PMID- 24403861
OWN - NLM
STAT- MEDLINE
DCOM- 20140908
LR  - 20220114
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 15
IP  - 12
DP  - 2013 Dec
TI  - Combining molecular targeted drugs to inhibit both cancer cells and activated 
      stromal cells in gastric cancer.
PG  - 1391-9
AB  - Recent studies have revealed that PDGF plays a role in promoting progressive 
      tumor growth in several cancers, including gastric cancer. Cancer-associated 
      fibroblasts, pericytes, and lymphatic endothelial cells in stroma express high 
      levels of PDGF receptor (PDGF-R); cancer cells and vascular endothelial cells do 
      not. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that 
      increases the production of proteins that stimulate key cellular processes such 
      as cell growth and proliferation, cell metabolism, and angiogenesis. In the 
      present study, we examined the effects of PDGF-R tyrosine kinase inhibitor 
      (nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude 
      mice model of human gastric cancer. Expression of PDGF-B and PDGF-Rbeta mRNAs was 
      associated with stromal volume. Treatment with nilotinib did not suppress tumor 
      growth but significantly decreased stromal reactivity, lymphatic invasion, 
      lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, 
      treatment with everolimus decreased tumor growth and microvessel density but not 
      stromal reactivity. Nilotinib and everolimus in combination reduced both the 
      growth rate and stromal reaction. Target molecule-based inhibition of 
      cancer-stromal cell interaction appears promising as an effective antitumor 
      therapy.
FAU - Onoyama, Mieko
AU  - Onoyama M
AD  - Department of Gastroenterology and Metabolism, Graduate School of Biomedical and 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Kitadai, Yasuhiko
AU  - Kitadai Y
AD  - Department of Gastroenterology and Metabolism, Graduate School of Biomedical and 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Tanaka, Yuichiro
AU  - Tanaka Y
AD  - Department of Gastroenterology and Metabolism, Graduate School of Biomedical and 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Yuge, Ryo
AU  - Yuge R
AD  - Department of Gastroenterology and Metabolism, Graduate School of Biomedical and 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Shinagawa, Kei
AU  - Shinagawa K
AD  - Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
FAU - Tanaka, Shinji
AU  - Tanaka S
AD  - Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
FAU - Yasui, Wataru
AU  - Yasui W
AD  - Department of Molecular Pathology, Graduate School of Biomedical and Health 
      Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Chayama, Kazuaki
AU  - Chayama K
AD  - Department of Gastroenterology and Metabolism, Graduate School of Biomedical and 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 0 (Pyrimidines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - F41401512X (nilotinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/pathology
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Everolimus
MH  - Female
MH  - Gene Expression
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Molecular Targeted Therapy
MH  - Proto-Oncogene Proteins c-sis/genetics/metabolism
MH  - Pyrimidines/administration & dosage
MH  - Receptor, Platelet-Derived Growth Factor beta/genetics/metabolism
MH  - Signal Transduction
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - Stomach Neoplasms/*drug therapy/pathology
MH  - Stromal Cells/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC3884530
EDAT- 2014/01/10 06:00
MHDA- 2014/09/10 06:00
PMCR- 2013/12/01
CRDT- 2014/01/10 06:00
PHST- 2013/09/20 00:00 [received]
PHST- 2013/09/20 00:00 [revised]
PHST- 2013/11/06 00:00 [accepted]
PHST- 2014/01/10 06:00 [entrez]
PHST- 2014/01/10 06:00 [pubmed]
PHST- 2014/09/10 06:00 [medline]
PHST- 2013/12/01 00:00 [pmc-release]
AID - 131668 [pii]
AID - 10.1593/neo.131668 [doi]
PST - ppublish
SO  - Neoplasia. 2013 Dec;15(12):1391-9. doi: 10.1593/neo.131668.