KDR activation in astrocytic neoplasms

• Published in: Cancer Vol. 86; no. 7; pp. 1335 - 1341
• Main Authors: Carroll, Rona S., Zhang, Jianping, Bello, Lorenzo, Melnick, Michael B., Maruyama, Taka, McL Black, Peter
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01-10-1999; Wiley-Liss
• Subjects: angiogenesis; Antibodies; Astrocytoma - metabolism; Astrocytoma - pathology; Biological and medical sciences; Blotting, Western; Brain; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; carcinoma; Cell Line; Disease Progression; Endothelial Growth Factors - metabolism; Female; Glioblastoma - metabolism; Humans; Lymphokines - metabolism; Male; Medical sciences; Neovascularization, Pathologic; Neurology; Phosphorylation; Protein Isoforms - metabolism; Receptor Protein-Tyrosine Kinases - immunology; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Growth Factor - immunology; Receptors, Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor; Tumors of the nervous system. Phacomatoses; vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Human; Intracranial; Nervous system diseases; Angiogenic factor; Cytokine; Activation; Malignant tumor; Carcinogenesis; Cerebral disorder; Malignant glioma; Angiogenesis; Vascular endothelium growth factor; Malignant astrocytoma; Central nervous system disease; Tumor progression; Neovascularization; Growth factor; Biological receptor
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/(SICI)1097-0142(19991001)86:7<1335::AID-CNCR32>3.0.CO;2-Z

BACKGROUND
The development of new capillary networks appears to be necessary for the growth of solid tumors. Tumor angiogenesis is believed to be mediated by soluble factors released from tumor cells that then act on endothelial cells in a paracrine manner. Vascular endothelial growth factor (VEGF) is a prime regulator of normal and tumor angiogenesis as well as vasculogenesis. VEGF is expressed in glioma cells and its receptors (Flt‐1 and KDR) are expressed in the same gliomas. The two receptors are tyrosine kinases and have an extracellular domain containing seven immunoglobulin‐like loops and a split tyrosine‐kinase domain. KDR is a receptor for the various VEGF isoforms and for VEGF‐C; Flt‐1 is a receptor for the various isoforms. Studies suggest that the VEGF receptors are induced in endothelial cells during tumor angiogenesis. Stimulation of aortic endothelial cells results in receptor tyrosine phosphorylation (receptor activation). In this study the activation state of the KDR receptors was determined in low grade, anaplastic, and high grade gliomas.
METHODS
A synthetic tyrosine phosphopeptide was used to raise an antibody that recognizes the phosphorylation state of tyrosine 1054/1059 in the KDR receptor. Western blot analysis was performed on 37 astrocytic neoplasms (7 low grade astrocytomas, 13 anaplastic astrocytomas, and 17 cases of glioblastoma multiforme).
RESULTS
Immunoblotting with this antibody found that tyrosines 1054/1059 were phosphorylated constitutively within multiple fresh surgical specimens of glioblastomas (71%) and anaplastic gliomas (15%), but not in low grade gliomas.
CONCLUSIONS
The findings of the current study strongly support the hypothesis that the onset of angiogenesis is an important event during the disease progression of gliomas. Cancer 1999;86:1335–41. © 1999 American Cancer Society.
In this study the authors determined the activation state of the vascular endothelial growth factor receptor, KDR, in all grades of astrocytic neoplasms using an antibody that recognizes the phosphorylation state of tyrosines 1054/1059 in the receptor. Immunoblotting with this antibody shows that the receptor is phosphorylated constitutively within multiple fresh surgical specimens of glioblastomas (70%) and anaplastic gliomas (15%), but not in low grade gliomas. This strongly supports the hypothesis that the onset of angiogenesis is an important event during disease progression in gliomas.