title: Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals.
abstract: Glioblastomas frequently harbour genetic lesions that stimulate the activity of mammalian target of rapamycin complex 1 (mTORC1). Loss of heterozygosity of tuberous sclerosis complex 1 (TSC1) or TSC2, which together form a critical negative regulator of mTORC1, is also seen in glioblastoma; however, it is not known how loss of the TSC complex affects the development of malignant gliomas. Here we investigated the role of Tsc1 in gliomagenesis in mice. Tsc1 deficiency up-regulated mTORC1 activity and suppressed the proliferation of neural stem/progenitor cells (NSPCs) in a serial neurosphere-forming assay, suggesting that Tsc1-deficient NSPCs have defective self-renewal activity. The neurosphere-forming capacity of Tsc1-deficient NSPCs was restored by p16(Ink4a)p19(Arf) deficiency. Combined Tsc1 and p16(Ink4a)p19(Arf) deficiency in NSPCs did not cause gliomagenesis in vivo. However, in a glioma model driven by an active mutant of epidermal growth factor receptor (EGFR), EGFRvIII, loss of Tsc1 resulted in an earlier onset of glioma development. The mTORC1 hyperactivation by Tsc1 deletion accelerated malignant phenotypes, including increased tumour mass and enhanced microvascular formation, leading to intracranial haemorrhage. These data demonstrate that, although mTORC1 hyperactivation itself may not be sufficient for gliomagenesis, it is a potent modifier of glioma development when combined with oncogenic signals.
authors.affiliation: Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.forename: Shingo
authors.initials: S
authors.lastname: Tanaka
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Hegazy
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tadokoro
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ohta
authors.forename: Masaya
authors.initials: M
authors.lastname: Ueno
authors.forename: Mohamed A E
authors.initials: MA
authors.lastname: Ali
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000378:metabolism; D066246:ErbB Receptors / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: TSC1; gliomagenesis; mTORC1; neural stem; progenitor cells