NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts

Xing Fan, Leila Khaki, Thant S. Zhu, Mary E. Soules, Caroline E. Talsma, Naheed Gul, Cheryl Koh, Jiangyang Zhang, Yue Ming Li, Jarek Maciaczyk, Guido Nikkhah, Francesco DiMeco, Sara Piccirillo, Angelo L. Vescovi, Charles G. Eberhart

Research output: Contribution to journalArticle

428 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5-16
Number of pages12
JournalStem Cells
Volume28
Issue number1
DOIs
StatePublished - Jan 1 2010

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Neoplastic Stem Cells
Glioblastoma
Heterografts
Stem Cells
Growth
Neoplasms
Amyloid Precursor Protein Secretases
Survival
Dimethyl Sulfoxide
Nude Mice
Glioma
Polymers
Radiotherapy
Cell Count
Phosphorylation
Apoptosis
Drug Therapy
Brain
Pharmaceutical Preparations

Keywords

  • γ-Secretase inhibitor
  • Cancer stem cell
  • Glioblastoma
  • NOTCH

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Fan, X., Khaki, L., Zhu, T. S., Soules, M. E., Talsma, C. E., Gul, N., ... Eberhart, C. G. (2010). NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells, 28(1), 5-16. https://doi.org/10.1002/stem.254

NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. / 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.

In: Stem Cells, Vol. 28, No. 1, 01.01.2010, p. 5-16.

Research output: Contribution to journalArticle

Fan, X, Khaki, L, Zhu, TS, Soules, ME, Talsma, CE, Gul, N, Koh, C, Zhang, J, Li, YM, Maciaczyk, J, Nikkhah, G, DiMeco, F, Piccirillo, S, Vescovi, AL & Eberhart, CG 2010, 'NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts', Stem Cells, vol. 28, no. 1, pp. 5-16. https://doi.org/10.1002/stem.254
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. / NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. In: Stem Cells. 2010 ; Vol. 28, No. 1. pp. 5-16.
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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.",
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AU - Fan, Xing

AU - Khaki, Leila

AU - Zhu, Thant S.

AU - Soules, Mary E.

AU - Talsma, Caroline E.

AU - Gul, Naheed

AU - Koh, Cheryl

AU - Zhang, Jiangyang

AU - Li, Yue Ming

AU - Maciaczyk, Jarek

AU - Nikkhah, Guido

AU - DiMeco, Francesco

AU - Piccirillo, Sara

AU - Vescovi, Angelo L.

AU - Eberhart, Charles G.

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N2 - 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.

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