Expression of the neuroendocrine cell marker 7B2 in human ACTH secreting tumours.

Abstract

Pro-opiomelanocortin gene expression is a ubiquitous phenomenon which takes place not only in the pituitary but also in many normal and tumoral non-pituitary tissues. However, the clinical features of the ectopic ACTH syndrome are rarely encountered. To further investigate this problem we examined series of normal human pituitaries and endocrine tumours evaluating the tissue content of pro-opiomelanocortin peptides, and the state of neuroendocrine differentiation as indicated by the biochemical marker 7B2. Tissue concentration of 7B2, pro-opiomelanocortin products (joining peptide and beta-endorphin) were measured in 13 pituitary corticotrophic adenomas and 13 non-pituitary tumours associated with the ectopic ACTH syndrome (five out of 20 bronchial carcinoid tumours, two out of 19 phaeochromocytomas, one out of 11 medullary thyroid carcinomas, three pancreatic and two thymic carcinoid tumours). Molecular weight forms of immunoreactive 7B2 and 7B2 RNA messenger were determined using Western and Northern blot analysis respectively. In all tissues examined, concentrations of immunoreactive beta-endorphin (fmol/mg tissue wet weight) showed widely distributed values from less than 0.7 to 1,340,000, which were correlated (r = 0.975, P less than 0.01) with that of immunoreactive joining peptide, another pro-opiomelanocortin fragment. In the 13 non-pituitary tumours associated with the ectopic ACTH syndrome, immunoreactive beta-endorphin concentrations ranged from 8.6 to 548,000, whereas in normal and tumoral pituitaries they varied from 16,600 to 364,800, and 5000 to 1,340,000, respectively. Immunoreactive 7B2 was detected in 67 of 68 neuroendocrine tumours. Tissue concentrations (fmol/mg tissue wet weight) of immunoreactive 7B2 varied from 135 to 1787 in pituitary tumours; from less than 0.5 to 555 in bronchial carcinoids; from 21.7 to 793 in phaeochromocytomas; from less than 1.6 to 948 in medullary thyroid carcinomas. Western blot analysis showed a predominant molecular weight form of immunoreactive 7B2 at 22 kDa. Northern blot analysis of RNA extracted from ACTH secreting pituitary and non-pituitary tumours showed a predominant signal hybridizing at 1.5 kb with a 7B2 probe. These results show that all ACTH secreting tumours have biochemical markers for neuroendocrine differentiation. Tissue concentrations of pro-opiomelanocortin peptides are variable, being extremely high in the most benign tumours and low in those with an aggressive growing pattern, and are not correlated with the biochemical neuroendocrine markers.