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Article

HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models

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Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
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Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, 01069 Dresden, Germany
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Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany
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Department of Internal Medicine III, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany
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Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany
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German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
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Department of Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
*
Authors to whom correspondence should be addressed.
J.P. and M.U. share senior authorship.
Academic Editors: Raquel Rodrigues and Graça Minas
Cancers 2021, 13(3), 385; https://doi.org/10.3390/cancers13030385
Received: 16 December 2020 / Revised: 15 January 2021 / Accepted: 18 January 2021 / Published: 21 January 2021
(This article belongs to the Special Issue Cancer-on-a-Chip: Applications and Challenges)
Low oxygen levels (hypoxia) as well as genetic defects activating hypoxia signaling pathways (pseudohypoxia) are known to contribute to tumorigenesis and therapy resistance in various cancers. The genetic background of pheochromocytomas and paragangliomas is well characterized and indicates that pseudohypoxia plays a role in tumor formation and metastatic spread in a subgroup of these tumors. It is, however, unknown how pseudohypoxia affects susceptibility to radiation treatments, which is of particular interest, since targeted radionuclide therapy is one of the few options used against metastatic pheochromocytomas and paragangliomas. To date, no curative treatment is available for metastatic disease. Here, we report on the radioprotective effects of pseudohypoxia against both external irradiation and beta particle-emitting lutetium-177 in a pheochromocytoma tumor spheroid model expressing hypoxia-inducible factor 2 alpha. Our findings highlight hypoxia signaling pathways as potential targets for neo-adjuvant—in particular, radiosensitizing—therapies in pseudohypoxic pheochromocytomas and paragangliomas.
Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare neuroendocrine tumors arising from chromaffin tissue located in the adrenal or ganglia of the sympathetic or parasympathetic nervous system. The treatment of non-resectable or metastatic PCCs/PGLs is still limited to palliative measures, including somatostatin type 2 receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE as one of the most effective approaches to date. Nevertheless, the metabolic and molecular determinants of radiation response in PCCs/PGLs have not yet been characterized. This study investigates the effects of hypoxia-inducible factor 2 alpha (HIF2α) on the susceptibility of PCCs/PGLs to radiation treatments using spheroids grown from genetically engineered mouse pheochromocytoma (MPC) cells. The expression of Hif2α was associated with the significantly increased resistance of MPC spheroids to external X-ray irradiation and exposure to beta particle-emitting [177Lu]LuCl3 compared to Hif2α-deficient controls. Exposure to [177Lu]LuCl3 provided an increased long-term control of MPC spheroids compared to single-dose external X-ray irradiation. This study provides the first experimental evidence that HIF2α-associated pseudohypoxia contributes to a radioresistant phenotype of PCCs/PGLs. Furthermore, the external irradiation and [177Lu]LuCl3 exposure of MPC spheroids provide surrogate models for radiation treatments to further investigate the metabolic and molecular determinants of radiation responses in PCCs/PGLs and evaluate the effects of neo-adjuvant—in particular, radiosensitizing—treatments in combination with targeted radionuclide therapies. View Full-Text
Keywords: paraganglioma; radionuclide therapy; lutetium-177; spheroid control dose; SCD50; spheroid re-growth; irradiation; X-ray; radioresistance paraganglioma; radionuclide therapy; lutetium-177; spheroid control dose; SCD50; spheroid re-growth; irradiation; X-ray; radioresistance
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MDPI and ACS Style

Seifert, V.; Richter, S.; Bechmann, N.; Bachmann, M.; Ziegler, C.G.; Pietzsch, J.; Ullrich, M. HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models. Cancers 2021, 13, 385. https://doi.org/10.3390/cancers13030385

AMA Style

Seifert V, Richter S, Bechmann N, Bachmann M, Ziegler CG, Pietzsch J, Ullrich M. HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models. Cancers. 2021; 13(3):385. https://doi.org/10.3390/cancers13030385

Chicago/Turabian Style

Seifert, Verena, Susan Richter, Nicole Bechmann, Michael Bachmann, Christian G. Ziegler, Jens Pietzsch, and Martin Ullrich. 2021. "HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models" Cancers 13, no. 3: 385. https://doi.org/10.3390/cancers13030385

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