Overexpression of the EGFR/FKBP12/HIF-2 Pathway Identified in Childhood Astrocytomas by Angiogenesis Gene Profiling1,2

Intense angiogenesis proliferation, a histopathological hallmark distin- guishing malignant from benign astrocytoma, is vital for tumor progres- sion. Thus, identifying and targeting specific pathways that promote malignant astrocytoma-induced angiogenesis could have substantial ther- apeutic benefit. Expression profiling of 13 childhood astrocytomas to determine the expression pattern of 133 angiogenesis-related genes re- vealed that 44 (33%) genes were differentially expressed (17 were over- expressed, 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 angio- genesis-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 pro- tein 2 (IGFBP2), a target gene of HIF activity. Differential protein expres- sion 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.