NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts
dc.contributor.author | Fan, Xing | en_US |
dc.contributor.author | Khaki, Leila | en_US |
dc.contributor.author | Zhu, Thant S. | en_US |
dc.contributor.author | Soules, Mary E. | en_US |
dc.contributor.author | Talsma, Caroline E. | en_US |
dc.contributor.author | Gul, Naheed | en_US |
dc.contributor.author | Koh, Cheryl | en_US |
dc.contributor.author | Zhang, Jiangyang | en_US |
dc.contributor.author | Li, Yue-Ming | en_US |
dc.contributor.author | Maciaczyk, Jarek | en_US |
dc.contributor.author | Nikkhah, Guido | en_US |
dc.contributor.author | DiMeco, Francesco | en_US |
dc.contributor.author | Piccirillo, Sara | en_US |
dc.contributor.author | Vescovi, Angelo L. | en_US |
dc.contributor.author | Eberhart, Charles G. | en_US |
dc.date.accessioned | 2010-02-02T15:32:22Z | |
dc.date.available | 2011-03-01T16:26:46Z | en_US |
dc.date.issued | 2010-01 | en_US |
dc.identifier.citation | Fan, Xing; Khaki, Leila; Zhu, Thant S.; Soules, Mary E.; Talsma, Caroline E.; Gul, Naheed; Koh, Cheryl; Zhang, Jiangyang; Li, Yue-Ming; Maciaczyk, Jarek; Nikkhah, Guido; DiMeco, Francesco; Piccirillo, Sara; Vescovi, Angelo L.; Eberhart, Charles G. (2010). "NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts." STEM CELLS 28(1): 5-16. <http://hdl.handle.net/2027.42/64927> | en_US |
dc.identifier.issn | 1066-5099 | en_US |
dc.identifier.issn | 1549-4918 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/64927 | |
dc.description.abstract | Cancer stem cells (CSCs) are thought to be critical for the engraftment and long-term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem-like cells with higher NOTCH activity. We therefore used low-passage and established GBM-derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by Γ-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug-impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem-like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem-like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas. S TEM C ELLS 2010;28:5–16 | en_US |
dc.format.extent | 1610663 bytes | |
dc.format.extent | 3118 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.publisher | Wiley Subscription Services, Inc., A Wiley Company | en_US |
dc.subject.other | Life and Medical Sciences | en_US |
dc.subject.other | Cell and Molecular Biology | en_US |
dc.title | NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Telephone: 734-615-7266; Fax: 734-763-7322 ; Assistant Professor of Neurosurgery and Cell & Developmental Biology, University of Michigan Medical School, Department of Neurosurgery, 109 Zina Pitcher Place, 5,018 BSRB, Ann Arbor, Michigan 48109-2200, USA | en_US |
dc.contributor.affiliationum | Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA | en_US |
dc.contributor.affiliationum | Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA | en_US |
dc.contributor.affiliationum | Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA | en_US |
dc.contributor.affiliationother | Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA | en_US |
dc.contributor.affiliationother | Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA | en_US |
dc.contributor.affiliationother | Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA | en_US |
dc.contributor.affiliationother | Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA | en_US |
dc.contributor.affiliationother | Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA | en_US |
dc.contributor.affiliationother | Department of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany | en_US |
dc.contributor.affiliationother | Department of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany | en_US |
dc.contributor.affiliationother | Department of Neurological Surgery, Johns Hopkins University, Baltimore, Maryland, USA ; Department of Neurosurgery, Istituto Nazionale Neurologico C. Besta, Milan, Italy | en_US |
dc.contributor.affiliationother | Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy | en_US |
dc.contributor.affiliationother | Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy | en_US |
dc.contributor.affiliationother | Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA ; Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA ; Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland, USA | en_US |
dc.identifier.pmid | 19904829 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/64927/1/254_ftp.pdf | |
dc.identifier.doi | 10.1002/stem.254 | en_US |
dc.identifier.source | STEM CELLS | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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