title: Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors.
abstract: BACKGROUND
  Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets.
  
  
  METHODS
  The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRβ, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-β [p-IGF-1Rβ]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples.
  
  
  RESULTS
  The immunohistochemical results were as follows: p-Akt, 56.0% (nuclear and cytoplasmic staining); p-mTOR, 69.6% (nuclear and cytoplasmic staining); p-4EBP1, 80.3% (nuclear and cytoplasmic staining); p-S6RP, 69.6% (cytoplasmic staining); p-PDGFRα, 39.0% (cytoplasmic staining); p-PDGFRβ, 52.0% (cytoplasmic staining); p-c-met, 37.8% (nuclear staining) and 19.6% (cytoplasmic staining); and p-IGF-1Rβ, 16.6% (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRβ and p-IGF-1Rβ were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings.
  
  
  CONCLUSIONS
  The Akt/mTOR pathway was activated in approximately 50% of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kohashi
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Fushimi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Nokitaka
authors.initials: N
authors.lastname: Setsu
authors.forename: Makoto
authors.initials: M
authors.lastname: Endo
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Tokunaga
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000150:complications; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D054364:Solitary Fibrous Tumors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C546842:MTOR protein, human; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt; hemangiopericytoma; mammalian target of rapamycin (mTOR); receptor tyrosine kinase; solitary fibrous tumor