EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis

Krishna M. Talasila, Anke Soentgerath, Philipp Euskirchen, Gro V. Rosland, Jian Wang, Peter C. Huszthy, Lars Prestegarden, Kai Ove Skaftnesmo, Per Øystein Sakariassen, Eskil Eskilsson, Daniel Stieber, Olivier Keunen, Narve Brekka, Ingrid Moen, Janice M. Nigro, Olav K. Vintermyr, Morten Lund-Johansen, Simone Niclou, Sverre J. Mørk, Per Øyvind EngerRolf Bjerkvig, Hrvoje Miletic*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

97 Citations (Scopus)

Abstract

Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, longterm expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth.

Original languageEnglish
Pages (from-to)683-698
Number of pages16
JournalActa Neuropathologica
Volume125
Issue number5
DOIs
Publication statusPublished - May 2013

Keywords

  • EGFR amplification
  • Glioblastoma
  • Invasion

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