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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Shalaby, A; Presneau, N; Ye, H; Halai, D; Berisha, F; Idowu, B; Leithner, A; Liegl, B; Briggs, TR; Bacsi, K; Kindblom, LG; Athanasou, N; Amary, MF; Hogendoorn, PC; Tirabosco, R; Flanagan, AM.
The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target.
J Pathol. 2011; 223(3): 336-346.
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Autor/innen der Med Uni Graz:
Leithner Andreas
Liegl-Atzwanger Bernadette
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Abstract:
Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of chordoma. Paraffin-embedded material from 173 chordomas from 160 patients [sacro-coccygeal (n = 94), skull-based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative chordomas analysed by FISH, 38% revealed high-level EGFR polysomy, 4% high-level polysomy with focal amplification, 18% low-level polysomy, and 39% disomy. Phospho-receptor tyrosine kinase array membranes showed EGFR activation in the chordoma cell line U-CH1 and all of the three chordomas analysed. Direct sequencing of EGFR (exons 18-21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed chordomas, only one of which revealed high-level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists.
Find related publications in this database (using NLM MeSH Indexing)
Antineoplastic Agents - pharmacology
Bone Neoplasms - genetics
Cell Proliferation - drug effects
Chordoma - genetics
DNA Mutational Analysis - methods
Dose-Response Relationship, Drug -
Drug Evaluation, Preclinical - methods
Enzyme Inhibitors - pharmacology
Humans -
In Situ Hybridization, Fluorescence -
Mutation -
Neoplasm Proteins - metabolism
Receptor Protein-Tyrosine Kinases - metabolism
Receptor, Epidermal Growth Factor - antagonists and inhibitors
Receptor, erbB-2 - metabolism
Skull Base Neoplasms - metabolism
Tumor Cells, Cultured -
Tyrphostins - pharmacology

Find related publications in this database (Keywords)
EGFR
chordoma
polysomy
amplification
genetics
PTEN
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