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Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background

1
Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
2
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at the Technische Universität Dresden, 01307 Dresden, Germany
3
Faculty of Medicine Carl Gustav Carus, School of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
4
Human Cancer Genetics Programme, Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain
5
Department of Internal Medicine; Sections of Endocrinology and Vascular Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
6
Department of Medicine III, University Hospital Carl Gustav Carus at the TU Dresden, 01307 Dresden, Germany
7
Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain
8
Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, 01069 Dresden, Germany
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(6), 743; https://doi.org/10.3390/cancers11060743
Received: 30 April 2019 / Revised: 22 May 2019 / Accepted: 24 May 2019 / Published: 28 May 2019
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Abstract

Cyclooxygenase 2 (COX-2) is a key enzyme of the tumorigenesis-inflammation interface and can be induced by hypoxia. A pseudohypoxic transcriptional signature characterizes pheochromocytomas and paragangliomas (PPGLs) of the cluster I, mainly represented by tumors with mutations in von Hippel–Lindau (VHL), endothelial PAS domain-containing protein 1 (EPAS1), or succinate dehydrogenase (SDH) subunit genes. The aim of this study was to investigate a possible association between underlying tumor driver mutations and COX-2 in PPGLs. COX-2 gene expression and immunoreactivity were examined in clinical specimens with documented mutations, as well as in spheroids and allografts derived from mouse pheochromocytoma (MPC) cells. COX-2 in vivo imaging was performed in allograft mice. We observed significantly higher COX-2 expression in cluster I, especially in VHL-mutant PPGLs, however, no specific association between COX-2 mRNA levels and a hypoxia-related transcriptional signature was found. COX-2 immunoreactivity was present in about 60% of clinical specimens as well as in MPC spheroids and allografts. A selective COX-2 tracer specifically accumulated in MPC allografts. This study demonstrates that, although pseudohypoxia is not the major determinant for high COX-2 levels in PPGLs, COX-2 is a relevant molecular target. This potentially allows for employing selective COX-2 inhibitors as targeted chemotherapeutic agents and radiosensitizers. Moreover, available models are suitable for preclinical testing of these treatments. View Full-Text
Keywords: VHL; NF1; EPAS1; hypoxia-inducible factor; inflammation; radiosensitization; succinate dehydrogenase; mouse pheochromocytoma cells; immunohistochemistry; fluorescence imaging VHL; NF1; EPAS1; hypoxia-inducible factor; inflammation; radiosensitization; succinate dehydrogenase; mouse pheochromocytoma cells; immunohistochemistry; fluorescence imaging
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Ullrich, M.; Richter, S.; Seifert, V.; Hauser, S.; Calsina, B.; Martínez-Montes, Á.M.; ter Laak, M.; Ziegler, C.G.; Timmers, H.; Eisenhofer, G.; Robledo, M.; Pietzsch, J. Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background. Cancers 2019, 11, 743.

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