PMID- 17230506
OWN - NLM
STAT- MEDLINE
DCOM- 20070417
LR  - 20211203
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 120
IP  - 8
DP  - 2007 Apr 15
TI  - Mammalian target of rapamycin is activated in human gastric cancer and serves as 
      a target for therapy in an experimental model.
PG  - 1803-10
AB  - The mammalian target of rapamycin (mTOR) has become an interesting target for 
      cancer therapy through its influence on oncogenic signals, which involve 
      phosphatidylinositol-3-kinase and hypoxia-inducible factor-1alpha (HIF-1alpha). 
      Since mTOR is an upstream regulator of HIF-1alpha, a key mediator of gastric 
      cancer growth and angiogenesis, we investigated mTOR activation in human gastric 
      adenocarcinoma specimens and determined whether rapamycin could inhibit gastric 
      cancer growth in mice. Expression of phospho-mTOR was assessed by 
      immunohistochemical analyses of human tissues. For in vitro studies, human 
      gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1alpha 
      activation and cancer cell motility upon rapamycin treatment. Effects of 
      rapamycin on tumor growth and angiogenesis in vivo were assessed in both a 
      subcutaneous tumor model and in an experimental model with orthotopically grown 
      tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or 
      diluent per intra-peritoneal injections. In addition, antiangiogenic effects were 
      monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical 
      analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% 
      of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment 
      effectively blocked S6K1, 4E-BP-1 and HIF-1alpha activation, and significantly 
      impaired tumor cell migration. In vivo, rapamycin-treatment led to significant 
      inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and 
      reduced tumor cell proliferation. Similar significant results were obtained in an 
      orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, 
      rapamycin-treatment significantly inhibited tumor vascularization in vivo. In 
      conclusion, mTOR is frequently activated in human gastric cancer and represents a 
      promising new molecular target for therapy.
CI  - (c) 2007 Wiley-Liss, Inc.
FAU - Lang, Sven A
AU  - Lang SA
AD  - Department of Surgery, University of Regensburg, Medical Center, Regensburg, 
      Germany.
FAU - Gaumann, Andreas
AU  - Gaumann A
FAU - Koehl, Gudrun E
AU  - Koehl GE
FAU - Seidel, Ulrike
AU  - Seidel U
FAU - Bataille, Frauke
AU  - Bataille F
FAU - Klein, Dagmar
AU  - Klein D
FAU - Ellis, Lee M
AU  - Ellis LM
FAU - Bolder, Ulrich
AU  - Bolder U
FAU - Hofstaedter, Ferdinand
AU  - Hofstaedter F
FAU - Schlitt, Hans-Jurgen
AU  - Schlitt HJ
FAU - Geissler, Edward K
AU  - Geissler EK
FAU - Stoeltzing, Oliver
AU  - Stoeltzing O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenocarcinoma/drug therapy/metabolism/pathology
MH  - Animals
MH  - Antibiotics, Antineoplastic/*therapeutic use
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - *Disease Models, Animal
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Intestinal Neoplasms/drug therapy/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neovascularization, Pathologic/*prevention & control
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*therapeutic use
MH  - Stomach Neoplasms/*drug therapy/metabolism/pathology
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/metabolism
EDAT- 2007/01/19 09:00
MHDA- 2007/04/18 09:00
CRDT- 2007/01/19 09:00
PHST- 2007/01/19 09:00 [pubmed]
PHST- 2007/04/18 09:00 [medline]
PHST- 2007/01/19 09:00 [entrez]
AID - 10.1002/ijc.22442 [doi]
PST - ppublish
SO  - Int J Cancer. 2007 Apr 15;120(8):1803-10. doi: 10.1002/ijc.22442.