Macrophage HIF‐2α regulates tumor‐suppressive Spint1 in the tumor microenvironment

  • 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.

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Author:Rosa M. Susen, Rebekka BauerORCiDGND, Catherine OleschORCiDGND, Dominik Christian FuhrmannORCiDGND, Annika F. FinkGND, Nathalie DehneORCiDGND, Arpit JainORCiD, Ingo EbersbergerORCiDGND, Tobias SchmidORCiDGND, Bernhard BrüneORCiD
Parent Title (English):Molecular carcinogenesis
Publisher:Wiley Interscience
Place of publication:New York, NY
Document Type:Article
Date of Publication (online):2019/08/22
Date of first Publication:2019/08/22
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/12/08
Tag:HAI‐1; HGF; hypoxia; proliferation; tumor‐associated macrophages
Page Number:12
First Page:2127
Last Page:2138
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0