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Technische Universität Dresden, School of Medicine, Faculty of Medicine Carl Gustav Carus, Dresden, Germany
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Technische Universität Dresden, University Hospital Carl Gustav Carus, Institute of Clinical Chemistry and Laboratory Medicine, Dresden, Germany
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Department of Internal Medicine III, Technische Universität Dresden, University Hospital Carl Gustav Carus, Dresden, Germany
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Department of Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Technische Universität Dresden, University Hospital Carl Gustav Carus, Universitäts Krebs Centrum (UCC), Tumorimmunology, Dresden, Germany
Technische Universität Dresden, National Center for Tumor Diseases (NCT), Dresden, Germany
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Technische Universität Dresden, University Hospital Carl Gustav Carus, Institute of Clinical Chemistry and Laboratory Medicine, Dresden, Germany
Department of Internal Medicine III, Technische Universität Dresden, University Hospital Carl Gustav Carus, Dresden, Germany
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Technische Universität Dresden, School of Science, Faculty of Chemistry and Food Chemistry, Dresden, Germany
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Somatostatin receptor-targeting endoradiotherapy offers potential for treating metastatic pheochromocytomas and paragangliomas, an approach likely to benefit from combination radiosensitization therapy. To provide reliable preclinical in vivo models of metastatic disease, this study characterized the metastatic spread of luciferase-expressing mouse pheochromocytoma (MPC) cells in mouse strains with different immunologic conditions. Bioluminescence imaging showed that, in contrast to subcutaneous non-metastatic engraftment of luciferase-expressing MPC cells in NMRI-nude mice, intravenous cell injection provided only suboptimal metastatic spread in both NMRI-nude mice and hairless SCID (SHO) mice. Treatment of NMRI-nude mice with anti-Asialo GM1 serum enhanced metastatic spread due to substantial depletion of natural killer (NK) cells. However, reproducible metastatic spread was only observed in NK cell-defective SCID/beige mice and in hairless immunocompetent SKH1 mice bearing disseminated or liver metastases, respectively. Liquid chromatography tandem mass spectrometry of urine samples showed that subcutaneous and metastasized tumor models exhibit comparable renal monoamine excretion profiles characterized by increasing urinary dopamine, 3-methoxytyramine, norepinephrine and normetanephrine. Metastases-related epinephrine and metanephrine were only detectable in SCID/beige mice. Positron emission tomography and immunohistochemistry revealed that all metastases maintained somatostatin receptor-specific radiotracer uptake and immunoreactivity, respectively. In conclusion, we demonstrate that intravenous injection of luciferase-expressing MPC cells into SCID/beige and SKH1 mice provides reproducible and clinically relevant spread of catecholamine-producing and somatostatin receptor-positive metastases. These standardized preclinical models allow for precise monitoring of disease progression and should facilitate further investigations on theranostic approaches against metastatic pheochromocytomas and paragangliomas.
