title: Vascular endothelial growth factor directly stimulates tumour cell proliferation in non-small cell lung cancer.
abstract: Vascular endothelial growth factor (VEGF) is a key stimulator of physiological and pathological angiogenesis. VEGF signals primarily through VEGF receptor 2 (VEGFR2), a receptor tyrosine kinase whose expression is found predominantly on endothelial cells. The purpose of this study was to determine the role of VEGFR2 expression in NSCLC cells. NSCLC cells and tissue sections were stained for VEGFR2 expression by immunohistochemistry (IHC). Immunoblotting and ELISA were used to determine the activation and inhibition of VEGFR2 and its downstream signalling pathways. Five-day proliferation assays were carried out in the presence or absence of VEGF. IHC analysis of NSCLC demonstrated tumour cell VEGFR2 expression in 20% of samples. Immunoblot analysis showed expression of VEGFR2 protein in 3/8 NSCLC cell lines that correlated with VEGFR2 mRNA expression levels. VEGF-dependent VEGFR2 activation was apparent in NSCLC cells, and was associated with increased tumor cell proliferation. Cediranib treatment or siRNA against VEGFR2 inhibited VEGF-dependent increases in cell proliferation. Inhibition of VEGFR2 tyrosine kinase activity using cediranib was more effective than inhibition of AKT (MK2206) or MEK (AZD6244) for overcoming VEGFR2-driven cell proliferation. VEGF treatment did not affect cell survival following treatment with radiation, cisplatin, docetaxel or gemcitabine. Our data suggest that a subset of NSCLC tumour cells express functional VEGFR2 which can act to promote VEGF-dependent tumour cell growth. In this tumour subset, therapies targeting VEGFR2 signalling, such as cediranib, have the potential to inhibit both tumour cell proliferation and angiogenesis.
authors.affiliation: CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Aoife M
authors.initials: AM
authors.lastname: Devery
authors.affiliation: CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Rekha
authors.initials: R
authors.lastname: Wadekar
authors.affiliation: CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Sivan M
authors.initials: SM
authors.lastname: Bokobza
authors.affiliation: CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Anika M
authors.initials: AM
authors.lastname: Weber
authors.affiliation: CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
mesh_terms: D001562:Benzimidazoles; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism*; D007211:Indoles
chemical_list: D001562:Benzimidazoles; D006575:Heterocyclic Compounds, 3-Ring; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C517975:AZD 6244; C548887:MK 2206; C000588866:KDR protein, human; C500926:cediranib; D007211:Indoles