title: Loss of HIF-1α in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model.
abstract: 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.
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Henke
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Martina G
authors.initials: MG
authors.lastname: Ding
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Essler
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Dominik C
authors.initials: DC
authors.lastname: Fuhrmann
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Geis
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dehne
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
chemical_list: C497397:Arnt protein, mouse; D002273:Carcinogens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D008748:Methylcholanthrene
keywords: CYP1A1; DNA damage; breast cancer; fibrosarcoma; xenobiotics