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

摘要: Activation of hypoxia-inducible factor (HIF) and macrophage infiltration solid tumors independently promote tumor progression. As little is known how myeloid HIF affects development, we injected the polycyclic aromatic hydrocarbon (PAH) procarcinogen 3-methylcholanthrene (MCA; 100 μg/100 μl) subcutaneously into myeloid-specific Hif-1α Hif-2α knockout mice (C57BL/6J) to induce fibrosarcomas (n = 16). Deletion but not in macrophages diminished outgrowth MCA-model. While analysis initiation phase showed comparable inflammation after MCA-injection, metabolism MCA was impaired absence Hif-1α. An ex vivo macrophage/fibroblast coculture recapitulated reduced DNA damage MCA-stimulation fibroblasts cocultures with LysM-/- compared wild type macrophages. A loss decreased RNA levels arylhydrocarbon receptor (AhR)/arylhydrocarbon nuclear translocator (ARNT) targets such as Cyp1a1 because Arnt unchanged Ahr expression. Cocultures using stimulated carcinogen 7,12-dimethylbenz[a]anthracene (DMBA; 2 μg/ml) also attenuated a response fibroblasts, while damage-inducing metabolite DMBA-trans-3,4-dihydrodiol remained effective In chemical-induced carcinogenesis, HIF-1α maintains ARNT expression facilitate PAH-biotransformation. This implies metabolic activation PAHs stromal cells, i.e. myeloid-derived be crucial for initiation.