Abstract
The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs. It promotes both EC network formation and enhances directed migration toward basic fibroblast growth factor. Activation of αvβ3 and bone marrow tyrosine kinase on chromosome X (BMX) is required for migration stimulated by direct binding but not for migration stimulated by soluble factors. RGD-peptide treatment of mice with established intracerebral GBM xenografts significantly reduced the percentage of Sox2-positive tumor cells and CSCs in close proximity to ECs, decreased integrin αvβ3 and BMX activation and p130CAS phosphorylation in the ECs, and reduced the vessel surface area. These results reveal a previously unrecognized aspect of the regulation of angiogenesis in GBM that can impact therapeutic anti-angiogenic targeting.
Highlights
A highly angiogenic phenotype is a distinctive feature of glioblastoma (GBM), and is thought to contribute to the aggressive growth, invasive phenotype and post-therapy recurrence of these tumors [1,2,3]
Direct contact of endothelial cells (ECs) and cells with cancer stemlike properties (CSCs) involving cellcell adhesion mediated by integrin αvβ3 on ECs and L1CAM on CSCs
Using a cell-cell adhesion assay, we found that the CSCs readily adhere/bind to a confluent monolayer of ECs plated on collagen and that 4-fold more CSCs adhered/ bound to ECs than to astrocytes (Figure 1A, SFigure 1A)
Summary
A highly angiogenic phenotype is a distinctive feature of glioblastoma (GBM), and is thought to contribute to the aggressive growth, invasive phenotype and post-therapy recurrence of these tumors [1,2,3]. In GBM and other cancers, pro-angiogenic signaling molecules, including basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGF-A), are secreted by stromal cells and tumor www.impactjournals.com/oncotarget cells. These factors promote endothelial (EC) activation, survival, protease secretion, sprouting and migration [2,3,4,5]. Cell surface-expressed integrins recognize and are activated by ligands typically localized in the extracellular environment. L1CAM binds to RGDpeptide-binding integrins, including integrin αvβ due to the presence of an RGD-peptide in its extracellular sixth Ig domain and this peptide appears to be necessary for the pro-migratory and pro-invasive effects of L1CAM in cancer cells [13,14,15,16,17,18]
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