The cellular and molecular basis of the ectopic ACTH syndrome.
In recent years the techniques of molecular and cellular biology have made it possible to begin to dissect the origins and behaviour of the ACTH-secreting tumour cell. It is becoming apparent that these tumours represent undifferentiated neuroendocrine cells, and it may be that their peptide-secreting properties may have no more sinister oncological significance. However, an autocrine role for beta-endorphin may confer a selective growth advantage on the POMC-expressing cell. It is still not clear why glucocorticoids fail to inhibit the POMC gene in these extra-pituitary tumours despite the presence of glucocorticoid receptors. This may not be resolved until the mechanism for inhibition of POMC by glucocorticoids in the normal pituitary is understood, although it is tempting to speculate that a mutation in the glucocorticoid receptor or a tissue specific interaction is responsible for the resistance of POMC observed in the ectopic ACTH syndrome. In studying the peptides secreted by the extra-pituitary tumours responsible for the ectopic ACTH syndrome it would appear that direct measurement of ACTH precursors and comparison with the circulating concentrations of ACTH can give valuable information on the percentage of tumours which do not effectively process the ACTH precursors. However, far more data have to be collected on patients with occult tumours in order to identify whether this type of processing is tissue specific. Nevertheless, these studies provide useful insights into the mechanisms of intracellular signalling and regulation in such tumours which may identify unique pharmacological tools to inhibit ACTH secretion or more importantly tumour growth.
Department of Medicine, University of Manchester, Hope Hospital, Salford, UK.
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Clark
D000182:ACTH Syndrome, Ectopic / Q000235:genetics* / Q000473:pathology; D000310:Adrenal Gland Neoplasms / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D002276:Carcinoid Tumor / Q000235:genetics; D018288:Carcinoma, Small Cell / Q000235:genetics*; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics*
D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone