E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells

Jan Theys*, Barry Jutten, Roger Habets, Kim Paesmans, Arjan J. Groot, Philippe Lambin, Brad G. Wouters, Guido Lammering, Marc Vooijs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

171 Citations (Web of Science)

Abstract

Background and purpose: Hypoxia is a hallmark of solid cancers and associated with metastases and treatment failure. During tumor progression epithelial cells often acquire mesenchymal features, a phenomenon known as epithelial-to-mesenchymal transition (EMT). Intratumoral hypoxia has been linked to EMT induction. We hypothesized that signals from the tumor microenvironment such as growth factors and tumor oxygenation collaborate to promote EMT and thereby contribute to radioresistance. Materials and methods: Gene expression changes under hypoxia were analyzed using microarray and validated by qRT-PCR. Conversion of epithelial phenotype upon hypoxic exposure, TGF beta addition or oncogene activation was investigated by Western blot and immunofluorescence. Cell survival following ionizing radiation was assayed using clonogenic survival. Results: Upon hypoxia, TGF beta addition or EGFRvIII expression, MCF7, A549 and NMuMG epithelial cells acquired a spindle shape and lost cell-cell contacts. Expression of epithelial markers such as E-cadherin decreased, whereas mesenchymal markers such as vimentin and N-cadherin increased. Combining hypoxia with TGF beta or EGFRvIII expression, lead to more rapid and pronounced EMT-like phenotype. Interestingly, E-cadherin expression and the mesenchymal appearance were reversible upon reoxygenation. Mesenchymal conversion and E-cadherin loss were associated with radioresistance. Conclusions: Our findings describe a mechanism by which the tumor microenvironment may contribute to tumor radioresistance via E-cadherin loss and EMT.
Original languageEnglish
Pages (from-to)392-397
JournalRadiotherapy and Oncology
Volume99
Issue number3
DOIs
Publication statusPublished - Jun 2011

Keywords

  • Tumor hypoxia
  • Microenvironment
  • E-Cadherin
  • Radioresistance
  • EMT

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