Overexpression of the EGFR/FKBP12/HIF-2α pathway identified in childhood astrocytomas by angiogenesis gene profiling

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-04, Vol.63 (8), p.1865-1870
• Main Authors: KHATUA, Soumen, PETERSON, Katia M, BROWN, Kevin M, LAWLOR, Christopher, SANTI, Maria R, LAFLEUR, Bonnie, DRESSMAN, Devin, STEPHAN, Dietrich A, MACDONALD, Tobey J
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Neurology; Tumors of the nervous system. Phacomatoses
• ISSN: 0008-5472; 1538-7445

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 alpha 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 alpha was validated in an independent group of 16 astrocytomas (P = 0.02). We conclude that the EGFR/FKBP12/HIF-2 alpha pathway is important in childhood HGA and represents a potential new therapeutic target.