title: In vivo fluorescence imaging and urinary monoamines as surrogate biomarkers of disease progression in a mouse model of pheochromocytoma.
abstract: Pheochromocytoma (PHEO) is a rare but potentially lethal neuroendocrine tumor arising from catecholamine-producing chromaffin cells. Especially for metastatic PHEO, the availability of animal models is essential for developing novel therapies. For evaluating therapeutic outcome in rodent PHEO models, reliable quantification of multiple organ lesions depends on dedicated small-animal in vivo imaging, which is still challenging and only available at specialized research facilities. Here, we investigated whether whole-body fluorescence imaging and monitoring of urinary free monoamines provide suitable parameters for measuring tumor progression in a murine allograft model of PHEO. We generated an mCherry-expressing mouse PHEO cell line by lentiviral gene transfer. These cells were injected subcutaneously into nude mice to perform whole-body fluorescence imaging of tumor development. Urinary free monoamines were measured by liquid chromatography with tandem mass spectrometry. Tumor fluorescence intensity and urinary outputs of monoamines showed tumor growth-dependent increases (P < .001) over the 30 days of monitoring post-tumor engraftment. Concomitantly, systolic blood pressure was increased significantly during tumor growth. Tumor volume correlated significantly (P < .001) and strongly with tumor fluorescence intensity (rs = 0.946), and urinary outputs of dopamine (rs = 0.952), methoxytyramine (rs = 0.947), norepinephrine (rs = 0.756), and normetanephrine (rs = 0.949). Dopamine and methoxytyramine outputs allowed for detection of lesions at diameters below 2.3 mm. Our results demonstrate that mouse pheochromocytoma (MPC)-mCherry cell tumors are functionally similar to human PHEO. Both tumor fluorescence intensity and urinary outputs of free monoamines provide precise parameters of tumor progression in this sc mouse model of PHEO. This animal model will allow for testing new treatment strategies for chromaffin cell tumors.
authors.affiliation: Department of Radiopharmaceutical and Chemical Biology (M.U., R.B., J.P.), Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Department of Medicine III (M.U., N.Q., M.E.-B., G.E., S.R.B., C.G.Z.), University Hospital Carl Gustav Carus, 01307 Dresden, Germany; Institute for Clinical Chemistry and Laboratory Medicine (M.P., N.Q., G.E.), Technische Universität Dresden, Germany; Department of Radioimmunology (M.C.), Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany; Department of Chemistry and Food Chemistry (J.P.), Technische Universität Dresden, Dresden, Germany; and VA Medical Center Miami FL and Department of Pathology and Medicine (N.L.B., A.V.S.), Division of Endocrinology and Hematology-Oncology, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Martin
authors.initials: M
authors.lastname: Ullrich
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Mirko
authors.initials: M
authors.lastname: Peitzsch
authors.forename: Marc
authors.initials: M
authors.lastname: Cartellieri
authors.forename: Nan
authors.initials: N
authors.lastname: Qin
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Christian G
authors.initials: CG
authors.lastname: Ziegler
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000652:urine; D000588:Amines / Q000652:urine*; D000818:Animals; D014408:Biomarkers, Tumor / Q000652:urine*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D061848:Optical Imaging / Q000379:methods*; D010673:Pheochromocytoma / Q000175:diagnosis* / Q000473:pathology / Q000652:urine; D016482:Urinalysis
chemical_list: D000588:Amines; D014408:Biomarkers, Tumor