Ectopic expression of serotonin7 receptors in an adrenocortical carcinoma co-secreting renin and cortisol

Abstract

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 serotonin 7 (5-HT 7 ) 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-HT 7 receptor antagonist SB269970. In addition, immunohistochemistry showed the occurrence of 5-HT 7 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-HT 7 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-HT 7 receptors.

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

“…43 In some cases, the corticotropic effect of 5-HT was mediated by ectopic 5-HT 7 receptors. 44,45 5-HT 7 receptor-like immunoreactivity was identified in the central zones of the hyperplastic nodules, spongiocytic cells, small compact cells, arterial walls of hyperplasia, 44 and carcinoma cells.…”

“…Both 5-HT and cisapride, a 5-HT 4 receptor agonist, stimulated cortisol production in vivo, 42 in cultured cells from adrenal hyperplasia 37,43,44 and adrenocortical carcinoma. 45 Patients with Cushing's syndrome treated with 5-HT 4 receptor agonists cisapride, 43,46-50 metoclopramide, 46,48 and zacopride demonstrated increased cortisol levels. 51 The presence of 5-HT4 receptor was also detected by reverse transcription polymerase chain reaction (RT-PCR) in other studies.…”

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

“…Expression of renin has been observed in adrenocortical cortisol-secreting and non-secreting adenomas and carcinomas (72,199), sometimes associated with the occurrence of angiotensinogen (72,199). In one case, renin secretion by cultured tumor cells was found to be inhibited by 5-HT in a paracrine fashion revealing complex regulations within the tumor tissue (72).…”

“…In one case, renin secretion by cultured tumor cells was found to be inhibited by 5-HT in a paracrine fashion revealing complex regulations within the tumor tissue (72). The pathophysiological relevance of these findings is not clear but the recent identification of a membrane receptor for renin, which mediates angiogenic and mitogenic actions of the protein through interaction with the Wnt/b-catenin pathway (200,201), could suggest that renin may be involved in adrenocortical tumorigenesis (202,203,204).…”

“…5-HT 7 receptors, which are not physiologically present in normal adrenocortical cells, must therefore be considered as adrenal ectopic membrane receptors together with receptors for glucose-dependent insulinotropic peptide and luteinizing hormone (1, 121,122,169). Abnormal expression of 5-HT 7 receptor has also been observed in a case of ACC co-secreting cortisol and renin (72). More rarely, 5-HT may paradoxically inhibit cortisol secretion in some benign adrenocortical neoplasms (170).…”