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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.

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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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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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