PMID- 20817788
OWN - NLM
STAT- MEDLINE
DCOM- 20110204
LR  - 20220318
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Linking)
VI  - 17
IP  - 4
DP  - 2010 Dec
TI  - Mammalian target of rapamycin signaling activation patterns in neuroendocrine 
      tumors of the lung.
PG  - 977-87
LID - 10.1677/ERC-10-0157 [doi]
AB  - Among alternative therapeutic strategies in clinically aggressive neuroendocrine 
      tumors (NETs) of the lung, promising results have been obtained in experimental 
      clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in 
      the absence of a proven mTOR signaling activation status. This study analyzed the 
      expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal 
      p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 
      (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, 
      including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large 
      cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By 
      immunohistochemistry, low-to-intermediate-grade tumors as compared with 
      high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) 
      (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly 
      expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was 
      proved by the strong correlation of p-mTOR with p-S6K and somatostatin 
      receptor(s). Western blot analysis of NET tumor samples confirmed such findings, 
      and differential sensitivity to mTOR inhibition according to mTOR pathway 
      activation characteristics was determined in two lung carcinoid cell lines in 
      vitro. None of the investigated molecules had an impact on survival. However, in 
      low-grade tumors, low p-mTOR expression correlated with lymph node metastases 
      (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data 
      demonstrate a differential mTOR activation status in the spectrum of pulmonary 
      NETs, possibly suggesting that mTOR pathway profiling might play a predictive 
      role in candidate patients for mTOR-targeted therapies.
FAU - Righi, Luisella
AU  - Righi L
AD  - Division of Pathology, Department of Clinical and Biological Sciences, University 
      of Turin at San Luigi Hospital, Regione Gonzole 10, Orbassano, Turin, Italy. 
      luisella.righi@unito.it
FAU - Volante, Marco
AU  - Volante M
FAU - Rapa, Ida
AU  - Rapa I
FAU - Tavaglione, Veronica
AU  - Tavaglione V
FAU - Inzani, Frediano
AU  - Inzani F
FAU - Pelosi, Giuseppe
AU  - Pelosi G
FAU - Papotti, Mauro
AU  - Papotti M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101029
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Analysis of Variance
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - Lung Neoplasms/*metabolism/mortality/pathology
MH  - Lymphatic Metastasis
MH  - Male
MH  - Middle Aged
MH  - Neuroendocrine Tumors/*metabolism/mortality/pathology
MH  - Phosphorylation
MH  - Prognosis
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
EDAT- 2010/09/08 06:00
MHDA- 2011/02/05 06:00
CRDT- 2010/09/07 06:00
PHST- 2010/09/07 06:00 [entrez]
PHST- 2010/09/08 06:00 [pubmed]
PHST- 2011/02/05 06:00 [medline]
AID - ERC-10-0157 [pii]
AID - 10.1677/ERC-10-0157 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2010 Oct 29;17(4):977-87. doi: 10.1677/ERC-10-0157. Print 
      2010 Dec.