title: Increased Notch Signaling Enhances Radioresistance of Malignant Stromal Cells Induced by Glioma Stem/ Progenitor Cells.
abstract: BACKGROUND
  Host malignant stromal cells induced by glioma stem/progenitor cells were revealed to be more radiation-resistant than the glioma stem/progenitor cells themselves after malignant transformation in nude mice. However, the mechanism underlying this phenomenon remains unclear.
  
  
  METHODS
  Malignant stromal cells induced by glioma stem/progenitor cell 2 (GSC-induced host brain tumor cells, ihBTC2) were isolated and identified from the double color-coded orthotopic glioma nude mouse model. The survival fraction at 2 Gy (SF2) was used to evaluate the radiation resistance of ihBTC2, the human glioma stem/progenitor cell line SU3 and its radiation-resistant sub-strain SU3-5R and the rat C6 glioma cell line. The mRNA of Notch 1 and Hes1 from ihBTC2 cells were detected using qPCR before and after 4 Gy radiation. The expression of the Notch 1, pAkt and Bcl-2 proteins were investigated by Western blot. To confirm the role of the Notch pathway in the radiation resistance of ihBTC2, Notch signaling blocker gamma secretase inhibitors (GSIs) were used.
  
  
  RESULTS
  The ihBTC2 cells had malignant phenotypes, such as infinite proliferation, hyperpentaploid karyotype, tumorigenesis in nude mice and expression of protein markers of oligodendroglia cells. The SF2 of ihBTC2 cells was significantly higher than that of any other cell line (P<0.05, n = 3). The expression of Notch 1 and Hes1 mRNAs from ihBTC2 cells was significantly increased after radiation. Moreover, the Notch 1, pAkt and Bcl-2 proteins were significantly increased after radiation (P<0.05, n = 3). Inhibition of Notch signaling markedly enhanced the radiosensitivity of ihBTC2 cells.
  
  
  CONCLUSIONS
  In an orthotopic glioma model, the malignant transformation of host stromal cells was induced by glioma stem/progenitor cells. IhBTC2 cells are more radiation-resistant than the glioma stem/progenitor cells, which may be mediated by activation of the Notch signaling pathway.
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Yuntian
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Neurosurgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.|Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Jinshi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Ma
authors.affiliation: Laboratory Center, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Hong
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Xueguan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Laboratory Center, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Aidong
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004815:Epidermal Growth Factor / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011836:Radiation Tolerance; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000595707:BCL2 protein, human; C497761:NOTCH1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D004815:Epidermal Growth Factor; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt