Cancer Stem Cells

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NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts†‡§

  1. Xing Fan1,2,¶,*,
  2. Leila Khaki3,
  3. Thant S. Zhu1,
  4. Mary E. Soules1,
  5. Caroline E. Talsma1,
  6. Naheed Gul3,
  7. Cheryl Koh3,
  8. Jiangyang Zhang4,
  9. Yue-Ming Li8,
  10. Jarek Maciaczyk9,
  11. Guido Nikkhah9,
  12. Francesco DiMeco7,10,
  13. Sara Piccirillo11,
  14. Angelo L. Vescovi11,
  15. Charles G. Eberhart3,5,6

Article first published online: 10 NOV 2009

DOI: 10.1002/stem.254

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 1, pages 5–16, January 2010

Additional Information

How to Cite

Fan, X., Khaki, L., Zhu, T. S., Soules, M. E., Talsma, C. E., Gul, N., Koh, C., Zhang, J., Li, Y.-M., Maciaczyk, J., Nikkhah, G., DiMeco, F., Piccirillo, S., Vescovi, A. L. and Eberhart, C. G. (2010), NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts. STEM CELLS, 28: 5–16. doi: 10.1002/stem.254

Author Information

  1. 1

    Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

  2. 2

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA

  3. 3

    Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA

  4. 4

    Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA

  5. 5

    Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA

  6. 6

    Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland, USA

  7. 7

    Department of Neurological Surgery, Johns Hopkins University, Baltimore, Maryland, USA

  8. 8

    Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

  9. 9

    Department of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany

  10. 10

    Department of Neurosurgery, Istituto Nazionale Neurologico C. Besta, Milan, Italy

  11. 11

    Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy

  1. 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

  1. †

    Author contributions: X.F.: conception and design, financial support, administrative support, provision of study material, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; L.K., T.S.Z., M.E.S., C.E.T., N.G., C.K., J.Z.: collection and/or assembly of data; Y.-M.L., J.M., G.N., F.D., S.P., A.L.V.: provision of study material; C.G.E.: conception and design, financial support, administrative support, provision of study material, data analysis and interpretation, manuscript writing.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLS EXPRESS November 10, 2009.

Publication History

  1. Issue published online: 12 JAN 2010
  2. Article first published online: 10 NOV 2009
  3. Accepted manuscript online: 10 NOV 2009 12:00AM EST
  4. Manuscript Accepted: 30 OCT 2009
  5. Manuscript Received: 29 MAY 2009

Funded by

  • Accelerate Brain Cancer Cure Project Award
  • American Brain Tumor Association Translational Grant
  • Voices Against Brain Cancer Research Grant. Grant Number: NIH/NS55089
  • Brain Tumor Funders Collaborative

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Keywords:

  • Cancer Stem Cell;
  • NOTCH;
  • Glioblastoma;
  • γ-Secretase inhibitor

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. STEM CELLS 2010;28:5–16

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