Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling.
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)-2alpha 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-2alpha was validated in an independent group of 16 astrocytomas (P = 0.02). We conclude that the EGFR/FKBP12/HIF-2alpha pathway is important in childhood HGA and represents a potential new therapeutic target.
Khatua
Soumen
S
Center for Cancer Research, Children's Research Institute, Washington, DC 20010, USA.
Peterson
Katia M
KM
Brown
Kevin M
KM
Lawlor
Christopher
C
Santi
Maria R
MR
LaFleur
Bonnie
B
Dressman
Devin
D
Stephan
Dietrich A
DA
MacDonald
Tobey J
TJ
D001254:Astrocytoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D002648:Child; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D022061:Tacrolimus Binding Protein 1A / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D022061:Tacrolimus Binding Protein 1A; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1