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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / metabolism
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Amides
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Amidohydrolases / deficiency
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Amidohydrolases / genetics
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Animals
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Antineoplastic Agents / therapeutic use
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Apoptosis
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Arachidonic Acids / metabolism
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Arachidonic Acids / pharmacology
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Brain / growth & development
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Brain / metabolism
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Brain Neoplasms / drug therapy
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology*
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Capsaicin / analogs & derivatives
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Capsaicin / pharmacology
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Capsaicin / therapeutic use
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Cell Movement
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Culture Media, Conditioned / pharmacology
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Dopamine / analogs & derivatives
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Dopamine / metabolism
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Dopamine / pharmacology
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Endocannabinoids / metabolism
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Endocannabinoids / pharmacology
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Ethanolamines / pharmacology
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Female
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Gene Expression Regulation, Neoplastic
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Glioblastoma / drug therapy
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Glioblastoma / metabolism
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Glioblastoma / pathology*
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Neoplasm Proteins / agonists
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neural Stem Cells / metabolism
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Neural Stem Cells / physiology*
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Oleic Acids / metabolism
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Oleic Acids / pharmacology
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Palmitic Acids / pharmacology
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Polyunsaturated Alkamides / pharmacology
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RNA, Small Interfering / pharmacology
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Real-Time Polymerase Chain Reaction
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TRPV Cation Channels / agonists
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TRPV Cation Channels / analysis
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TRPV Cation Channels / biosynthesis
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TRPV Cation Channels / genetics
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TRPV Cation Channels / physiology*
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / pathology
Substances
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Amides
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Antineoplastic Agents
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Arachidonic Acids
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Culture Media, Conditioned
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Endocannabinoids
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Ethanolamines
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Neoplasm Proteins
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Oleic Acids
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Palmitic Acids
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Polyunsaturated Alkamides
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RNA, Small Interfering
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TRPV Cation Channels
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TRPV1 protein, human
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TRPV1 protein, mouse
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arachidonyl dopamine
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arvanil
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oleoylethanolamide
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palmidrol
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Amidohydrolases
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fatty-acid amide hydrolase
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Capsaicin
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anandamide
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Dopamine