Cancerous stem cells can arise from pediatric brain tumors

Creators: Hemmati, Houman D.^{1, 2}; Nakano, Ichiro^{1, 2}; Lazareff, Jorge A.^{1, 2}; Masterman-Smith, Michael^{1, 2}; Geschwind, Daniel H.^{1, 2}; Kornblum, Harley I.^{1, 2}; Bronner-Fraser, Marianne^{1, 2}

1. California Institute of Technology
2. University of California, Los Angeles

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Abstract

Pediatric brain tumors are significant causes of morbidity and mortality. It has been hypothesized that they derive from self-renewing multipotent neural stem cells. Here, we tested whether different pediatric brain tumors, including medulloblastomas and gliomas, contain cells with properties similar to neural stem cells. We find that tumor-derived progenitors form neurospheres that can be passaged at clonal density and are able to self-renew. Under conditions promoting differentiation, individual cells are multipotent, giving rise to both neurons and glia, in proportions that reflect the tumor of origin. Unlike normal neural stem cells, however, tumor-derived progenitors have an unusual capacity to proliferate and sometimes differentiate into abnormal cells with multiple differentiation markers. Gene expression analysis reveals that both whole tumors and tumor-derived neurospheres express many genes characteristic of neural and other stem cells, including CD133, Sox2, musashi-1, bmi-1, maternal embryonic leucine zipper kinase, and phosphoserine phosphatase, with variation from tumor to tumor. After grafting to neonatal rat brains, tumor-derived neurosphere cells migrate, produce neurons and glia, and continue to proliferate for more than 4 weeks. The results show that pediatric brain tumors contain neural stem-like cells with altered characteristics that may contribute to tumorigenesis. This finding may have important implications for treatment by means of specific targeting of stem-like cells within brain tumors.

Additional Information

Copyright © 2003 by the National Academy of Sciences. Communicated by Michael E. Phelps, University of California School of Medicine, Los Angeles, CA, October 8, 2003 (received for review June 20, 2003). Published online before print November 26, 2003, 10.1073/pnas.2036535100 We are grateful to Simon Bababeygy, Benjamin Rafii, Miguel Minera, and Alexandra Lowry for laboratory assistance and patient recruitment, Keith Tatsukawa for performing animal surgeries, Lori Shoemaker for supplying neurosphere-conditioned medium, Gary Mathern, Dennis Chute, and Beth Johnson for brain specimens, and Bud Saxton and Marcos Paiva for their guidance and support. We thank Drs. Jeffrey Twiss and Paul Mischel for helpful comments on the manuscript. This work was supported by U.S. Public Health Service Grant NS42287 (to M.B.-F.), National Institute of Mental Health Grant MH65756 (to H.I.K.), and the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. H.D.H. was supported by the McCallum Fund at California Institute of Technology, Medical Scientist Training Program Grant GM08042, and the Aesculapians Fund of the David Geffen School of Medicine at the University of California, Los Angeles.

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