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

Johansson, Elinn LU ; Grassi, Elisa LU ; Pantazopoulou, Vasiliki LU ; Tong, Bei LU ; Lindgren, David LU ; Berg, Tracy LU ; Pietras, Elin; Axelson, Håkan LU and Pietras, Alexander LU (2017) In Cell Reports 20(7). p.1641-1653
Abstract (Swedish)
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Reports
volume
20
issue
7
pages
1641 - 1653
publisher
Cell Press
external identifiers
  • scopus:85027866438
  • wos:000407924300013
ISSN
2211-1247
DOI
10.1016/j.celrep.2017.07.049
language
English
LU publication?
yes
id
d48c66fb-c8e2-4e91-94db-53ac1d7c2bbd
date added to LUP
2017-08-23 17:54:52
date last changed
2018-07-08 04:26:28
@article{d48c66fb-c8e2-4e91-94db-53ac1d7c2bbd,
  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.},
  author       = {Johansson, Elinn and Grassi, Elisa and Pantazopoulou, Vasiliki and Tong, Bei and Lindgren, David and Berg, Tracy and Pietras, Elin and Axelson, Håkan and Pietras, Alexander},
  issn         = {2211-1247},
  language     = {eng},
  number       = {7},
  pages        = {1641--1653},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {CD44 interacts with HIF-2α to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells},
  url          = {http://dx.doi.org/10.1016/j.celrep.2017.07.049},
  volume       = {20},
  year         = {2017},
}