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Wiedemann, T. ; Peitzsch, M.* ; Qin, N.* ; Neff, F. ; Ehrhart-Bornstein, M.* ; Eisenhofer, G.* ; Pellegata, N.S.

Morphology, biochemistry and pathophysiology of MENX-related pheochromocytoma recapitulate the clinical features.

Endocrinology 157, 3157-3166 (2016)
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Pheochromocytomas (PCCs) are tumors arising from neural crest-derived chromaffin cells. There are currently few animal models of PCC that recapitulate the key features of human tumors. Since such models may be useful for investigations of molecular pathomechanisms and development of novel therapeutic interventions, we characterized a spontaneous animal model (MENX rats) that develops endogenous PCCs with complete penetrance. Urine was longitudinally collected from wild-type (wt) and MENX-affected (mutant) rats and outputs of catecholamines and their O-methylated metabolites determined by mass spectrometry. Adrenal catecholamine contents, cellular ultrastructure and expression of phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, were also determined in wt and mutant rats. Blood pressure was longitudinally measured and end-organ pathology assessed. Compared to wt rats, mutant animals showed age-dependent increases in urinary outputs of norepinephrine (P=0.0079) and normetanephrine (P=0.0014) that correlated in time with development of tumor nodules, increases in blood pressure and development of hypertension-related end-organ pathology. Development of tumor nodules, which lacked expression of PNMT, occurred on a background of adrenal medullary morphological and biochemical changes occurring as early as 1 month of age and involving increased adrenal medullary concentrations of dense cored vesicles, tissue contents of both norepinephrine and epinephrine and urinary outputs of metanephrine, the metabolite of epinephrine. Taken together, MENX-affected rats share several biochemical and pathophysiological features with PCC patients. This model thus provides a suitable platform to study the pathogenesis of PCC for preclinical translational studies aimed at development of novel therapies for aggressive forms of human tumors.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Multiple Endocrine Neoplasia; In-vivo; Malignant Pheochromocytoma; Differential Expression; Adrenal-medulla; Animal-model; Plasma Dopa; Cell-lines; Mice; Catecholamines
ISSN (print) / ISBN 0013-7227
e-ISSN 1945-7170
Journal Endocrinology
Quellenangaben Volume: 157, Issue: 8, Pages: 3157-3166 Article Number: , Supplement: ,
Publisher Endocrine Society
Publishing Place Chevy Chase, Md.
Reviewing status Peer reviewed