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

Cancers

ChristianG. Ziegler¹  Mercedes Robledo¹  Marjolein ter Laak²  Graeme Eisenhofer²  Henri Timmers³  Martin Ullrich⁴  Verena Seifert⁴  Sandra Hauser⁴  Bruna Calsina⁵  ÁngelM. Martínez-Montes⁵  Susan Richter⁶  Jens Pietzsch⁶ 

[1] Sections of Endocrinology and Vascular Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands;Department of Internal Medicine;Department of Medicine III, University Hospital Carl Gustav Carus at the TU Dresden, 01307 Dresden, Germany;Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany;Human Cancer Genetics Programme, Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain;Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at the Technische Universität Dresden, 01307 Dresden, Germany;

关键词: VHL;    NF1;    EPAS1;    hypoxia-inducible factor;    inflammation;    radiosensitization;    succinate dehydrogenase;    mouse pheochromocytoma cells;    immunohistochemistry;    fluorescence imaging;   

DOI  :  10.3390/cancers11060743

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown