CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells

TY - JOUR

T1 - CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells

AU - Johansson, Elinn

AU - Grassi, Elisa S.

AU - Pantazopoulou, Vasiliki

AU - Tong, Bei

AU - Lindgren, David

AU - Berg, Tracy J.

AU - Pietras, Elin J.

AU - Axelson, Håkan

AU - Pietras, Alexander

PY - 2017/8/15

Y1 - 2017/8/15

N2 - 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.

AB - 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.

KW - CD44

KW - glioma

KW - HIF-1α

KW - HIF-2α

KW - hypoxia

KW - hypoxic niche

KW - perivascular niche

KW - stem cell niche

KW - stemness

U2 - 10.1016/j.celrep.2017.07.049

DO - 10.1016/j.celrep.2017.07.049

M3 - Journal article

C2 - 28813675

AN - SCOPUS:85027866438

SN - 2639-1856

VL - 20

SP - 1641

EP - 1653

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -