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  • Original Paper
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Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid

Oncogene volume 24, pages 8025–8037 (2005)Cite this article

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.

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Abbreviations

VEGF:

vascular endothelial growth factor

rhVEGF165:

recombinant human vascular endothelial growth factor (165 amino-acid isoform)

PlGF:

placenta growth factor

VEGFR:

vascular endothelial growth factor receptor

flt1:

fms-like tyrosine kinase receptor (or VEGFR1)

KDR:

kinase insert domain-containing receptor (or VEGFR2)

NRP:

neuropilin

RMS:

rhabdomyosarcoma

ARMS:

alveolar rhabdomyosarcoma

ERMS:

embryonal rhabdomyosarcoma

AtRA:

all-trans-retinoic acid

IGF-II:

insulin-like growth factor-II

bFGF:

basic fibroblast growth factor

EGF:

epidermal growth factor

TGF-β:

transforming growth factor

ERK:

extracellular signal-regulated kinase

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Acknowledgements

This work was funded by the Andrew Mizzoni Cancer Research Fund and the James Birrell Research Fund and through studentships of the Ontario Student Opportunity Trust Fund – Hospital for Sick Children Foundation Student Scholarship Program (MG, BD) and the Brainchild Foundation (BD). RT is supported in part by the Scotiabank Clinician-Scientist Training Program Fund and the Research Training Centre, Hospital for Sick Children, Toronto. DM is a Research Scientist of the National Cancer Institute of Canada/Canadian Cancer Society. We are grateful for helpful discussions with Drs Herman Yeger and Meredith Irwin.

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  1. Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Matthew F W Gee, Rika Tsuchida, Claudia Eichler-Jonsson, Bikul Das, Sylvain Baruchel & David Malkin

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Matthew F W Gee & David Malkin

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Gee, M., Tsuchida, R., Eichler-Jonsson, C. et al. Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid. Oncogene 24, 8025–8037 (2005). https://doi.org/10.1038/sj.onc.1208939

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