المؤلفون: Junca, Audelaure, Villalva, Claire, Tachon, Gaëlle, Rivet, Pierre, Cortes, Ulrich, Guilloteau, Karline, Balbous, Anaïs, Godet, Julie, Wager, Michel, Karayan‐Tapon, Lucie

المصدر: Cancer Medicine; Nov2017, Vol. 6 Issue 11, p2625-2634, 10p

مصطلحات موضوعية: GLIOBLASTOMA multiforme treatment, CRIZOTINIB, IMMUNOHISTOCHEMISTRY, NUCLEOTIDE sequencing, GENETIC mutation, THERAPEUTICS

مستخلص: Glioblastoma stem cells (GSCs) are believed to be involved in the mechanisms of tumor resistance, therapeutic failures, and recurrences after conventional glioblastoma therapy. Therefore, elimination of GSCs might be a prerequisite for the development of successful therapeutic strategies. ALK, ROS1, and MET are targeted by Crizotinib, a tyrosine kinase inhibitor which has been approved for treatment of ALK-rearranged non-small-cell lung cancer. In this study we investigated ALK, ROS1, and MET status in nine glioblastoma stem cell lines and tumors from which they arise. Fluorescent in situ hybridization (FISH), Sanger's direct sequencing, and immunohistochemistry were used to screen genomic rearrangements (or amplifications), genomic mutations, and protein expression, respectively. The immunohistochemical and FISH studies revealed no significant dysregulation of ROS1 in GSCs and associated tumors. Neither amplification nor polysomy of ALK was observed in GSC, but weak overexpression was detected by IHC in three of nine GSCs. Similarly, no MET amplification was found by FISH but three GSCs presented significant immunohistochemical staining. No ALK or MET mutation was found by Sanger's direct sequencing. In this study, we show no molecular rearrangement of ALK, ROS1, and MET that would lead us not to propose, as a valid strategy, the use of crizotinib to eradicate GSCs. However, MET was overexpressed in all GSCs with mesenchymal subtype and three GSCs presented an overexpression of ALK. Therefore, our study corroborates the idea that MET and ALK may assume a role in the tumorigenicity of GSC. [ABSTRACT FROM AUTHOR]

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المؤلفون: Balbous, Anaïs, Cortes, Ulrich, Guilloteau, Karline, Rivet, Pierre, Pinel, Baptiste, Duchesne, Mathilde, Godet, Julie, Boissonnade, Odile, Wager, Michel, Bensadoun, René Jean, Chomel, Jean-Claude, Karayan-Tapon, Lucie

المصدر: BMC Cancer; 8/5/2016, Vol. 16, p1-13, 13p, 1 Chart, 5 Graphs

مصطلحات موضوعية: GLIOBLASTOMA multiforme, GLIOMAS, STEM cells, IONIZING radiation, DNA damage, AGAR, CELL lines, DNA, ELECTROPHORESIS, FLOW cytometry, IMMUNOHISTOCHEMISTRY, RADIATION, WESTERN immunoblotting, TISSUE arrays

مستخلص: Background: Radioresistant glioblastoma stem cells (GSCs) contribute to tumor recurrence and identification of the molecular targets involved in radioresistance mechanisms is likely to enhance therapeutic efficacy. This study analyzed the DNA damage response following ionizing radiation (IR) in 10 GSC lines derived from patients.Methods: DNA damage was quantified by Comet assay and DNA repair effectors were assessed by Low Density Array. The effect of RAD51 inhibitor, RI-1, was evaluated by comet and annexin V assays.Results: While all GSC lines displayed efficient DNA repair machinery following ionizing radiation, our results demonstrated heterogeneous responses within two distinct groups showing different intrinsic radioresistance, up to 4Gy for group 1 and up to 8Gy for group 2. Radioresistant cell group 2 (comprising 5 out of 10 GSCs) showed significantly higher RAD51 expression after IR. In these cells, inhibition of RAD51 prevented DNA repair up to 180 min after IR and induced apoptosis. In addition, RAD51 protein expression in glioblastoma seems to be associated with poor progression-free survival.Conclusion: These results underscore the importance of RAD51 in radioresistance of GSCs. RAD51 inhibition could be a therapeutic strategy helping to treat a significant number of glioblastoma, in combination with radiotherapy. [ABSTRACT FROM AUTHOR]

: Copyright of BMC Cancer is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)