Significance of epidermal growth factor receptor in the radiation resistance of glioblastoma tumors

Miklós Petrás, Tamás Lajtos, Éva Pintye, Burt G. Feuerstein, János Szöllosi, György Vereb

Research output: Contribution to journalConference article

Abstract

In the United States, a dramatically increased incidence and mortality of brain tumors have been observed over the past decades. Of the ∼44 thousand new cases of primary malignant and benign brain tumors diagnosed per year, high grade astrocytomas or multiform glioblastomas show particularly bad prognosis in spite of therapeutic developments. Current management of multiform glioblastoma includes the most extensive surgical resection possible, followed by adjuvant radio- and chemotherapy. However, treatment is frequently hampered by decreased radiosensitivity of the tumor. Recent studies revealed that subpopulations of glioblastoma cells show amplified checkpoint activation of the cell cycle upon ionizing radiation, which induces overactivation of DNA repair processes and leads to maintained proliferation rate as well as clinically observed radioresistance and recurrence of the tumor over time. In addition, overexpression of some transmembrane receptors has also been implicated in radioresistance. However, the role of the overexpressed proteins can only be interpreted reliably if their multi-faceted molecular interactions are properly characterized. Thus, based on recent evidence for the functional crosstalk between certain cell adhesion molecules and receptor tyrosine kinases, we have examined the molecular interactions of the receptor tyrosine kinase EGFR and the cell adhesion molecule β1-integrin using flow cytometric and microscopic fluorescence resosnance energy transfer (FRET) measurements on two cellular model systems showing similar expression patterns to low and high grade astrocytomas. On the one hand, U251 glioblastoma clones established by introducing varying amounts of extra chromosome 7 into the cells, and on the other hand stable, high and low EGFR expressing transfenctant U251 NCI sublines were investigated. The results revealed that increased EGFR and β1-integrin expression levels correlate with stronger EGFR - β1-integrin heteroassociation, while concurrently the EGFR homoassociation is decreased, suggesting that β1-integrins may dynamically modulate the homoassociation state of EGFR receptors. This functional relationship may play an important role in decreasing radiosensitivity and tumor progression, especially since the EGFR - β1-integrin molecular interaction appears to promote radioresistance via the Akt pathway.

Original languageEnglish
Pages (from-to)204-217
Number of pages14
JournalAIP Conference Proceedings
Volume1080
DOIs
Publication statusPublished - Dec 1 2008
Event5th International Conference on Radiation Damage in Biomolecular Systems, RADAM 2008 - Debrecen, Hungary
Duration: Jun 13 2008Jun 15 2008

Keywords

  • β1-integrin
  • Astrocytoma
  • EGFR
  • Fluorescence resonance energy transfer
  • Laser scanning confocal microscopy
  • Radioresistance
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Physics and Astronomy(all)

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