title: Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling.
abstract: 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.
authors.affiliation: Center for Cancer Research, Children's Research Institute, Washington, DC 20010, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Khatua
authors.forename: Katia M
authors.initials: KM
authors.lastname: Peterson
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.forename: Christopher
authors.initials: C
authors.lastname: Lawlor
authors.forename: Maria R
authors.initials: MR
authors.lastname: Santi
authors.forename: Bonnie
authors.initials: B
authors.lastname: LaFleur
authors.forename: Devin
authors.initials: D
authors.lastname: Dressman
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
mesh_terms: 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
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D022061:Tacrolimus Binding Protein 1A; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1