title: Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model.
abstract: Aberrant expression of ectopic G protein-coupled receptors (GPCRs) in adrenal cortex tissue has been observed in several cases of ACTH-independent macronodular adrenal hyperplasias and adenomas associated with Cushing's syndrome. Although there is clear clinical evidence for the implication of these ectopic receptors in abnormal regulation of cortisol production, whether this aberrant GPCR expression is the cause or the consequence of the development of an adrenal hyperplasia is still an open question. To answer it, we genetically engineered primary bovine adrenocortical cells to have them express the gastric inhibitory polypeptide receptor. After transplantation of these modified cells under the renal capsule of adrenalectomized immunodeficient mice, tissues formed had their functional and histological characteristics analyzed. We observed the formation of an enlarged and hyperproliferative adenomatous adrenocortical tissue that secreted cortisol in a gastric inhibitory polypeptide-dependent manner and induced a mild Cushing's syndrome with hyperglycemia. Moreover, we show that tumor development was ACTH independent. Thus, a single genetic event, inappropriate expression of a nonmutated GPCR gene, is sufficient to initiate the complete phenotypic alterations that ultimately lead to the formation of a benign adrenocortical tumor.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Equipe Mixte 105, DRDC, CEA, Grenoble, France.
authors.forename: Tania L
authors.initials: TL
authors.lastname: Mazzuco
authors.forename: Olivier
authors.initials: O
authors.lastname: Chabre
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sturm
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.forename: Michaël
authors.initials: M
authors.lastname: Thomas
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002417:Cattle; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D017690:Cell Transplantation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006854:Hydrocortisone / Q000378:metabolism; D006965:Hyperplasia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009752:Nutritional Status; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C064658:RAG-1 protein; C041086:gastric inhibitory polypeptide receptor; D006854:Hydrocortisone