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

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


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.

Keywords: HAI-1; HGF; hypoxia; proliferation; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / genetics
  • Hepatocyte Growth Factor / genetics
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Membrane Glycoproteins / genetics
  • Mice
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Proteinase Inhibitory Proteins, Secretory / genetics*
  • RNA, Messenger
  • Tumor Microenvironment / genetics*


  • Basic Helix-Loop-Helix Transcription Factors
  • Membrane Glycoproteins
  • Proteinase Inhibitory Proteins, Secretory
  • RNA, Messenger
  • Spint1 protein, mouse
  • endothelial PAS domain-containing protein 1
  • Hepatocyte Growth Factor