Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background
AbstractCyclooxygenase 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
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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.
Ullrich M, Richter S, Seifert V, Hauser S, Calsina B, Martínez-Montes ÁM, ter Laak M, Ziegler CG, Timmers H, Eisenhofer G, Robledo M, Pietzsch J. Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background. Cancers. 2019; 11(6):743.Chicago/Turabian Style
Ullrich, Martin; Richter, Susan; Seifert, Verena; Hauser, Sandra; Calsina, Bruna; Martínez-Montes, Ángel M.; ter Laak, Marjolein; Ziegler, Christian G.; Timmers, Henri; Eisenhofer, Graeme; Robledo, Mercedes; Pietzsch, Jens. 2019. "Targeting Cyclooxygenase-2 in Pheochromocytoma and Paraganglioma: Focus on Genetic Background." Cancers 11, no. 6: 743.
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