrome, which produced intact ACTH, but no CLIP. These data strongly suggest that, as in rodents, PC2 is responsible for the production of smaller POMC end products, such as CLIP, frequently observed in ACTH-secreting nonpituitary tumors in man.

Topics: Adrenocorticotropic Hormone; Base Sequence; Bronchial Neoplasms; Carcinoid Tumor; Carcinoma, Small Cell; Corticotropin-Like Intermediate Lobe Peptide; DNA, Neoplasm; Humans; Lung Neoplasms; Molecular Sequence Data; Peptide Fragments; Pituitary Neoplasms; Proprotein Convertase 2; Subtilisins; Thymus Neoplasms; Tumor Cells, Cultured

In order to evaluate which of human (h) corticotrophin-like intermediary lobe peptide (CLIP) or h beta-melanocyte stimulating hormone5-22 (h beta MSH5-22) was the better marker of alternate pro-opiomelanocortin (POMC) processing, both peptides were simultaneously sought in the same tissue extracts from a normal human pituitary, six corticotrophic adenomas, and four non-pituitary tumours responsible for an ectopic ACTH syndrome. Human CLIP was detected using a combination of gel exclusion chromatography and two different radioimmunoassays (RIAs): a mid-ACTH RIA which recognized ACTH but not CLIP, and a COOH-ACTH RIA which recognized both molecules. Human beta MSH5-22 had been measured previously. Neither hCLIP nor h beta MSH5-22 were detected in the normal or tumoural pituitaries. The four non-pituitary tumours, in contrast, contained both peptides; the hCLIP and h beta MSH5-22 ratios (CLIP/CLIP + ACTH and h beta MSH5-22/h beta MSH5-22 + h gamma LPH) ranged from 40 to 94% and from 24 to 46%, respectively. In a given tissue the hCLIP ratio was always higher than the h beta MSH5-22 ratio. hCLIP is therefore the better marker of alternate POMC processing.

Topics: ACTH Syndrome, Ectopic; Adenoma; Adrenocorticotropic Hormone; Biomarkers, Tumor; Bronchial Neoplasms; Carcinoid Tumor; Chromatography, Gel; Corticotropin-Like Intermediate Lobe Peptide; Humans; Melanocyte-Stimulating Hormones; Paraneoplastic Endocrine Syndromes; Peptide Fragments; Pituitary Neoplasms; Pro-Opiomelanocortin; Radioimmunoassay; Thymus Neoplasms