Editors' ChoiceCancer

Cancer-Fighting Vanilloids

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Science Signaling  14 Aug 2012:
Vol. 5, Issue 237, pp. ec211
DOI: 10.1126/scisignal.2003491

Malignant gliomas, such as astrocytomas and glioblastomas, are among the most common and deadly types of adult brain tumors. In mice, neural precursor cells (NPCs) migrate to gliomas and inhibit their growth. Working with cultured high-grade astrocytoma (HGA) cells, which are associated with higher mortality, and NPCs, Stock et al. identified endovanilloids, which can activate the nociceptive receptor transient receptor potential vanilloid subfamily 1 (TRPV1), as candidates for mediating this tumor-suppressive activity. Medium conditioned by NPCs isolated from mice induced death of cultured HGA cells, but this effect was abrogated by TRPV1 antagonists or by knocking down TRPV1 by RNA interference in the HGA cells. Conditioned medium from mouse NPCs induced TRPV1-dependent calcium influx in primary human glioblastoma cells and in cultured human, rat, and mouse HGAs. Medium conditioned by human NPCs also induced death in human HGA cell lines and in primary human glioblastoma cells. In tumors that arose from HGA cells transplanted into the brains of mice, TRPV1 was enriched in HGAs compared with normal brain tissue. NPCs isolated from mice abundantly produced several endovanilloids, whereas HGA cells and differentiated descendants of NPCs produced only small amounts of endovanilloids. When implanted into mice engineered to produce abnormally high amounts of endovanilloids, HGA cells lacking TRPV1 gave rise to larger tumors than did control HGA cells, suggesting that TRPV1 was the only target through which endovanilloids inhibited tumor growth. In young mice, implantation of TRPV1-knockdown HGA cells into the brain resulted in larger tumors than in mice injected with control HGAs; in older mice, there was no difference in tumor size after injection with the two types of HGA cells. These results are consistent with young mice, which have more NPCs than adult mice, producing more endovanilloids. Treating adult HGA-implanted mice with the synthetic vanilloid arvanil inhibited tumor growth and increased survival time compared with arvanil-treated adult mice injected with TRPV1-knockdown HGAs and compared with untreated adult mice injected with control HGAs. Arvanil treatment also increased survival time for mice receiving transplants of primary human glioblastoma cells. TRPV1 was localized to the endoplasmic reticulum (ER) membrane in mouse HGAs, and NPC-conditioned medium or application of a synthetic vanilloid caused enlargement of the ER in cultured HGAs. In vitro experiments with mouse and human cells indicated that NPC-conditioned medium induced expression of ER stress markers, including activating transcription factor 3 (ATF3), and that ATF3 was necessary and sufficient for the TRPV1-mediated death of HGA cells induced by conditioned medium. Harnessing the ability of vanilloids to induce death of glioma cells may, therefore, be an effective strategy for slowing the growth of glioblastomas in human patients, as discussed in commentary by Schonberg et al.

K. Stock, J. Kumar, M. Synowitz, S. Petrosino, R. Imperatore, E. St. J. Smith, P. Wend, B. Purfürst, U. A. Nuber, U. Gurok, V. Matyash, J. H. Wälzlein, S. R. Chirasani, G. Dittmar, B. F. Cravatt, S. Momma, G. R. Lewin, A. Ligresti, L. De Petrocellis, L. Cristino, V. Di Marzo, H. Kettenmann, R. Glass, Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat. Med. 18, 1232–1239 (2012). [PubMed]

D. L. Schonberg, S. Bao, J. N. Rich, TRP-ing up brain tumors. Nat. Med. 18, 1175–1176 (2012). [PubMed]

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