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Patient-derived glioblastoma stem cells respond differentially to targeted therapies

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dc.contributor.authorKanabur, Pratiken
dc.contributor.authorGuo, Sujuanen
dc.contributor.authorSimonds, Gary S.en
dc.contributor.authorKelly, Deborah F.en
dc.contributor.authorGourdie, Robert G.en
dc.contributor.authorVerbridge, Scott S.en
dc.contributor.authorSheng, Zhien
dc.contributor.committeechairRodgers, Cara M.en
dc.date.accessioned2017-06-07T20:43:54Zen
dc.date.available2017-06-07T20:43:54Zen
dc.date.issued2016-12-27en
dc.description.abstractThe dismal prognosis of glioblastoma is, at least in part, attributable to the difficulty in eradicating glioblastoma stem cells (GSCs). However, whether this difficulty is caused by the differential responses of GSCs to drugs remains to be determined. To address this, we isolated and characterized ten GSC lines from established cell lines, xenografts, or patient specimens. Six lines formed spheres in a regular culture condition, whereas the remaining four lines grew as monolayer. These adherent lines formed spheres only in plates coated with poly-2-hydroxyethyl methacrylate. The self-renewal capabilities of GSCs varied, with the cell density needed for sphere formation ranging from 4 to 23.8 cells/well. Moreover, a single non-adherent GSC either remained quiescent or divided into two cells in four-seven days. The stem cell identity of GSCs was further verified by the expression of nestin or glial fibrillary acidic protein. Of the two GSC lines that were injected in immunodeficient mice, only one line formed a tumor in two months. The protein levels of NOTCH1 and platelet derived growth factor receptor alpha positively correlated with the responsiveness of GSCs to γ-secretase inhibitor IX or imatinib, two compounds that inhibit these two proteins, respectively. Furthermore, a combination of temozolomide and a connexin 43 inhibitor robustly inhibited the growth of GSCs. Collectively, our results demonstrate that patient-derived GSCs exhibit different growth rates in culture, possess differential capabilities to form a tumor, and have varied responses to targeted therapies. Our findings underscore the importance of patient-derived GSCs in glioblastoma research and therapeutic development.en
dc.description.versionPublished versionen
dc.format.extent86406 - 86419 (14) page(s)en
dc.identifier.doihttps://doi.org/10.18632/oncotarget.13415en
dc.identifier.issn1949-2553en
dc.identifier.issue52en
dc.identifier.orcidGourdie, RG [0000-0001-6021-0796]en
dc.identifier.orcidVerbridge, SS [0000-0002-4074-8799]en
dc.identifier.orcidSheng, Z [0000-0002-0029-8666]en
dc.identifier.urihttp://hdl.handle.net/10919/77941en
dc.identifier.volume7en
dc.languageEnglishen
dc.publisherImpact Journalsen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000391422500060&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 3.0 Unporteden
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectOncologyen
dc.subjectCell Biologyen
dc.subjectglioblastomaen
dc.subjectglioblastoma stem cellsen
dc.subjectpatient-derived glioblastoma stem cellsen
dc.subjecttargeted therapiesen
dc.subjectTUMOR-INITIATING CELLSen
dc.subjectRECURRENT GLIOBLASTOMAen
dc.subjectMALIGNANT GLIOMAen
dc.subjectXENOGRAFT MODELSen
dc.subjectGROWTH-FACTORen
dc.subjectCANCERen
dc.subjectNOTCHen
dc.subjectHETEROGENEITYen
dc.subjectTEMOZOLOMIDEen
dc.subjectINHIBITIONen
dc.titlePatient-derived glioblastoma stem cells respond differentially to targeted therapiesen
dc.title.serialONCOTARGETen
dc.typeArticle - Refereeden
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Engineeringen
pubs.organisational-group/Virginia Tech/Engineering/Biomedical Engineering and Mechanicsen
pubs.organisational-group/Virginia Tech/Engineering/COE T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Fralin Affiliated Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Virginia Tech Carilion Research Instituteen

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