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Mutation of the cell cycle regulator p27kip1 drives pseudohypoxic pheochromocytoma development.
Cancers 13:126 (2021)
BACKGROUND: Pseudohypoxic tumors activate pro-oncogenic pathways typically associated with severe hypoxia even when sufficient oxygen is present, leading to highly aggressive tumors. Prime examples are pseudohypoxic pheochromocytomas and paragangliomas (p-PPGLs), neuroendendocrine tumors currently lacking effective therapy. Previous attempts to generate mouse models for p-PPGLs all failed. Here, we describe that the rat MENX line, carrying a Cdkn1b (p27) frameshift-mutation, spontaneously develops pseudohypoxic pheochromocytoma (p-PCC). METHODS: We compared rat p-PCCs with their cognate human tumors at different levels: histology, immunohistochemistry, catecholamine profiling, electron microscopy, transcriptome and metabolome. The vessel architecture and angiogenic potential of pheochromocytomas (PCCs) was analyzed by light-sheet fluorescence microscopy ex vivo and multi-spectral optoacoustic tomography (MSOT) in vivo. RESULTS: The analysis of tissues at various stages, from hyperplasia to advanced grades, allowed us to correlate tumor characteristics with progression. Pathological changes affecting the mitochrondrial ultrastructure where present already in hyperplasias. Rat PCCs secreted high levels of norepinephrine and dopamine. Transcriptomic and metabolomic analysis revealed changes in oxidative phosphorylation that aggravated over time, leading to an accumulation of the oncometabolite 2-hydroxyglutarate, and to hypermethylation, evident by the loss of the epigenetic mark 5-hmC. While rat PCC xenografts showed high oxygenation, induced by massive neoangiogenesis, rat primary PCC transcriptomes possessed a pseudohypoxic signature of high Hif2a, Vegfa, and low Pnmt expression, thereby clustering with human p-PPGL. CONCLUSION: Endogenous rat PCCs recapitulate key phenotypic features of human p-PPGLs. Thus, MENX rats emerge as the best available animal model of these aggressive tumors. Our study provides evidence of a link between cell cycle dysregulation and pseudohypoxia.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
2-hydroxyglutarate ; 5-hmc ; Menx ; Ppgls ; Angiogenesis ; Animal Model ; Cell Cycle ; Endogenous Pheochromocytoma ; Hypermethylation ; Mitochondrial Dysfunction ; Oncometabolites ; Pseudohypoxia; Optoacoustic Tomography Msot; Endocrine Neoplasia Syndrome; Malignant Pheochromocytoma; Mitochondrial Cristae; Deficient Cells; Expression; Catecholamines; Inhibition; Therapy; Models
ISSN (print) / ISBN
2072-6694
Journal
Cancers
Quellenangaben
Volume: 13,
Issue: 1,
Article Number: 126
Publisher
MDPI
Publishing Place
St Alban-anlage 66, Ch-4052 Basel, Switzerland
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Cancer (IDC)
Institute of Biological and Medical Imaging (IBMI)
Institute of Biological and Medical Imaging (IBMI)
Grants
Deutsche Forschungsgemeinschaft