PMID- 19648884
OWN - NLM
STAT- MEDLINE
DCOM- 20091203
LR  - 20230210
IS  - 1530-0285 (Electronic)
IS  - 0893-3952 (Linking)
VI  - 22
IP  - 10
DP  - 2009 Oct
TI  - EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft 
      tissue tumors.
PG  - 1328-40
LID - 10.1038/modpathol.2009.104 [doi]
AB  - To gain the insight into the involvement of signaling mediated by the mammalian 
      target of rapamycin (mTOR) in the phenotype and biological profiles of tumors and 
      tumor-like lesions of the bone and soft tissue, we analyzed the expression and 
      phosphorylation (activation) of mTOR and its correlation with the status of 
      upstream and downstream modulator proteins Akt, p70S6-kinase (S6K), and 
      eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), which we refer to 
      collectively as mTOR cassette proteins. Immunohistochemical analysis of 140 cases 
      showed activation of Akt in 55% (61% in malignant and 27% in benign), and mTOR 
      expression in 61% (66% in malignant and 39% in benign). The preponderance of mTOR 
      activation was found in tumors of peripheral nerve sheath (malignant peripheral 
      nerve sheath tumor and schwannoma), skeletal muscle origin (rhabdomyosarcoma), 
      and in those exhibiting epithelial nature (chordoma and synovial sarcoma). 
      Together with the result of immunoblotting analysis, it was shown that many of 
      those particular tumors with mTOR activation exhibited activation of Akt, S6K, 
      and 4E-BP1, suggesting the constitutive activation of the Akt/mTOR pathway. In 
      addition, although activation of the Akt/mTOR pathway was largely independent of 
      activation of epidermal growth factor receptor (EGFR), mutation of EGFR was 
      frequently accompanied by constitutive activation of Akt-mTOR-S6K/4E-BP1. By 
      clinicopathological analysis, activation of Akt correlates with statistically 
      higher probability of metastasis. We conclude that mTOR-mediated signaling 
      proteins function not only in the proliferation of the tumor cells, but also in 
      the differentiation and/or maintenance of morphological phenotypes in tumors of 
      rhabdomyoblastic and nerve sheath cell origin. Furthermore, mTOR signaling may 
      also modulate morphogenesis of tumors exhibiting epithelial nature. Additionally, 
      activated Akt may have a function in metastasis. Overall, these results suggest 
      that inhibitors of mTOR cassette may be useful as novel components of combined 
      chemotherapy for a defined subset of bone and soft tissue sarcomas.
FAU - Dobashi, Yoh
AU  - Dobashi Y
AD  - Department of Pathology, Saitama Medical Center, Jichi Medical University, 1-847 
      Amanuma, Omiya, Saitama, Japan. ydobashi@omiya.jichi.ac.jp
FAU - Suzuki, Shioto
AU  - Suzuki S
FAU - Sato, Eiichi
AU  - Sato E
FAU - Hamada, Yoshiki
AU  - Hamada Y
FAU - Yanagawa, Takashi
AU  - Yanagawa T
FAU - Ooi, Akishi
AU  - Ooi A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090731
PL  - United States
TA  - Mod Pathol
JT  - Modern pathology : an official journal of the United States and Canadian Academy 
      of Pathology, Inc
JID - 8806605
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*analysis
MH  - Bone Neoplasms/*enzymology/genetics/mortality/secondary
MH  - Cell Cycle Proteins
MH  - Cell Proliferation
MH  - Enzyme Activation
MH  - ErbB Receptors/*analysis/genetics
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Mutation
MH  - Neoplasm Staging
MH  - Phosphoproteins/*analysis
MH  - Phosphorylation
MH  - Prognosis
MH  - Protein Kinases/*analysis
MH  - Proto-Oncogene Proteins c-akt/*analysis
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*analysis
MH  - *Signal Transduction
MH  - Soft Tissue Neoplasms/*enzymology/genetics/mortality/secondary
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/08/04 09:00
MHDA- 2009/12/16 06:00
CRDT- 2009/08/04 09:00
PHST- 2009/08/04 09:00 [entrez]
PHST- 2009/08/04 09:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
AID - S0893-3952(22)02455-3 [pii]
AID - 10.1038/modpathol.2009.104 [doi]
PST - ppublish
SO  - Mod Pathol. 2009 Oct;22(10):1328-40. doi: 10.1038/modpathol.2009.104. Epub 2009 
      Jul 31.