title: The Akt/mammalian target of rapamycin pathway is activated and associated with adverse prognosis in soft tissue leiomyosarcomas.
abstract: BACKGROUND
  The Akt/mammalian target of rapamycin (mTOR) pathway mediates cell survival and proliferation and contributes to tumor progression. Soft tissue leiomyosarcoma continues to show poor prognosis, and little is known about its mechanisms of tumor progression. Here the authors investigated the significance of activation of the Akt/mTOR pathway in soft tissue leiomyosarcomas.
  
  
  METHODS
  The phosphorylation status of Akt, mTOR, S6, and the eukaryotic translation initiation factor 4E-binding protein (4E-BP1) and the protein expression of phosphatase and tensin homologue (PTEN) were assessed by immunohistochemistry in 145 formalin-fixed paraffin-embedded samples of soft tissue leiomyosarcoma including 129 primary tumors. The expression of phosphorylated Akt and mTOR in comparison with their total forms was assessed by Western blot analysis in 13 frozen samples, which were paired with normal tissue samples. Moreover, 39 frozen tumor samples were analyzed for PIK3CA and AKT1 gene mutation.
  
  
  RESULTS
  Immunohistochemically, phosphorylated forms of Akt, mTOR, S6, and 4E-BP1 were positive in 78.3%, 72.6%, 74.5%, and 70.5% of the samples, respectively. These results were correlated with each other, and associated with higher mitotic activity and adverse prognosis. Decreased expression of PTEN was recognized in only 19.7% and had no statistically significant correlation with Akt or other molecules. Immunoblotting showed a high degree of Akt and mTOR phosphorylation in tumor samples compared with that in non-neoplastic tissue. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots.
  
  
  CONCLUSIONS
  The Akt/mTOR pathway was activated in most cases of soft tissue leiomyosarcoma and associated with worse clinical behavior and aggressive pathological findings.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Nokitaka
authors.initials: N
authors.lastname: Setsu
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kohashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Endo
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yokoyama
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yoh
authors.initials: Y
authors.lastname: Dobashi
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007890:Leiomyosarcoma / Q000737:chemistry / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D051059:PTEN Phosphohydrolase / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012509:Sarcoma / Q000737:chemistry / Q000401:mortality* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human