- Activation of hypoxia-inducible factor (HIF) and macrophage infiltration of solid tumors independently promote tumor progression. As little is known how myeloid HIF affects tumor development, we injected the polycyclic aromatic hydrocarbon (PAH) and procarcinogen 3-methylcholanthrene (MCA; 100 μg/100 μl) subcutaneously into myeloid-specific Hif-1α and Hif-2α knockout mice (C57BL/6J) to induce fibrosarcomas (n = 16). Deletion of Hif-1α but not Hif-2α in macrophages diminished tumor outgrowth in the MCA-model. While analysis of the tumor initiation phase showed comparable inflammation after MCA-injection, metabolism of MCA was impaired in the absence of Hif-1α. An ex vivo macrophage/fibroblast coculture recapitulated reduced DNA damage after MCA-stimulation in fibroblasts of cocultures with Hif-1α LysM-/- macrophages compared to wild type macrophages. A loss of myeloid Hif-1α decreased RNA levels of arylhydrocarbon receptor (AhR)/arylhydrocarbon receptor nuclear translocator (ARNT) targets such as Cyp1a1 because of reduced Arnt but unchanged Ahr expression. Cocultures using Hif-1α LysM-/- macrophages stimulated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA; 2 μg/ml) also attenuated a DNA damage response in fibroblasts, while the DNA damage-inducing metabolite DMBA-trans-3,4-dihydrodiol remained effective in the absence of Hif-1α. In chemical-induced carcinogenesis, HIF-1α in macrophages maintains ARNT expression to facilitate PAH-biotransformation. This implies a metabolic activation of PAHs in stromal cells, i.e. myeloid-derived cells, to be crucial for tumor initiation.
MetadatenAuthor: | Nina Henke, Nerea Ferreirós BouzasORCiDGND, Gerd GeisslingerORCiDGND, Martina G. Ding, Silke Essler, Dominik Christian FuhrmannORCiDGND, Theresa Geis, Dmitry NamgaladzeORCiD, Nathalie DehneORCiDGND, Bernhard BrüneORCiD |
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URN: | urn:nbn:de:hebis:30:3-452295 |
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DOI: | https://doi.org/10.18632/oncotarget.8297 |
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ISSN: | 1949-2553 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27015123 |
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Parent Title (English): | OncoTarget |
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Publisher: | Impact Journals LLC |
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Place of publication: | [s. l.] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2016 |
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Date of first Publication: | 2016/03/23 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/12/12 |
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Tag: | CYP1A1; DNA damage; breast cancer; fibrosarcoma; xenobiotics |
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Volume: | 7 |
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Issue: | 18 |
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Page Number: | 15 |
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First Page: | 25915 |
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Last Page: | 25929 |
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Note: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
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HeBIS-PPN: | 426120728 |
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Institutes: | Medizin / Medizin |
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| Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 3.0 |
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