Direct contact with perivascular tumor cells enhances integrin βvβ3 signaling and migration of endothelial cells

被引:29
|
作者
Burgett, Monica E. [1 ,6 ]
Lathia, Justin D. [2 ]
Roth, Patrick [7 ]
Nowacki, Amy S. [4 ]
Galileo, Deni S. [10 ,11 ,12 ]
Pugacheva, Elena [8 ]
Huang, Ping [1 ]
Vasanji, Amit [9 ]
Li, Meizhang [2 ]
Byzova, Tatiana [5 ]
Mikkelsen, Tom [13 ]
Bao, Shideng [3 ]
Rich, Jeremy N. [3 ]
Weller, Michael [7 ]
Gladson, Candece L. [1 ]
机构
[1] Cleveland Clin, Dept Canc Biol, Cleveland, OH 44106 USA
[2] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA
[3] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44106 USA
[4] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA
[5] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA
[6] Kent State Univ, Sch Biomed Sci, Kent, OH 44242 USA
[7] Univ Hosp, Lab Mol Neurooncol, Dept Neurol, Zurich, Switzerland
[8] West Virginia Univ, Dept Biochem, Morgantown, VA USA
[9] Image IQ Inc, Cleveland, OH USA
[10] Univ Delaware, Dept Biol Sci, Newark, DE USA
[11] Helen F Graham Canc Ctr, Newark, DE USA
[12] Christiana Care Hlth Syst, Res Inst, Newark, DE USA
[13] Henry Ford Hosp, Dept Neurosurg, Detroit, MI 48202 USA
关键词
endothelial cells; glioblastoma; angiogenesis; integrin alpha v beta 3; cancer stem cells; ADHESION MOLECULE L1; GLIOBLASTOMA; GROWTH; KINASE; PROLIFERATION; ANGIOGENESIS; PATHWAYS; PROMOTES; L1CAM; BRAIN;
D O I
10.18632/oncotarget.9700
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 alpha v beta 3 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 alpha v beta 3 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 alpha v beta 3 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.
引用
收藏
页码:43852 / 43867
页数:16
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