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Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model
Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, includ...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834104/ https://www.ncbi.nlm.nih.gov/pubmed/35159368 http://dx.doi.org/10.3390/cells11030560 |
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author | Helm, Jana Drukewitz, Stephan Poser, Isabel Richter, Susan Friedemann, Markus William, Doreen Mohr, Hermine Nölting, Svenja Robledo, Mercedes Bornstein, Stefan R. Eisenhofer, Graeme Bechmann, Nicole |
author_facet | Helm, Jana Drukewitz, Stephan Poser, Isabel Richter, Susan Friedemann, Markus William, Doreen Mohr, Hermine Nölting, Svenja Robledo, Mercedes Bornstein, Stefan R. Eisenhofer, Graeme Bechmann, Nicole |
author_sort | Helm, Jana |
collection | PubMed |
description | Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible factor (HIF) 2α. To address this shortcoming, we investigated whether recurrent hypoxia cycles lead to continuous activation of hypoxia pathways under normoxic conditions and whether this pseudohypoxia is associated with increased cellular aggressiveness. Rat pheochromocytoma cells (PC12) were incubated under hypoxia for 24 h every 3–4 days, up to 20 hypoxia–reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2α in PC12 Z20 cells and a pseudohypoxic gene signature that overlapped with the gene signature of pseudohypoxic PPGLs. PC12 Z20 cells showed a higher growth rate, and the migration and adhesion capacity were significantly increased compared with control cells. Changes in global methylation, together with the pseudohypoxic conditions, may be responsible for the increased aggressiveness of this new model. The established sub-cell line with characteristics of pseudohypoxic PPGLs represent a complementary model for further investigations, for example, with regard to new therapeutic approaches. |
format | Online Article Text |
id | pubmed-8834104 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88341042022-02-12 Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model Helm, Jana Drukewitz, Stephan Poser, Isabel Richter, Susan Friedemann, Markus William, Doreen Mohr, Hermine Nölting, Svenja Robledo, Mercedes Bornstein, Stefan R. Eisenhofer, Graeme Bechmann, Nicole Cells Article Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible factor (HIF) 2α. To address this shortcoming, we investigated whether recurrent hypoxia cycles lead to continuous activation of hypoxia pathways under normoxic conditions and whether this pseudohypoxia is associated with increased cellular aggressiveness. Rat pheochromocytoma cells (PC12) were incubated under hypoxia for 24 h every 3–4 days, up to 20 hypoxia–reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2α in PC12 Z20 cells and a pseudohypoxic gene signature that overlapped with the gene signature of pseudohypoxic PPGLs. PC12 Z20 cells showed a higher growth rate, and the migration and adhesion capacity were significantly increased compared with control cells. Changes in global methylation, together with the pseudohypoxic conditions, may be responsible for the increased aggressiveness of this new model. The established sub-cell line with characteristics of pseudohypoxic PPGLs represent a complementary model for further investigations, for example, with regard to new therapeutic approaches. MDPI 2022-02-05 /pmc/articles/PMC8834104/ /pubmed/35159368 http://dx.doi.org/10.3390/cells11030560 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Helm, Jana Drukewitz, Stephan Poser, Isabel Richter, Susan Friedemann, Markus William, Doreen Mohr, Hermine Nölting, Svenja Robledo, Mercedes Bornstein, Stefan R. Eisenhofer, Graeme Bechmann, Nicole Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model |
title | Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model |
title_full | Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model |
title_fullStr | Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model |
title_full_unstemmed | Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model |
title_short | Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model |
title_sort | treatment of pheochromocytoma cells with recurrent cycles of hypoxia: a new pseudohypoxic in vitro model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834104/ https://www.ncbi.nlm.nih.gov/pubmed/35159368 http://dx.doi.org/10.3390/cells11030560 |
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