title: Intrinsic radiation resistance of mesenchymal cancer stem cells and implications for treatment response in a murine sarcoma model.
abstract: Cancer stem cells are emerging as a new critical target for successful outcome in radiation treatment, as prognosis for patients with stem cell positive tumours are worse than average. The majority of the cells composing the tumour burden may be killed off by the radiation doses normally used in standard treatment, but the cancer stem cells may escape cell death due to their heightened damage resistance. Whereas the influence of hypoxic areas on radiation therapy is well described and countered by selective extra treatment when needed, there is currently no specific treatment against cancer stem cells. Therefore, understanding the fundamental mechanisms of cancer stem cells' resistance to treatment and their response to radiotherapy is of interest.  Several cell lines derived from a unique human mesenchymal cancer stem cell model, consisting of both a non-tumourigenic and several tumourigenic stem cell lines, were used to investigate the relationship between tumourigenicity, radiation resistance and stemness of cancer cells.  Using the non-tumourigenic and tumourigenic clones the relationship between tumourigenicity and radiation resistance of stem cells was investigated. The cancer stem cells were more radiation resistant than normal stem cells and this could be due to the described difference in gene expression. Several genes involved in matrix maintenance and apoptosis had altered levels of expression and this could be the driving force behind the cancer stem cells enhanced radiation resistance.  Difference in in vitro radiation resistance was found between two closely related tumourigenic clones. The enhanced radiation resistance seems to stem from the overexpression on the NNMT gene. This gene is linked with resistance to both chemotherapy and radiation and encodes an enzyme, which consumes nicotinamide. The DNA single strand repair protein PARP1 is inhibited by nicotinamide and lower cellular levels may enhance DNA damage repair, thereby granting radiation resistance.  The observed in vitro radiation resistance was found to predict in vivo radiation resistance of the same clones as measured by tumour control. The xenografts were found to have no difference in microenvironmental factors, hereunder especially hypoxia. This corroborates the genetic cause for radiation resistance.  Overall the results indicate a link between tumourigenicity and radiation resistance for cancer stem cells. These results support the cancer stem cell theory and furthermore underscore the need for targeting cancer stem cell in the clinic.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Bldg. 5, 8000 Aarhus C, Denmark. filippo@oncology.dk
authors.forename: Filippo Peder
authors.initials: FP
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000528:radiation effects*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011836:Radiation Tolerance; D012509:Sarcoma / Q000235:genetics / Q000532:radiotherapy*