Research Papers:

Loss of HIF-1β in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model

Nina Henke, Nerea Ferreirós, Gerd Geisslinger, Martina G. Ding, Silke Essler, Dominik C. Fuhrmann, Theresa Geis, Dmitry Namgaladze, Nathalie Dehne and Bernhard Brüne _

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Oncotarget. 2016; 7:25915-25929. https://doi.org/10.18632/oncotarget.8297

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Nina Henke1, Nerea Ferreirós2, Gerd Geisslinger2, Martina G. Ding1, Silke Essler1, Dominik C. Fuhrmann1, Theresa Geis1, Dmitry Namgaladze1, Nathalie Dehne1,*, Bernhard Brüne1,*

1Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany

2Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, 60590 Frankfurt, Germany

*Shared senior authorship

Correspondence to:

Bernhard Brüne, e-mail: [email protected]

Keywords: xenobiotics, CYP1A1, DNA damage, breast cancer, fibrosarcoma

Received: September 21, 2015     Accepted: March 11, 2016     Published: March 23, 2016


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.

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