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

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

doi:10.1016/j.celrep.2017.07.049

Elinn Johansson, Elisa S Grassi + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2017.07.049

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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.

Highlights

Glioblastoma multiforme (GBM), the highest-grade glioma and deadliest brain tumor, responds well to surgery and irradiation but invariably recurs as incurable treatment-resistant disease (Huse and Holland, 2010)
We previously found that the stem cell marker CD44 is expressed in the perivascular niche (PVN) of proneural GBM and that its cleavage by gamma-secretase can release an intracellular domain (CD44ICD) capable of enhancing target gene activation by hypoxia-inducible factors (HIFs) (Pietras et al, 2014)
Tumors were stained for CD44 and the neural stem cell marker nestin to identify stemlike GBM cells and the PVN in vivo

Summary

Introduction

Glioblastoma multiforme (GBM), the highest-grade glioma and deadliest brain tumor, responds well to surgery and irradiation but invariably recurs as incurable treatment-resistant disease (Huse and Holland, 2010). Solid tumors frequently develop areas of hypoxia due in part to tumors outgrowing the vascular supply and in part to tumor vasculature malfunctioning (Semenza, 2012). This is true for GBMs, as one hallmark pathognomonic feature of GBMs is pseudopalisading necrosis with surrounding hypoxia (Huse and Holland, 2010). While HIF-1a and HIF-2a share regulation by oxygen and the majority of target genes, it appears that HIF-2a is the primary driver of this hypoxia-induced dedifferentiation, as well as of pseudo-hypoxic phenotypes of apparently well-vascularized stem-like glioma cells (Pietras et al, 2010). Little is known about the differential regulation of HIF-a subunits in stem-like versus tumor bulk cells in glioma and other solid tumor types

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