title: Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells.
abstract: BACKGROUND
  Resistance to radiation therapy remains a serious impediment to cancer therapy. We previously reported heterogeneity for clonogenic survival when testing in vitro radiation resistance among single-cell derived clones from a human mesenchymal cancer stem cell model (hMSC). Here we aimed to determine whether this heterogeneity persisted in tumours established from these clones, and whether the response to radiation treatment was principally governed by cell-intrinsic qualities or by factors pertaining to the tumour microenvironment, such as the degree of hypoxia and vascularization.
  
  
  METHODS
  Immune-deficient female mice were implanted on the backs with cells from one of the clones. The subsequent tumours were subjected to either radiation treatment or had the tumour microenvironment assayed, when they reached 400 mm³. Radiation was given as a single fraction of 0-15 Gy and the degree of tumour control and time to three times the treatment volume were noted. Tumours used for the microenvironmental assay had intratumoral hypoxia measured by the Eppendorf oxygen electrode and pimonidazole staining, and the extent of vascularization determined by a microvasculature density assay using endothelial-specific staining.
  
  
  RESULTS
  All microenvironmental assays indicated a similar degree of hypoxia and vascularization for the selected clones. Nonetheless, the tumours responded differently to radiation treatment since the BB3 clone displayed tumour control at 5, 10 and 15 Gy, whereas tumour control was not seen below 15 Gy with the CE8 clone.
  
  
  CONCLUSIONS
  For tumours that displayed similar degrees of oxygenation and vascularization, the clone-specific in vitro radiation resistance could predict the in vivo response to radiation treatment. These results favor the hypothesis that intrinsic genetic factors can govern radiation resistance in this cancer stem cell model.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. filippo@oncology.dk
authors.forename: Filippo P
authors.initials: FP
authors.lastname: D'Andrea
authors.forename: Akmal
authors.initials: A
authors.lastname: Safwat
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Burns
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.forename: Michael R
authors.initials: MR
authors.lastname: Horsman
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000532:radiotherapy; D059630:Mesenchymal Stem Cells / Q000473:pathology* / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000528:radiation effects; D010100:Oxygen / Q000378:metabolism; D011836:Radiation Tolerance; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000209:etiology* / Q000473:pathology / Q000532:radiotherapy*; D059016:Tumor Microenvironment / Q000235:genetics / Q000528:radiation effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010100:Oxygen