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Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors.

AbstractAIMS:
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.
AuthorsTakashi Shida, Takashi Kishimoto, Mitsuko Furuya, Takashi Nikaido, Keiji Koda, Shigetsugu Takano, Fumio Kimura, Hiroaki Shimizu, Hiroyuki Yoshidome, Masayuki Ohtsuka, Tohru Tanizawa, Yukio Nakatani, Masaru Miyazaki
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 65 Issue 5 Pg. 889-93 (Apr 2010) ISSN: 1432-0843 [Electronic] Germany
PMID19657638 (Publication Type: Journal Article)
Chemical References
  • Intracellular Signaling Peptides and Proteins
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Large Cell (metabolism)
  • Carcinoma, Neuroendocrine (metabolism)
  • Carcinoma, Small Cell (metabolism)
  • Female
  • Gastrointestinal Neoplasms (metabolism)
  • Humans
  • Intracellular Signaling Peptides and Proteins (metabolism)
  • Male
  • Middle Aged
  • Pancreatic Neoplasms (metabolism)
  • Protein Serine-Threonine Kinases (metabolism)
  • TOR Serine-Threonine Kinases
  • Young Adult

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