title: Morphology, Biochemistry, and Pathophysiology of MENX-Related Pheochromocytoma Recapitulate the Clinical Features.
abstract: 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. Because such models may be useful for investigations of molecular pathomechanisms and development of novel therapeutic interventions, we characterized a spontaneous animal model (multiple endocrine neoplasia [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, which converts norepinephrine to epinephrine, were also determined in wt and mutant rats. Blood pressure was longitudinally measured and end-organ pathology assessed. Compared with wt rats, mutant animals showed age-dependent increases in urinary outputs of norepinephrine (P = .0079) and normetanephrine (P = .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 N-methyltransferase, 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 the development of novel therapies for aggressive forms of human tumors.
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wiedemann
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Peitzsch
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Qin
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.affiliation: Institute for Diabetes and Cancer (T.W., N.S.P.) and Institute of Experimental Genetics (F.N.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, and Department of Internal Medicine III (M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, and Division of Molecular Endocrinology (M.E.-B., G.E.), Medical Clinic III, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D000313:Adrenal Medulla / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D004837:Epinephrine / Q000097:blood; D005260:Female; D008297:Male; D008676:Metanephrine / Q000097:blood; D009377:Multiple Endocrine Neoplasia / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009638:Norepinephrine / Q000097:blood; D009647:Normetanephrine / Q000097:blood; D010673:Pheochromocytoma / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
chemical_list: D009647:Normetanephrine; D008676:Metanephrine; D009638:Norepinephrine; D004837:Epinephrine