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

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...

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Bibliographic Details
Published in:Cancers 2019-05, Vol.11 (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: Article
Language:English
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
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Summary: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 ( ), endothelial PAS domain-containing protein 1 ( ), or succinate dehydrogenase ( ) subunit genes. The aim of this study was to investigate a possible association between underlying tumor driver mutations and COX-2 in PPGLs. 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 expression in cluster I, especially in -mutant PPGLs, however, no specific association between 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11060743