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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.

Background and purpose To investigate the effect of radiotherapy planning with a dedicated combined PET-CT simulator of patients with locally advanced non-small cell lung cancer. Patients and methods Twenty-one patients underwent a pre-treatment simulation on a dedicated hybrid PET-CT-simulator. For each patient, two 3D conformal treatment plans were made: one with a CT based PTV and one with a PET-CT based PTV, both to deliver 60 Gy in 30 fractions. The maximum tolerable prescribed radiation dose for CT versus PET-CT PTV was calculated based on constraints for the lung, the oesophagus, and the spinal cord, and the Tumour Control Probability (TCP) was estimated. Results For the same toxicity levels of the lung, oesophagus and spinal cord, the dose could be increased from 55.2±2.0 Gy with CT planning to 68.9±3.3 Gy with the use of PET-CT (P=0.002), with corresponding TCP's of 6.3±1.5% for CT and 24.0±5.6% for PET-CT planning (P=0.01). Conclusions The use of a combined dedicated PET-CT-simulator reduced radiation exposure of the oesophagus and the lung, and thus allowed significant radiation dose escalation whilst respecting all relevant normal tissue constraints.