Abstract
Development of hypoxic regions is an indicator of poor prognosis in many tumors. Here, we demonstrate that HIF1alpha, the direct effector of hypoxia, partly through increases in SDF1alpha, induces recruitment of bone marrow-derived CD45+ myeloid cells containing Tie2+, VEGFR1+, CD11b+, and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells to promote neovascularization in glioblastoma. MMP-9 activity of bone marrow-derived CD45+ cells is essential and sufficient to initiate angiogenesis by increasing VEGF bioavailability. In the absence of HIF1alpha, SDF1alpha levels decrease, and fewer BM-derived cells are recruited to the tumors, decreasing MMP-9 and mobilization of VEGF. VEGF also directly regulates tumor cell invasiveness. When VEGF activity is impaired, tumor cells invade deep into the brain in the perivascular compartment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation / metabolism
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Benzylamines
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Bone Marrow Cells / enzymology*
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Bone Marrow Cells / immunology
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Bone Marrow Transplantation
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Brain Neoplasms / blood supply*
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Brain Neoplasms / enzymology
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Brain Neoplasms / pathology
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Cell Hypoxia
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Cell Line
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Cell Movement
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Chemokine CXCL12 / metabolism
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Cyclams
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Endothelial Cells / enzymology
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Glioblastoma / blood supply*
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Glioblastoma / enzymology*
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Glioblastoma / pathology
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Heterocyclic Compounds / pharmacology
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Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Leukocyte Common Antigens / metabolism
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Matrix Metalloproteinase 9 / deficiency
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Knockout
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Monocytes / enzymology
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Neoplasm Invasiveness
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Neovascularization, Pathologic / enzymology*
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Neovascularization, Pathologic / pathology
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Pericytes / enzymology
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Receptor, TIE-2 / metabolism
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / metabolism
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Signal Transduction
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Transduction, Genetic
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
Substances
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Antigens, Differentiation
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Benzylamines
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Chemokine CXCL12
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Cxcl12 protein, mouse
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Cxcr4 protein, rat
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Cyclams
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Heterocyclic Compounds
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Receptors, CXCR4
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Vascular Endothelial Growth Factor A
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monocyte-macrophage differentiation antigen
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-1
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Leukocyte Common Antigens
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Ptprc protein, mouse
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse
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plerixafor