TY  - JOUR
A1  - Susen, Rosa M.
A1  - Bauer, Rebekka
A1  - Olesch, Catherine
A1  - Fuhrmann, Dominik Christian
A1  - Fink, Annika F.
A1  - Dehne, Nathalie
A1  - Jain, Arpit
A1  - Ebersberger, Ingo
A1  - Schmid, Tobias
A1  - Brüne, Bernhard
T1  - Macrophage HIF‐2α regulates tumor‐suppressive Spint1 in the tumor microenvironment
T2  - Molecular carcinogenesis
N2  - 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.
KW  - HAI‐1
KW  - HGF
KW  - hypoxia
KW  - proliferation
KW  - tumor‐associated macrophages
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57190
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-571906
SN  - 1098-2744
SN  - 0899-1987
VL  - 58
IS  - 11
SP  - 2127
EP  - 2138
PB  - Wiley Interscience
CY  - New York, NY
ER  -