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

Soumen Khatua, Katia M. Peterson, Kevin M. Brown, Christopher Lawlor, Maria R. Santi, Bonnie LaFleur, Devin Dressman, Dietrich A. Stephan, Tobey J. MacDonald

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)1865-1870
Number of pages6
JournalCancer Research
Volume63
Issue number8
StatePublished - Apr 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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