title: Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors.
abstract: BACKGROUND
  Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of various human cancers. However, expression of mTOR cascade components in pancreatic neuroendocrine tumors (PNETs) has not been fully explored. The aim of this study was to assess the expression of mTOR pathway in PNETs using immunohistochemistry.
  
  
  METHODS
  From December 1984 to April 2012, we surgically treated 42 patients with PNETs. We used immunohistochemistry to evaluate expression of mTOR, phosphorylated mTOR (p-mTOR), p70S6 kinase (S6K), phosphorylated S6 ribosomal protein (p-S6rp), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and phosphorylated 4E-BP1 (p-4E-BP1) in the resected specimens. The relation between the expression of these molecules and clinicopathological characteristics was investigated.
  
  
  RESULTS
  We identified the expression of mTOR (28.6%), p-mTOR (52.4%), S6K (52.4%), p-S6rp (40.5%), 4E-BP1 (81.0%), and p-4E-BP1 (26.2%) in PNETs. The expression of mTOR, p-mTOR, S6K, and p-S6rp was significantly associated with tumor invasion, proliferation, and an advanced-stage. Particularly, the expression of p-mTOR was related to clinically relevant factors such as tumor size, vascular invasion, extrapancreatic invasion, lymph node and/or distant metastasis, mitotic count, and European Neuroendocrine Tumor Society TNM staging as well as the 2004 and 2010 World Health Organization (WHO) classification. In addition, p-S6rp expression was related to vascular invasion, extrapancreatic invasion, lymph node and distant metastasis, mitotic count, and the 2010 WHO classification. In contrast, no significant relation between 4E-BP1 activation and clinicopathological factors was observed. The expression of p-mTOR was strongly correlated with that of p-S6rp (r = 0.474, P = 0.002).
  
  
  CONCLUSIONS
  Our results suggest that activation of the mTOR/S6K signaling pathway plays a significant role in tumorigenesis and progression of PNET.
authors.affiliation: Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan. komorin@oita-u.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Komori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohta
authors.forename: Hiroki
authors.initials: H
authors.lastname: Uchida
authors.forename: Yukio
authors.initials: Y
authors.lastname: Iwashita
authors.forename: Kengo
authors.initials: K
authors.lastname: Fukuzawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kashima
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inomata
authors.forename: Seigo
authors.initials: S
authors.lastname: Kitano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012189:Retrospective Studies; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Immunohistochemistry; Mammalian target of rapamycin inhibitor; Mammalian target of rapamycin signaling pathway; Pancreatic neuroendocrine tumors