| First Author | Susen RM | Year | 2019 |
| Journal | Mol Carcinog | Volume | 58 |
| Issue | 11 | Pages | 2127-2138 |
| PubMed ID | 31436357 | Mgi Jnum | J:290088 |
| Mgi Id | MGI:6435270 | Doi | 10.1002/mc.23103 |
| Citation | Susen RM, et al. (2019) Macrophage HIF-2alpha regulates tumor-suppressive Spint1 in the tumor microenvironment. Mol Carcinog 58(11):2127-2138 |
| abstractText | 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-1alpha is ubiquitously expressed, HIF-2alpha appears tissue-specific with consequences of HIF-2alpha expression in TAMs only being poorly characterized. An E0771 allograft breast tumor model revealed faster tumor growth in myeloid HIF-2alpha knockout (HIF-2alpha(LysM-/-) ) compared with wildtype (wt) mice. In an RNA-sequencing approach of FACS sorted wt and HIF-2alpha (LysM-/-) TAMs, serine protease inhibitor, Kunitz type-1 ( Spint1) emerged as a promising candidate for HIF-2alpha-dependent regulation. We validated reduced Spint1 messenger RNA expression and concomitant Spint1 protein secretion under hypoxia in HIF-2alpha-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-2alpha 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-2alpha in TAMs in breast tumor development. |
