title: Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors.
abstract: OBJECTIVE
  Gastroenteropancreatic neuroendocrine tumors are rare, and the current WHO classification divides this tumor entity into well-differentiated (neuro)endocrine tumors, well-differentiated (neuro)endocrine carcinomas, and poorly differentiated (neuro)endocrine carcinomas. Poorly differentiated (neuro)endocrine carcinoma is extremely aggressive, and no appropriate therapeutic approach has been established. The mammalian target of rapamycin (mTOR), an important regulator of cell proliferation and protein translation, is activated in various malignancies. Recent phase II trial has revealed the efficacy of mTOR inhibitor (RAD001; everolimus) against low-to-intermediate grade neuroendocrine tumors. However, the beneficial role of mTOR inhibitor against poorly neuroendocrine carcinoma remains uncertain. The purpose of the present study was to determine the activation of mTOR in gastropancreatic neuroendocrine tumors, especially in poorly differentiated neuroendocrine carcinomas.
  
  
  METHODS
  Expression of p-mTOR(Ser2448) was assessed by immunohistochemistry in 20 gastropancreatic neuroendocrine tumors (seven well-differentiated neuroendocrine tumors, four well-differentiated neuroendocrine carcinomas, and nine poorly differentiated neuroendocrine carcinomas). Double immunohistochemistry was performed with p-Akt for patients with high p-mTOR expression.
  
  
  RESULTS
  Expression of mTOR was seen in 9 (45%) of 20 gastroenteropancreatic neuroendocrine tumors. High expression of p-mTOR was seen in 6 (67%) of 9 poorly differentiated neuroendocrine carcinomas which was higher than the expression rate of well-differentiated neuroendocrine tumors and carcinomas, 3 (27%) of 11. All large cell neuroendocrine carcinomas showed high p-mTOR expression. Some tumor cells showed positive staining for p-mTOR co-expressed p-Akt.
  
  
  CONCLUSIONS
  High expression rate of p-mTOR in poorly differentiated neuroendocrine carcinomas (large-cell type) may suggest the potential role of mTOR inhibitors as effective therapeutic agents for this highly malignant disease.
authors: Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. shidax812@yahoo.co.jp
authors: Takashi
authors: T
authors: Shida
authors: Takashi
authors: T
authors: Kishimoto
authors: Mitsuko
authors: M
authors: Furuya
authors: Takashi
authors: T
authors: Nikaido
authors: Keiji
authors: K
authors: Koda
authors: Shigetsugu
authors: S
authors: Takano
authors: Fumio
authors: F
authors: Kimura
authors: Hiroaki
authors: H
authors: Shimizu
authors: Hiroyuki
authors: H
authors: Yoshidome
authors: Masayuki
authors: M
authors: Ohtsuka
authors: Tohru
authors: T
authors: Tanizawa
authors: Yukio
authors: Y
authors: Nakatani
authors: Masaru
authors: M
authors: Miyazaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism*; D018288:Carcinoma, Small Cell / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases