Abstract
BackgroundHost 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.MethodsMalignant 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.ResultsThe 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.ConclusionsIn 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.
Highlights
Drug resistance, the spread of tumors and the role of normal tissue are three mysteries for tumor researchers [1]
Notch Signaling Enhances Radioresistance of Malignant Stromal Cells significantly increased after radiation
In an orthotopic glioma model, the malignant transformation of host stromal cells was induced by glioma stem/progenitor cells
Summary
Drug resistance, the spread of tumors and the role of normal tissue are three mysteries for tumor researchers [1]. The second cell line was identified as an oligodendrocyte-like cell line, using immunocytochemical staining Because they are malignant host cells induced by human glioma stem/progenitor cells, they are named GSC-induced host brain tumor cells (ihBTC1 and ihBTC2). This cell line is confirmed to be cancer with immortalized characteristics in vitro and tumorigenicity in vivo and greater radiation-resistance than the glioma stem/progenitor cell SU3 and its radiation sub-strain SU3-5R. This new discovery may be helpful in solving the puzzle of the “role of normal tissues” in tumorigenesis, tumor progression and resistance to treatment, radiotherapy.
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