Unknown

Dataset Information

0

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


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.

SUBMITTER: Ullrich M 

PROVIDER: S-EPMC6627450 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3311650 | biostudies-literature
| S-EPMC7482423 | biostudies-literature
| S-EPMC4333031 | biostudies-literature
| S-EPMC10388674 | biostudies-literature
| S-EPMC7072390 | biostudies-literature
| S-EPMC4572836 | biostudies-literature
| S-EPMC7443979 | biostudies-literature
| S-EPMC6844179 | biostudies-literature
| S-EPMC7803589 | biostudies-literature
| S-EPMC7761866 | biostudies-literature