ArticleCancers2021
Mutation of the Cell Cycle Regulator p27kip1 Drives Pseudohypoxic Pheochromocytoma Development.
Article in Cancers, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Retinoic acid induced specific changes in the phosphoproteome of C17.2 neural stem cells.Journal of cellular and molecular medicine · 2024Article
- Simultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarizedNature communications · 2023Article
- Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management.Frontiers in endocrinology · 2022Review
- Aging Aggravates Cachexia in Tumor-Bearing Mice.Cancers · 2021Article
- Imaging pheochromocytoma in small animals: preclinical models to improve diagnosis and treatment.EJNMMI research · 2021Review
- Model systems in SDHx-related pheochromocytoma/paraganglioma.Cancer metastasis reviews · 2021Review
- Correlation of in vivo imaging to morphomolecular pathology in translational research: challenge accepted.EJNMMI research · 2021Article
- COX4I2 is a novel biomarker of blood supply in adrenal tumors.Translational andrology and urology · 2021Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundPseudohypoxic 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
methodsWe 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.
resultsThe 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
conclusionEndogenous 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.