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Mol Carcinog. 2019 Nov;58(11):2127-2138. doi: 10.1002/mc.23103. Epub 2019 Aug 22.

Macrophage HIF-2α regulates tumor-suppressive Spint1 in the tumor microenvironment.

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Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
Applied Bioinformatics Group, Institute of Cell Biology and Neuroscience, Goethe-University Frankfurt, Frankfurt, Germany.
Senckenberg Biodiversity and Climate Research Centre (BiK-F), Frankfurt, Germany.
German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany.
Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany.
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, Frankfurt, Germany.


In solid tumors, tumor-associated macrophages (TAMs) commonly accumulate within hypoxic areas. Adaptations to such environments evoke transcriptional changes by the hypoxia-inducible factors (HIFs). While HIF-1α is ubiquitously expressed, HIF-2α appears tissue-specific with consequences of HIF-2α expression in TAMs only being poorly characterized. An E0771 allograft breast tumor model revealed faster tumor growth in myeloid HIF-2α knockout (HIF-2αLysM-/- ) compared with wildtype (wt) mice. In an RNA-sequencing approach of FACS sorted wt and HIF-2α LysM-/- TAMs, serine protease inhibitor, Kunitz type-1 ( Spint1) emerged as a promising candidate for HIF-2α-dependent regulation. We validated reduced Spint1 messenger RNA expression and concomitant Spint1 protein secretion under hypoxia in HIF-2α-deficient bone marrow-derived macrophages (BMDMs) compared with wt BMDMs. In line with the physiological function of Spint1 as an inhibitor of hepatocyte growth factor (HGF) activation, supernatants of hypoxic HIF-2α knockout BMDMs, not containing Spint1, were able to release proliferative properties of inactive pro-HGF on breast tumor cells. In contrast, hypoxic wt BMDM supernatants containing abundant Spint1 amounts failed to do so. We propose that Spint1 contributes to the tumor-suppressive function of HIF-2α in TAMs in breast tumor development.


HAI-1; HGF; hypoxia; proliferation; tumor-associated macrophages


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