Abstract
Vascular endothelial growth factor (VEGF) is a potent signalling molecule that acts through two tyrosine kinase receptors, VEGFR1 and VEGFR2. The upregulation of VEGF and its receptors is important in tumour-associated angiogenesis; however, recent studies suggest that several tumour cells express VEGF receptors and may be influenced by autocrine VEGF signalling. Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, and is dependent on autocrine signalling for its growth. The alveolar subtype of RMS is often characterized by the presence of a PAX3-FKHR translocation, and when introduced into non-RMS cells, the resultant fusion protein induces expression of VEGFR1. In our study, we examined the expression of VEGF and its receptors in RMS, and autocrine effects of VEGF on cell growth. VEGF and receptor mRNA and protein were found to be expressed in RMS cells. Exogenous VEGF addition resulted in extracellular signal-regulated kinase-1/2 phosphorylation and cell proliferation, and both were reduced by VEGFR1 blockade. Growth was also slowed by VEGFR1 inhibitor alone. Treatment of RMS cells with all-trans-retinoic acid decreased VEGF secretion and slowed cell growth, which was rescued by VEGF. These data suggest that autocrine VEGF signalling likely influences RMS growth and its inhibition may be an effective treatment for RMS.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Autocrine Communication / drug effects*
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Autocrine Communication / physiology
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Blotting, Western
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Cell Count
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Cell Culture Techniques
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Cell Division / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Fluorescent Antibody Technique, Indirect
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Gene Expression Regulation, Neoplastic / drug effects
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HeLa Cells
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Humans
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Phosphorylation / drug effects
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RNA, Messenger / analysis
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Rhabdomyosarcoma, Alveolar / genetics
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Rhabdomyosarcoma, Alveolar / metabolism*
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Rhabdomyosarcoma, Alveolar / pathology
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Rhabdomyosarcoma, Embryonal / genetics
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Rhabdomyosarcoma, Embryonal / metabolism*
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Rhabdomyosarcoma, Embryonal / pathology
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Tretinoin / pharmacology*
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Umbilical Veins / cytology
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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 A / pharmacology*
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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RNA, Messenger
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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Tretinoin
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3