Abstract
Human glioblastomas (GBM) are thought to be initiated by glioma stem-like cells (GSLCs). GSLCs also participate in tumor neovascularization by transdifferentiating into vascular endothelial cells. Here, we report a critical role of GSLCs in the formation of vasculogenic mimicry (VM), which defines channels lined by tumor cells to supply nutrients to early growing tumors and tumor initiation. GSLCs preferentially expressed vascular endothelial growth factor receptor-2 (VEGFR-2) that upon activation by VEGF, mediated chemotaxis, tubule formation and increased expression of critical VM markers by GSLCs. Knockdown of VEGFR-2 in GSLCs by shRNA markedly reduced their capacity of self-renewal, forming tubules, initiating xenograft tumors, promoting vascularization and the establishment of VM. Our study demonstrates VEGFR-2 as an essential molecule to sustain the "stemness" of GSLCs, their capacity to initiate tumor vasculature, and direct initiation of tumor.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Disease Models, Animal
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression
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Gene Expression Regulation, Neoplastic
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glioma / genetics*
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Glioma / pathology*
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Heterografts
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Humans
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Mice
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Neovascularization, Pathologic / genetics*
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Neovascularization, Pathologic / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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RNA Interference
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / genetics*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Vascular Endothelial Growth Factor A
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Phosphatidylinositol 3-Kinases
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Vascular Endothelial Growth Factor Receptor-2
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases