{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:48:47Z","timestamp":1760150927730,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T00:00:00Z","timestamp":1644019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC\/Transregio 205\/2, Project No. 314061271 - TRR205"],"award-info":[{"award-number":["CRC\/Transregio 205\/2, Project No. 314061271 - TRR205"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016778","name":"Paradifference Foundation","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100016778","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","award":["ESF scholarship"],"award-info":[{"award-number":["ESF scholarship"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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) 2\u03b1. 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\u20134 days, up to 20 hypoxia\u2013reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2\u03b1 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.<\/jats:p>","DOI":"10.3390\/cells11030560","type":"journal-article","created":{"date-parts":[[2022,2,6]],"date-time":"2022-02-06T20:36:47Z","timestamp":1644179807000},"page":"560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model"],"prefix":"10.3390","volume":"11","author":[{"given":"Jana","family":"Helm","sequence":"first","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Drukewitz","sequence":"additional","affiliation":[{"name":"Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany"},{"name":"German Cancer Consortium (DKTK), 01307 Dresden, Germany"},{"name":"German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Poser","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-2477","authenticated-orcid":false,"given":"Susan","family":"Richter","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Friedemann","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-5073","authenticated-orcid":false,"given":"Doreen","family":"William","sequence":"additional","affiliation":[{"name":"Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany"},{"name":"German Cancer Consortium (DKTK), 01307 Dresden, Germany"},{"name":"German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hermine","family":"Mohr","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Cancer, Helmholtz Centre Munich, Ingolstaedter Landstr.1, 85764 Neuherberg, Germany"},{"name":"Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svenja","family":"N\u00f6lting","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), 8091 Zurich, Switzerland"},{"name":"Department of Medicine IV, University Hospital, LMU Munich, 80336 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6256-5902","authenticated-orcid":false,"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan R.","family":"Bornstein","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme","family":"Eisenhofer","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"},{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6932-333X","authenticated-orcid":false,"given":"Nicole","family":"Bechmann","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"},{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse 74, 01307 Dresden, Germany"},{"name":"German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558 Nuthetal, Germany"},{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ccell.2017.01.001","article-title":"Comprehensive molecular characterization of pheochromocytoma and paraganglioma","volume":"31","author":"Fishbein","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1530\/ERC-19-0024","article-title":"Genotype-phenotype correlations in pheochromocytoma and paraganglioma: A systematic review and individual patient meta-analysis","volume":"5","author":"Crona","year":"2019","journal-title":"Endocr. 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