Data from Neutrophils Promote the Malignant Glioma Phenotype through S100A4

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> In this study, we evaluated the effects of neutrophils on glioma biology both <i>in vitro</i> and <i>in vivo</i> and determined target genes by which neutrophils promote the malignant glioma phenotype during anti-VEGF therapy.</p><p><b>Results:</b> 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 <i>in vitro</i> and <i>in vivo</i>. Furthermore, S100A4 depletion increased the effectiveness of anti-VEGF therapy in glioma.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 20(1); 187–98. ©2013 AACR</i>.</p></div>

Insights into the glioblastoma tumor microenvironment: current and emerging therapeutic approaches

“…Another strategy is to target endothelial cell survival and migratory pathways such as PI3K/Akt and mTOR (Charles et al, 2012). However, these approaches have limitations and can interfere with normal endothelial cell functions, resulting in negative outcomes (Liang et al, 2014). Immunotherapy is another intriguing strategy that targets the immune regulatory activities of endothelial cells.…”