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The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell-mediated VEGF production and tumour angiogenesis via PI3K/AKT signalling.
- Source :
-
The Journal of pathology [J Pathol] 2011 Jul; Vol. 224 (3), pp. 344-54. Date of Electronic Publication: 2011 May 27. - Publication Year :
- 2011
-
Abstract
- Chemokines and their receptors are actively involved in inflammation, immune responses, and cancer development. Here we report the detection of CD133(+) glioma stem-like cells (GSCs) co-expressing a chemokine receptor CXCR4 in human primary glioma tissues. These GSCs were located in areas adjacent to tumour vascular capillaries, suggesting an association between GSCs and tumour angiogenesis. To test this hypothesis, we isolated CD133(+) GSCs from surgical specimens of human primary gliomas and glioma cell lines. As compared to CD133(-) cells, CD133(+) GSCs expressed significantly higher levels of CXCR4 mRNA and protein, and migrated more efficiently in response to the CXCR4 ligand CXCL12. In addition, CXCL12 induced vascular endothelial growth factor (VEGF) production by CD133(+) GSCs via activation of the PI3K/AKT signalling pathway. Furthermore, knocking down of CXCR4 using RNA interference or inhibition of CXCR4 function by an antagonist AMD3100 not only reduced VEGF production by CD133(+) GSCs in vitro, but also attenuated the growth and angiogenesis of tumour xenografts in vivo formed by CD133(+) GSCs in SCID mice. These results indicate that CXCL12 and its receptor CXCR4 promote GSC-initiated glioma growth and angiogenesis by stimulating VEGF production.<br /> (Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Subjects :
- AC133 Antigen
Animals
Antigens, CD metabolism
Benzylamines
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Cyclams
Gene Knockdown Techniques
Glioma blood supply
Glioma drug therapy
Glioma pathology
Glycoproteins metabolism
Heterocyclic Compounds pharmacology
Heterocyclic Compounds therapeutic use
Humans
Mice
Mice, SCID
Neoplasm Proteins metabolism
Neoplasm Proteins physiology
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Neovascularization, Pathologic drug therapy
Neovascularization, Pathologic pathology
Peptides metabolism
Phosphatidylinositol 3-Kinases physiology
Platelet Endothelial Cell Adhesion Molecule-1 metabolism
RNA, Small Interfering genetics
Receptors, CXCR4 antagonists & inhibitors
Receptors, CXCR4 genetics
Signal Transduction physiology
Tumor Stem Cell Assay
Xenograft Model Antitumor Assays
Chemokine CXCL12 physiology
Glioma metabolism
Neovascularization, Pathologic metabolism
Receptors, CXCR4 physiology
Vascular Endothelial Growth Factor A biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1096-9896
- Volume :
- 224
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 21618540
- Full Text :
- https://doi.org/10.1002/path.2908