title: Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors.
abstract: OBJECTIVE
  Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.
  
  
  METHODS
  Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.
  
  
  RESULTS
  Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro.
  
  
  CONCLUSIONS
  mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs.
authors.affiliation: Departments of Anatomic Pathology and Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Endo
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Nokitaka
authors.initials: N
authors.lastname: Setsu
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kohashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ishii
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Iida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Hakozaki
authors.forename: Mikiko
authors.initials: M
authors.lastname: Aoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Yoh
authors.initials: Y
authors.lastname: Dobashi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D000068338:Everolimus; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018317:Nerve Sheath Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus