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Updated: May 5, 2026
Coculture Assays to Study Macrophage and Microglia Stimulation of Glioblastoma Invasion
Published on: October 20, 2016
Neutrophils promote the malignant glioma phenotype through S100A4
Ji Liang1, Yuji Piao, Lindsay Holmes
1Authors' Affiliations: Departments of Neuro-Oncology, Neurosurgery, and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Antiangiogenic therapy is effective in blocking vascular permeability, inhibiting vascular proliferation, and slowing tumor growth, but studies in multiple cancer types have shown that tumors eventually acquire resistance to blockade of blood vessel growth. Currently, the mechanisms by which this resistance occurs are not well understood.
Experimental Design:
In this study, we evaluated the effects of neutrophils on glioma biology both in vitro and in vivo and determined target genes by which neutrophils promote the malignant glioma phenotype during anti-VEGF therapy.
Results:
We found that an increase in neutrophil infiltration into tumors is significantly correlated with glioma grade and in glioblastoma with acquired resistance to anti-VEGF therapy. Our data demonstrate that neutrophils and their condition media increased the proliferation rate of glioblastoma-initiating cells (GIC). In addition, neutrophils significantly increased GICs Transwell migration compared with controls. Consistent with this behavior, coculture with neutrophils promoted GICs to adopt morphologic and gene expression changes consistent with a mesenchymal signature. Neutrophil-promoting tumor progression could be blocked by S100A4 downregulation in vitro and in vivo. Furthermore, S100A4 depletion increased the effectiveness of anti-VEGF therapy in glioma.
Conclusions:
Collectively, these data suggest that increased recruitment of neutrophils during anti-VEGF therapy promotes glioma progression and may promote treatment resistance. Tumor progression with mesenchymal characteristics is partly mediated by S100A4, the expression of which is increased by neutrophil infiltration. Targeting granulocytes and S100A4 may be effective approaches to inhibit the glioma malignant phenotype and diminish antiangiogenic therapy resistance.
Insights
Neutrophils promote glioma progression and resistance to anti-VEGF therapy by increasing glioblastoma-initiating cell proliferation and migration. Targeting neutrophils and S100A4 may overcome this resistance.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Antiangiogenic therapy, including anti-VEGF, is crucial for blocking tumor vascularization but often faces acquired resistance.
- Mechanisms underlying tumor resistance to antiangiogenic therapy remain incompletely understood across various cancer types.
Purpose of the Study:
- To investigate the role of neutrophils in glioma progression and resistance to anti-VEGF therapy.
- To identify specific molecular targets mediating neutrophil-driven glioma malignancy.
Main Methods:
- In vitro and in vivo evaluation of neutrophil effects on glioma biology.
- Assessment of glioblastoma-initiating cells (GICs) proliferation, migration, and gene expression.
- Analysis of S100A4 as a potential mediator of neutrophil-induced tumor progression.
Main Results:
- Increased neutrophil infiltration correlates with higher glioma grade and resistance to anti-VEGF therapy.
- Neutrophils enhance GIC proliferation, migration, and induce a mesenchymal gene expression signature.
- S100A4 downregulation blocks neutrophil-driven tumor progression and enhances anti-VEGF therapy efficacy.
Conclusions:
- Neutrophil recruitment during anti-VEGF therapy promotes glioma progression and treatment resistance.
- Tumor progression, particularly with mesenchymal features, is partly mediated by S100A4, upregulated by neutrophils.
- Targeting granulocytes and S100A4 presents a potential strategy to overcome antiangiogenic therapy resistance in glioma.
