CD44 interacts with HIF-2α to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells

Elinn Johansson, Elisa Grassi, Vasiliki Pantazopoulou, Bei Tong, David Lindgren, Tracy Berg, Elin Pietras, Håkan Axelson, Alexander Pietras

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen.
Original languageEnglish
Pages (from-to)1641-1653
JournalCell Reports
Volume20
Issue number7
DOIs
Publication statusPublished - 2017 Aug

Subject classification (UKÄ)

  • Cell and Molecular Biology

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