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Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment

Rosberg, Rebecca LU orcid ; Smolag, Karolina I. LU orcid ; Sjölund, Jonas LU orcid ; Johansson, Elinn LU ; Bergelin, Christina LU ; Wahldén, Julia LU ; Pantazopoulou, Vasiliki LU orcid ; Ceberg, Crister LU orcid ; Pietras, Kristian LU orcid and Blom, Anna M. LU orcid , et al. (2024) In JCI Insight 9(19).
Abstract

Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single-cell, and spatially resolved transcriptomic data from patients with GBM. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level–dependent increase in C3 and C3AR1 expression in response to hypoxia in... (More)

Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single-cell, and spatially resolved transcriptomic data from patients with GBM. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level–dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. C3a induced M2 polarization of cultured microglia and macrophages in a C3aR-dependent fashion. Targeting C3aR using the antagonist SB290157 prolonged survival of glioma-bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM and support a role of hypoxia-induced C3a/C3aR signaling as a contributor to glioma aggressiveness by regulating macrophage polarization.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
9
issue
19
article number
e179854
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85206019853
  • pmid:39172519
ISSN
2379-3708
DOI
10.1172/jci.insight.179854
language
English
LU publication?
yes
id
fe1f6092-bc5d-43d8-88eb-a5a59e16cd86
date added to LUP
2024-12-04 15:23:07
date last changed
2025-07-17 10:07:40
@article{fe1f6092-bc5d-43d8-88eb-a5a59e16cd86,
  abstract     = {{<p>Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single-cell, and spatially resolved transcriptomic data from patients with GBM. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level–dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. C3a induced M2 polarization of cultured microglia and macrophages in a C3aR-dependent fashion. Targeting C3aR using the antagonist SB290157 prolonged survival of glioma-bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM and support a role of hypoxia-induced C3a/C3aR signaling as a contributor to glioma aggressiveness by regulating macrophage polarization.</p>}},
  author       = {{Rosberg, Rebecca and Smolag, Karolina I. and Sjölund, Jonas and Johansson, Elinn and Bergelin, Christina and Wahldén, Julia and Pantazopoulou, Vasiliki and Ceberg, Crister and Pietras, Kristian and Blom, Anna M. and Pietras, Alexander}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{19}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.179854}},
  doi          = {{10.1172/jci.insight.179854}},
  volume       = {{9}},
  year         = {{2024}},
}