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A restricted cell population propagates glioblastoma growth after chemotherapy

Nature volume 488, pages 522–526 (2012)Cite this article

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Abstract

Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year1. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.

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Figure 1: Characterization of the Nes-ΔTK-GFP transgene.
Figure 2: TMZ targets proliferating derivatives but not the GFP + quiescent cell population.
Figure 3: GCV treatment prolongs survival of Mut7;Nes-ΔTK mice.
Figure 4: Combination treatment of TMZ and GCV inhibits glioma progression in cerebrum.

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Acknowledgements

The authors thank S. McKinnon, A. Deshaw, L. McClellan, S. Kennedy and P. Leake for technical assistance, and Parada laboratory members for helpful suggestions and discussion. CldU and IdU preparation and staining protocol was provided by D. A. Peterson at Rosalind Franklin University. This work was supported by grants awarded to S.G.K. (RO1 NS048192-01) and to L.F.P. by the Goldhirsh Foundation, the James S. McDonnell Foundation (JSMF-220020206), Cancer Prevention Research Institute of Texas (RP 100782) and the National Institutes of Health (R01 CA131313). L.F.P. is an American Cancer Society Research Professor.

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Author notes

  1. Tzong-Shiue Yu & Steven G. Kernie

    Present address: Present address: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.,

Authors and Affiliations

  1. Department of Developmental Biology & Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, 75390-9133, Texas, USA

    Jian Chen, Yanjiao Li, Tzong-Shiue Yu, Renée M. McKay, Steven G. Kernie & Luis F. Parada

  2. Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA,

    Tzong-Shiue Yu & Steven G. Kernie

  3. Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA,

    Dennis K. Burns

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Contributions

J.C. and Y.L. performed the experiments. T.-S.Y. and S.G.K. contributed vital reagents. J.C. and L.F.P. designed the experiments. J.C., R.M.M., D.K.B. and L.F.P. analysed the data. J.C., R.M.M. and L.F.P. wrote the paper.

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Correspondence to Luis F. Parada.

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The authors declare no competing financial interests.

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Chen, J., Li, Y., Yu, TS. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012). https://doi.org/10.1038/nature11287

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