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¹ INSERM U413, EA4310, IFRMP 23, Laboratory of Differentiation and Neuronal and Neuroendocrine Communication, University of Rouen, Mont Saint Aignan 76821, France² Department of Endocrinology, Institute for Biomedical Research, University Hospital of Rouen, University of Rouen, Rouen 76031, France³ INSERM U833, Laboratory of Embryological ad Pathological Angiogenesis, Collège de France, Paris 75005, France⁴ , Laboratory of Biochemistry⁵ Department of Pathology, Institute for Biomedical Research, University Hospital of Rouen, University of Rouen, Rouen 76031, France

(Correspondence should be addressed to H Lefebvre who is now at EA4310, IFRMP 23, INSERM U413, Department of Endocrinology, Hospital of Boisguillaume, CHU of Rouen, 76031 Rouen Cedex, France; Email: herve.lefebvre{at}chu-rouen.fr)

Abnormal expression of membrane receptors has been previously described in benign adrenocortical neoplasms causing Cushing's syndrome. In particular, we have observed that, in some adreno corticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia tissues, cortisol secretion is controlled by ectopic serotonin₇ (5-HT₇) receptors. The objective of the present study was to investigate in vitro the effect of serotonin (5-hydroxy tryptamine; 5-HT) on cortisol and renin production by a left adrenocortical carcinoma removed from a 48-year-old female patient with severe Cushing's syndrome and elevated plasma renin levels. Tumor explants were obtained at surgery and processed for immunohistochemistry, in situ hybridization and cell culture studies. 5-HT-like immunoreactivity was observed in mast cells and steroidogenic cells disseminated in the tissue. 5-HT stimulated cortisol release by cultured cells. The stimulatory effect of 5-HT on cortisol secretion was suppressed by the 5-HT₇ receptor antagonist SB269970. In addition, immunohistochemistry showed the occurrence of 5-HT₇ receptor-like immunoreactivity in carcinoma cells. mRNAs encoding renin as well as renin-like immunoreactivity were detected in endothelial and tumor cells. Cell incubation studies revealed that the adrenocortical tissue also released renin. Renin production was inhibited by 5-HT but was not influenced by ACTH and angiotensin II (Ang II). In conclusion, the present report provides the first demonstration of ectopic serotonin receptors, i.e. 5-HT₇ receptors, in an adrenocortical carcinoma. Our results also indicate that 5-HT can influence the secretory activity of malignant adrenocortical tumors in an autocrine/paracrine manner. The effects of 5-HT on adrenocortical tumor cells included a paradoxical inhibitory action on renin production and a stimulatory action on cortisol secretion involving 5-HT₇ receptors.