EGFR signaling regulates tumor cell migration in craniopharyngiomas.

Abstract

PURPOSE:

Constitutive Wnt signaling caused by mutations in the β-catenin gene is a molecular hallmark of adamantinomatous craniopharyngiomas (adaCP) and promotes infiltration into adjacent brain tissue. Herein, we studied the pathogenic role of epidermal growth factor receptor (EGFR) activation in adaCP and whether tumor cell migration can be inhibited by the tyrosine kinase inhibitor gefitinib.

EXPERIMENTAL DESIGN:

EGFR expression and activation [phosphorylated EGFR (EGFR-P)] was examined in a cohort of 25 surgical adaCP samples by PCR and Western blotting. Regional and cellular localization patterns of EGFR-P, β-catenin, and its target gene product Fascin were determined by immunofluorescence microscopy. Mutation analysis and gene copy number assay were carried out to examine genetic alterations in the EGFR gene. The impact of EGFR signaling on tumor cell migration was studied in vitro by using 11 primary human adaCP cultures treated with the EGFR ligand EGF and its inhibitor gefitinib.

RESULTS:

Neither mutations nor amplifications in the EGFR gene were detected in our adaCP series. However, EGFR-P was detectable in tumor cell clusters located at the brain infiltration border and colocalized with nuclear β-catenin and Fascin. Activated EGFR significantly promoted tumor cell migration in vitro, whereas gefitinib reduced both tumor cell motility and Fascin expression.

CONCLUSION:

Our data suggest EGFR signaling to play a role in cell migration and brain infiltration of adaCP. Targeting the EGFR signaling pathway by gefitinib may present a promising pharmacologic option in the treatment of this challenging tumor disease.

• Authors: Annett Hölsken, Matthias Gebhardt, Michael Buchfelder, Rudolf Fahlbusch, Ingmar Blümcke, Rolf Buslei
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 13 Pg. 4367-77 (Jul 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21562037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Microfilament Proteins
• beta Catenin
• fascin
• ErbB Receptors

Topics

• Adolescent
• Adult
• Aged
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Cells, Cultured
• Child
• Child, Preschool
• Craniopharyngioma (genetics, pathology)
• DNA Copy Number Variations (genetics)
• ErbB Receptors (genetics, metabolism)
• Female
• Humans
• Male
• Microfilament Proteins (genetics, metabolism)
• Middle Aged
• Mutation (genetics)
• Phosphorylation
• Signal Transduction (genetics)
• Young Adult
• beta Catenin (genetics)