TUMOR CELL SYNTHESIS AND SECRETION OF PEPTIDE HORMONES

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The objective of this research is elucidation of the molecular events in pituitary and nonpituitary tumor cells which regulate synthesis, storage, and secretion of polypeptide hormones, particularly, the hormones derived from pro-opiolipomelanocortin (POMC). We examined pheochromocytomas and normal adrenal medulla for the presence of immunoreactive (IR)-POMC peptides and the hypothalamic peptide, corticotropin-releasing hormone (CRH), that stimulates pituitary POMC secretion. We found all of the POMC peptides in normal and neoplastic adrenomedullary extracts. The ACTH in one pheochromocytoma was fully biologically active. We also found about equal parts of intact CRH and Met21-O-CRH. The intact CRH was full bioactive. None of pheochromocytoma patients had clinical evidence for ectopic ACTH or CRH production. The significance of the coexistence in the adrenal medulla of POMC peptides with CRH, their releasing hormone in the pituitary, and of the presence of POMC peptides adjacent to the adrenal cortex, whose function they help regulate, remains to be elucidated. However, our data do suggest that "ectopic" production of ACTH by adrenomedullary tumors is more appropriately termed "inappropriate." We have also determined the nucleotide sequence of cDNA to POMC mRNA from a cultured human small cell lung carcinoma line. The 795 bases code for all except the extreme N-terminus of POMC. With the exception of a conservative G-to-T base change, the sequence is identical to that of genomic POMC DNA from human placenta and fetal liver. Northern blot analysis reveals two mRNA species with approximate sizes of 1,300 and 1,550, as compared to 1,200 for human pituitary mRNA. The presence of higher molecular weight POMC mRNA has been noted in three other nonpituitary tumors. These data indicate that ectopic POMC and, presumably, other ectopic hormones represent inappropriate expression of normal genes. However, POMC mRNA may be incompletely or abnormally processed in tumor cells. (C)