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

• Published in: Cancers Vol. 11; no. 6; p. 743
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.05.2019; MDPI
• Subjects: Abdomen; Allografts; Cancer therapies; Chemistry; Chemotherapy; Cyclooxygenase-2; Enzymes; Gene expression; Hypoxia; Immunoreactivity; Kinases; Medical research; Medicine; Metastasis; Mutation; Neck; Paraganglioma; Proteins; Radiosensitizers; Spheroids; Succinate dehydrogenase; Transcription; Tumorigenesis; Tumors; VHL protein; Germany; Spain; EPAS1; inflammation; fluorescence imaging; radiosensitization; NF1; hypoxia-inducible factor; VHL; immunohistochemistry; mouse pheochromocytoma cells; succinate dehydrogenase
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers11060743

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.