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Division of Endocrinology and Metabolism, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität, D-79106 Freiburg, Germany
¹ Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
² Steroid Research Unit, Center of Child and Adolescent Medicine, Justus-Liebig-University Giessen, Germany
³ Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
⁴ Medizinische Klinik - Innenstadt, Ludwig-Maximilians-University, Munich, Germany

(Requests for offprints should be addressed to F Beuschlein; Email: beuschlein{at}medizin.ukl.uni-freiburg.de)

Mouse models of adrenal tumorigenesis have the potential to give insights in the dysregulation of adrenal growth and differentiation. The inbred mouse strain CE/J has been reported to develop adrenal tumors upon gonadectomy (GDX) similar to mice with targeted deletions of the inhibin alpha subunit (Inh^–/–). We performed a detailed morphological and molecular characterization of adrenal glands from CE/J mice 8–50 weeks of age to define the cellular origin of these tumors as well as the spatial and temporal expression of marker genes associated with tumor growth. In contrast to the induction of x-zone growth upon GDX in Inh^–/– mice, GDX in CE/J mice induced the appearance of sub-capsular nests of densely packed cells that progress into adrenal tumors. Staining for proliferative cell nuclear antigen confirms a substantial increased in cellular proliferation within this sub-capsular compartment and lack of apoptosis upon GDX. Induction of adrenal tumor growth was accompanied by transcriptional changes that otherwise define gonadal endocrine cells. These regulated genes included transcription factors such as GATA-4, WT-1, FOG-1, and steroidogenic factor-1 (SF-1), peptide hormones such as Mullerian-inhibiting substance (MIS), hormone receptors including luteinizing hormone and MIS receptor, and steroidogenic enzymes such as P450c17 and P450 aromatase. The functional significance of steroid enzyme expression was demonstrated by a gradual increase of adrenal androgens after GDX. Taken together these data suggest that adrenal tumors in gonad-ectomized CE/J mice are direct derivatives from cells of the proposed sub-capsular stem cell zone. The distinct expression pattern of this cell population is consistent with a defect in the differentiation of these cells into a cell population with functional properties that otherwise define a gonadal endocrine phenotype.

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