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Molecular Biology and Genetics |
Pathway Identified in Childhood Astrocytomas by Angiogenesis Gene Profiling1 ,,2
Center for Cancer Research, Children’s Research Institute [S. K., K. M. P., C. L., T. J. M.], Research Center for Genetic Medicine, Children’s Research Institute [K. M. B., D. D., D. A. S.], and Department of Pathology [M. R. S.], Children’s National Medical Center, Washington, DC 20010; Department of Preventative Medicine, Division of Biostatistics, Vanderbilt University, Nashville, Tennessee 37232 [B. L.]; and Graduate Program in Genetics, George Washington University, Washington, DC 20052 [K. M. B.]
Intense angiogenesis proliferation, a histopathological hallmark distinguishing malignant from benign astrocytoma, is vital for tumor progression. Thus, identifying and targeting specific pathways that promote malignant astrocytoma-induced angiogenesis could have substantial therapeutic benefit. Expression profiling of 13 childhood astrocytomas to determine the expression pattern of 133 angiogenesis-related genes revealed that 44 (33%) genes were differentially expressed (17 were overexpressed, and 27 were underexpressed) between malignant high-grade astrocytomas (HGAs) and benign low-grade astrocytomas. Hierarchical clustering and principal components analysis using only the 133 angiogenesis-related genes distinguished HGA from low-grade astrocytoma in 100% of the samples analyzed, as did unsupervised analyses using the entire set of 9198 expressed genes represented on the array, indicating that the angiogenesis-related genes were reliable markers of pathological grade. A striking new finding was significant overexpression of hypoxia-inducible transcription factor (HIF)-2
as well as high-level expression of FK506-binding protein (FKBP) 12 by HGA. Furthermore, 9 of 21 (43%) genes overexpressed by HGA were HIF/FKBP-associated genes. This group included the epidermal growth factor receptor (EGFR), which promotes HIF synthesis, as well as insulin-like growth factor-binding protein 2 (IGFBP2), a target gene of HIF activity. Differential protein expression of HIF-2 was validated in an independent group of 16 astrocytomas (P = 0.02). We conclude that the EGFR/FKBP12/HIF-2 pathway is important in childhood HGA and represents a potential new therapeutic target.
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