Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Sanai, N., Alvarez-Buylla, A. & Berger, M.S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Ohgaki, H. & Kleihues, P. Epidemiology and etiology of gliomas. Acta Neuropathol. 109, 93–108 (2005).

    Article  PubMed  Google Scholar 

  3. Ohgaki, H. & Kleihues, P. Genetic pathways to primary and secondary glioblastoma. Am. J. Pathol. 170, 1445–1453 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Knoth, R. et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE 5, e8809 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Leuner, B., Kozorovitskiy, Y., Gross, C.G. & Gould, E. Diminished adult neurogenesis in the marmoset brain precedes old age. Proc. Natl. Acad. Sci. USA 104, 17169–17173 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Assanah, M. et al. Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor–expressing retroviruses. J. Neurosci. 26, 6781–6790 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Assanah, M.C. et al. PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain. Glia 1835–1847 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Glass, R. et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J. Neurosci. 25, 2637–2646 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walzlein, J.H. et al. The antitumorigenic response of neural precursors depends on subventricular proliferation and age. Stem Cells 26, 2945–2954 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Aboody, K.S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl. Acad. Sci. USA 97, 12846–12851 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Suzuki, T. et al. Inhibition of glioma cell proliferation by neural stem cell factor. J. Neurooncol. 74, 233–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Staflin, K. et al. Neural progenitor cell lines inhibit rat tumor growth in vivo. Cancer Res. 64, 5347–5354 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Staflin, K., Zuchner, T., Honeth, G., Darabi, A. & Lundberg, C. Identification of proteins involved in neural progenitor cell targeting of gliomas. BMC Cancer 9, 206 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Starowicz, K., Nigam, S. & Di Marzo, V. Biochemistry and pharmacology of endovanilloids. Pharmacol. Ther. 114, 13–33 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Tóth, A., Blumberg, P.M. & Boczan, J. Anandamide and the vanilloid receptor (TRPV1). Vitam. Horm. 81, 389–419 (2009).

    Article  PubMed  Google Scholar 

  16. Szallasi, A., Cortright, D.N., Blum, C.A. & Eid, S.R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov. 6, 357–372 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Chirasani, S.R. et al. Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain 133, 1961–1972 (2010).

    Article  PubMed  Google Scholar 

  18. Yamaguchi, M., Saito, H., Suzuki, M. & Mori, K. Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 11, 1991–1996 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Zhao, C., Deng, W. & Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Okano, H., Imai, T. & Okabe, M. Musashi: a translational regulator of cell fate. J. Cell Sci. 115, 1355–1359 (2002).

    CAS  PubMed  Google Scholar 

  21. Cullen, B.R. Enhancing and confirming the specificity of RNAi experiments. Nat. Methods 3, 677–681 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Lambert, D.M. & Di Marzo, V. The palmitoylethanolamide and oleamide enigmas: are these two fatty acid amides cannabimimetic? Curr. Med. Chem. 6, 757–773 (1999).

    CAS  PubMed  Google Scholar 

  23. Ueda, N., Puffenbarger, R.A., Yamamoto, S. & Deutsch, D.G. The fatty acid amide hydrolase (FAAH). Chem. Phys. Lipids 108, 107–121 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Cravatt, B.F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. USA 98, 9371–9376 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stürzebecher, A.S. et al. An in vivo tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors. J. Physiol. (Lond.) 588, 1695–1707 (2010).

    Article  Google Scholar 

  26. Caterina, M.J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Gallego-Sandín, S., Rodriguez-Garcia, A., Alonso, M.T. & Garcia-Sancho, J. The endoplasmic reticulum of dorsal root ganglion neurons contains functional TRPV1 channels. J. Biol. Chem. 284, 32591–32601 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hori, O. et al. Role of Herp in the endoplasmic reticulum stress response. Genes Cells 9, 457–469 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Xu, C., Bailly-Maitre, B. & Reed, J.C. Endoplasmic reticulum stress: cell life and death decisions. J. Clin. Invest. 115, 2656–2664 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kowalczyk, A. et al. The critical role of cyclin D2 in adult neurogenesis. J. Cell Biol. 167, 209–213 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Unal Cevik, I. & Dalkara, T. Intravenously administered propidium iodide labels necrotic cells in the intact mouse brain after injury. Cell Death Differ. 10, 928–929 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Melck, D. et al. Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors. Biochem. Biophys. Res. Commun. 262, 275–284 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Veldhuis, W.B. et al. Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J. Neurosci. 23, 4127–4133 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fisher, T. et al. Mechanisms operative in the antitumor activity of temozolomide in glioblastoma multiforme. Cancer J. 13, 335–344 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. McConville, P. et al. Magnetic resonance imaging determination of tumor grade and early response to temozolomide in a genetically engineered mouse model of glioma. Clin. Cancer Res. 13, 2897–2904 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Mrugala, M.M. & Chamberlain, M.C. Mechanisms of disease: temozolomide and glioblastoma–look to the future. Nat. Clin. Pract. Oncol. 5, 476–486 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Conover, J.C. & Shook, B.A. Aging of the subventricular zone neural stem cell niche. Aging Dis. 2, 149–163 (2011).

    PubMed  Google Scholar 

  38. Khan, M.A. & Lie, D.C. MicroRNA—a contributor to age-associated neural stem cell dysfunction? Aging 3, 182–183 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Di Marzo, V., Gobbi, G. & Szallasi, A. Brain TRPV1: a depressing TR(i)P down memory lane? Trends Pharmacol. Sci. 29, 594–600 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Maccarrone, M., Lorenzon, T., Bari, M., Melino, G. & Finazzi-Agro, A. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275, 31938–31945 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Izzo, A.A. et al. Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J. Mol. Med. 86, 89–98 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Prevarskaya, N., Zhang, L. & Barritt, G. TRP channels in cancer. Biochim. Biophys. Acta 1772, 937–946 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Bode, A.M. et al. Transient receptor potential type vanilloid 1 suppresses skin carcinogenesis. Cancer Res. 69, 905–913 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Visnyei, K. et al. A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells. Mol. Cancer Ther. 10, 1818–1828 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Morelli, M.B. et al. The Transient Receptor Potential Vanilloid-2 (TRPV2) cation channel impairs glioblastoma stem-like cell proliferation and promotes differentiation. Int. J. Cancer published online, doi:10.1002/ijc.27588 (11 April 2012).

  46. Lee, J. et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391–403 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Grünweller, A. et al. Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2′-O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res. 31, 3185–3193 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Gurok, U. et al. Gene expression changes in the course of neural progenitor cell differentiation. J. Neurosci. 24, 5982–6002 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Devane, W.A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. Bisogno, T., Maurelli, S., Melck, D., De Petrocellis, L. & Di Marzo, V. Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J. Biol. Chem. 272, 3315–3323 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. de Godoy, L.M. et al. Comprehensive mass-spectrometry–based proteome quantification of haploid versus diploid yeast. Nature 455, 1251–1254 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M. & Gage, F.H. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130, 391–399 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Reimer, T.A. et al. Reevaluation of the 22–1-1 antibody and its putative antigen, EBAG9/RCAS1, as a tumor marker. BMC Cancer 5, 47 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Rainer Glass.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 2687 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2827

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer