title: Granulosa cell tumor with activated mTOR-HIF-1alpha-VEGF pathway.
abstract: The DNA-binding activity of hypoxia-inducible factor-1 alpha (HIF-1alpha) has been analyzed for various gynecological tumors. Among the tumors that were studied, there was a finding of a high level of DNA-binding HIF-1alpha activity, although it was limited to one case of adult type granulosa cell tumor (GCT). In this case a 60-year-old female had marked immunohistochemical expression of HIF-1alpha. The expressions of the mammalian target of rapamycin (mTOR) and phosphorylated-mTOR (p-mTOR) were also marked, and vascular endothelial growth factor (VEGF) was moderately expressed. To compare the expression profiles, 11 consecutive cases with adult type GCT were used. All cases showed marked expressions of HIF-1alpha and mTOR, but p-mTOR expression was moderately to markedly observed in four of the 12 cases. VEGF was expressed in all cases in varying degrees. Based on the evidence that downregulation of the mTOR pathway due to treatment with rapamycin (everolimus) would suppress tumor cell growth, an experimental study using the GCT cell line was designed to clarify whether HIF-1alpha and VEGF expressions decline. As a result, the expressions of p-mTOR, HIF-1alpha and VEGF were suppressed, but those of mTOR were not. It was concluded that mTOR-targeted therapy may represent a promising strategy for some GCT with an activated mTOR-HIF-1alpha-VEGF pathway.
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuda
authors.forename: Mariko
authors.initials: M
authors.lastname: Fujita
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirasawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajiwara
authors.forename: Toshinari
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Sayuri
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Makiko
authors.initials: M
authors.lastname: Harasawa
authors.forename: Naruaki
authors.initials: N
authors.lastname: Matsui
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogane
authors.forename: Masaru
authors.initials: M
authors.lastname: Murakami
authors.forename: Mikio
authors.initials: M
authors.lastname: Mikami
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.forename: R Yoshiyuki
authors.initials: RY
authors.lastname: Osamura
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006106:Granulosa Cell Tumor / Q000378:metabolism* / Q000601:surgery; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000601:surgery; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases