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This version published online on October 27, 2005
Endocrinology, doi:10.1210/en.2005-0921
A more recent version of this article appeared on February 1, 2006
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Submitted on July 21, 2005
Accepted on October 14, 2005

Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model

Tânia L. Mazzuco, Olivier Chabre, Nathalie Sturm, Jean-Jacques Feige, and Michaël Thomas*

Institut National de la Santé et de la Recherche Médicale, Equipe Mixte 01-05, Département Réponse et Dynamique Cellulaires, Commissariat à l'Energie Atomique, 17 rue des Martyrs, 38054 Grenoble, Cedex 09, France; Service d'Endocrinologie, Département de Diabétologie, Urologie, Néphrologie et Endocrinologie, Centre Hospitalier Universitaire, Grenoble, France and Laboratoire de Pathologie Cellulaire, Département d'Anatomie et de Cytologie Pathologiques, Centre Hospitalier Universitaire, Grenoble, France

* To whom correspondence should be addressed. E-mail: michael.thomas{at}cea.fr.

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 (AIMAH) 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 (GIP) receptor. Following 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 GIP-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 non-mutated GPCR gene - is sufficient to initiate the complete phenotypic alterations that ultimately lead to the formation of a benign adrenocortical tumor.
Key words: Adrenal tumorigenesis • gastric inhibitory polypeptide receptor • cell transplantation




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