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Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1

Nature Medicine volume 18, pages 1232–1238 (2012)Cite this article

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Abstract

Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics.

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Figure 1: TRPV1 agonists released from NPCs induce HGA cell death.
Figure 2: NPC-released fatty acid ethanolamides induce cell death in HGAs.
Figure 3: TRPV1 agonists released by NPCs trigger the ATF3 pathway in HGAs.
Figure 4: TRPV1 agonists released by NPCs induce ER-stress–mediated cell death.
Figure 5: NPC-mediated tumor suppression by endovanilloids is restricted to the young brain.
Figure 6: The synthetic vanilloid arvanil has therapeutic effects on experimental HGAs.

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Acknowledgements

We thank G. Gargiulo, O. Daumke and J. Kurreck for discussion of the manuscript, S. Kitajima (Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan) for ATF3 constructs and L. Kaczmarek and M. Szymanska (Nencki Institute, Warsaw, Poland) for providing Ccnd2−/− mice. We acknowledge funding from the Helios Clinics (HeFoFö-ID1148) and the US National Institutes of Health (DA-009789 to V.D.M.).

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Author notes

  1. Peter Wend

    Present address: Present address: David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California, USA.,

  2. Kristin Stock, Jitender Kumar, Michael Synowitz, Helmut Kettenmann and Rainer Glass: These authors contributed equally to this work.

Authors and Affiliations

  1. Cellular Neuroscience, Max Delbrück Centre for Molecular Medicine (MDC), Berlin, Germany

    Kristin Stock, Jitender Kumar, Michael Synowitz, Vitali Matyash, Joo-Hee Wälzlein, Sridhar R Chirasani, Helmut Kettenmann & Rainer Glass

  2. Department of Neurosurgery, Charité, University Medicine Berlin, Berlin, Germany

    Michael Synowitz

  3. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy

    Stefania Petrosino, Alessia Ligresti & Vincenzo Di Marzo

  4. Endocannabinoid Research Group, Institute of Cybernetics, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy

    Roberta Imperatore, Luciano De Petrocellis & Luigia Cristino

  5. Molecular Physiology of Somatic Sensation, MDC, Berlin, Germany

    Ewan St J Smith & Gary R Lewin

  6. Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, New York, USA

    Ewan St J Smith

  7. Signal Transduction, Epithelial Differentiation, Invasion and Metastasis, MDC, Berlin, Germany

    Peter Wend

  8. Central Facility for Electron Microscopy, MDC, Berlin, Germany

    Bettina Purfürst

  9. Lund Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden

    Ulrike A Nuber

  10. Max Planck Institute for Molecular Genetics, Berlin, Germany

    Ulf Gurok

  11. Central Facility for Mass Spectrometry, MDC, Berlin, Germany

    Gunnar Dittmar

  12. The Scripps Research Institute, La Jolla, California, USA

    Benjamin F Cravatt

  13. Restorative Neurology, Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Frankfurt, Germany

    Stefan Momma

  14. Neurosurgical Research, Clinic for Neurosurgery, Ludwig Maximilians University of Munich, Munich, Germany

    Rainer Glass

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Contributions

S.P., R.I., A.L., L.D.P., U.G. and S.R.C. designed and conducted the experiments, and interpreted the data. K.S., J.K., E.S.J.S., P.W., B.P., U.A.N., V.M., B.F.C., S.M., V.D.M., J.-H.W., G.D. and L.C. contributed to manuscript preparation. G.R.L., V.D.M. and H.K. designed the experiments, supervised the project, interpreted the data and contributed to manuscript preparation. M.S. performed brain tumor resections and provided tumor samples. M.S. and R.G. designed and conducted the experiments, supervised the project, interpreted the data and prepared the manuscript.

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Correspondence to Rainer Glass.

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Stock, K., Kumar, J., Synowitz, M. et al. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat Med 18, 1232–1238 (2012). https://doi.org/10.1038/nm.2827

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