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, TGFβ addition or oncogene activation was investigated by 
Western blot and immunofluorescence. Cell survival following ionizing radiation 
was assayed using clonogenic survival.
RESULTS: Upon hypoxia, TGFβ 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 TGFβ 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.