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

Abstract

Primary astrocytomas of World Health Organization grade 3 and grade 4 (HG-astrocytomas) are preponderant among adults and are almost invariably fatal despite multimodal therapy. Here, we show that the juvenile brain has an endogenous defense mechanism against HG-astrocytomas. Neural precursor cells (NPCs) migrate to HG-astrocytomas, reduce glioma expansion and prolong survival by releasing a group of fatty acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is higher in HG-astrocytomas than in tumor-free brain and TRPV1 stimulation triggers tumor cell death via the activating transcription factor-3 (ATF3) controlled branch of the ER stress pathway. The anti-tumorigenic 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 hold potential as new HG-astrocytoma therapeutics.

Smac mimetic promotes glioblastoma cancer stem-like cell differentiation by activating NF-κB

“…To explore cancer cell-specific effects of BV6, we also used non-malignant neural stem cells (NSCs) that we recently characterized. 27 Up to a concentration of 1 mM, BV6 did not reduce cell viability or induce caspase-3 activation in GBM CSLCs or NSCs (Figures 1a and b). In parallel, we monitored the effect of BV6 on expression levels of IAP proteins.…”

“…NSCs were recently characterized and cultured as described. 27 The T98G glioblastoma cell line was obtained from ATCC (Manassas, VA, USA) and used as a positive control for cIAP2 expression. Cells were seeded after sphere dissociation on 10 mg/ml poly-DL-ornithine hydrobromide (Sigma)-coated plates.…”

Remodelling of Ca2+transport in cancer: how it contributes to cancer hallmarks?

“…Consistent with this notion, expression of the TRPV1 channel is positively correlated with grading of human glioma (astrocytoma) [52,53]. However, exogenous TRPV1 agonists, as well as its endogenous agonists, endocannabinoids, were shown to trigger the apoptosis of glioma cells, not apparently because of Ca 2þ entry via plasma membrane-localized TRPV1, but primarily via ER-stress owing to TRPV1 localization in the ER membrane [52].…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…On the basis of these findings, it was postulated that TRPV1 plays an antioncogenic role in the bladder (Santoni and Farfariello, 2011). By contrast, TRPV1 appears to be highly expressed in glioblastoma and only weakly expressed (or absent) in surrounding normal brain (Stock et al, 2012). This is a potential problem for drug development as an agent that may inhibit the growth of one kind of tumor might conversely promote the formation of a different kind of malignancy.…”