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A restricted cell population propagates glioblastoma growth after chemotherapy

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.

References

  1. Chen, J., McKay, R. M. & Parada, L. F. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149, 36–47 (2012)

    CAS  Article  Google Scholar 

  2. Alcantara Llaguno, S. et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15, 45–56 (2009)

    Article  Google Scholar 

  3. Kwon, C. H. et al. Pten haploinsufficiency accelerates formation of high grade astrocytomas. Cancer Res. 68, 3286–3294 (2008)

    CAS  Article  Google Scholar 

  4. Zhu, Y. et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130 (2005)

    CAS  Article  Google Scholar 

  5. Yu, T. S. et al. Traumatic brain injury-induced hippocampal neurogenesis requires activation of early nestin-expressing progenitors. J. Neurosci. 28, 12901–12912 (2008)

    CAS  Article  Google Scholar 

  6. Ishii-Morita, H. et al. Mechanism of ‘bystander effect’ killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment. Gene Ther. 4, 244–251 (1997)

    CAS  Article  Google Scholar 

  7. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005)

    CAS  Article  Google Scholar 

  8. Garcia, A. D. et al. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nature Neurosci. 7, 1233–1241 (2004)

    CAS  Article  Google Scholar 

  9. Deng, W. et al. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J. Neurosci. 29, 13532–13542 (2009)

    CAS  Article  Google Scholar 

  10. Singer, B. H. et al. Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proc. Natl Acad. Sci. USA 108, 5437–5442 (2011)

    ADS  CAS  Article  Google Scholar 

  11. Snyder, J. S. et al. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011)

    ADS  CAS  Article  Google Scholar 

  12. Bao, S. et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848 (2006)

    CAS  Article  Google Scholar 

  13. Liu, C. et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209–221 (2011)

    CAS  Article  Google Scholar 

  14. Clarke, M. F. et al. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006)

    CAS  Article  Google Scholar 

  15. Boiko, A. D. et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466, 133–137 (2010)

    ADS  CAS  Article  Google Scholar 

  16. Ishizawa, K. et al. Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 7, 279–282 (2010)

    CAS  Article  Google Scholar 

  17. Kelly, P. N. et al. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007)

    ADS  CAS  Article  Google Scholar 

  18. Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008)

    ADS  CAS  Article  Google Scholar 

  19. Vega, C. J. & Peterson, D. A. Stem cell proliferative history in tissue revealed by temporal halogenated thymidine analog discrimination. Nature Methods 2, 167–169 (2005)

    CAS  Article  Google Scholar 

Download references

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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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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