Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells
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Monica E. Burgett1,6, Justin D. Lathia2, Patrick Roth7, Amy S. Nowacki4, Deni S. Galileo10, Elena Pugacheva8, Ping Huang1, Amit Vasanji9, Meizhang Li2, Tatiana Byzova5, Tom Mikkelsen11, Shideng Bao3, Jeremy N. Rich3, Michael Weller7, Candece L. Gladson1
1Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA
2Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA
3Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA
4Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
5Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA
6School of Biomedical Sciences, Kent State University, Kent, OH, USA
7Department of Neurology, Laboratory of Molecular Neuro-Oncology, University Hospital, Zurich, Switzerland
8Department of Biochemistry, West Virginia University, Morgantown, VA, USA
9Image IQ, Inc., Cleveland, OH, USA
10Department of Biological Sciences, University of Delaware and Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA
11Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA
Candece L. Gladson, email: email@example.com
Keywords: endothelial cells, glioblastoma, angiogenesis, integrin αvβ3, cancer stem cells
Received: September 24, 2015 Accepted: May 13, 2016 Published: May 30, 2016
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.
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