PMID- 23970191
OWN - NLM
STAT- MEDLINE
DCOM- 20140519
LR  - 20130918
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 43
IP  - 5
DP  - 2013 Nov
TI  - HIF-1alpha is a crucial factor in the development of peritoneal dissemination via 
      natural metastatic routes in scirrhous gastric cancer.
PG  - 1431-40
LID - 10.3892/ijo.2013.2068 [doi]
AB  - The molecular mechanisms underlying the peritoneal dissemination of gastric 
      cancer remain unclear. Using in vivo metastatic models, this study attempted to 
      clarify the role of hypoxia inducible factor (HIF)-1alpha in the development of 
      peritoneal dissemination of gastric cancer. HIF-1alpha knockdown (KD) cells were 
      established in the scirrhous gastric cancer cell line 58As9. Using KD and control 
      (SC) cells, the presence of peritoneal dissemination was assessed in orthotopic 
      implantation (o.i.) and intraperitoneal injection (i.p.) models. A series of in 
      vitro analyses were also conducted. Finally, tumor angiogenesis was 
      immunohistochemically analyzed. In the o.i. model, peritoneal dissemination was 
      more frequently observed in the SC mice (93%) compared to the KD mice (13%) 
      (P<0.001). In the i.p. model, peritoneal dissemination occurred at a high rate in 
      both types of mice; however, a greater number of nodules was observed in the KD 
      mice (P=0.017). The in vitro assays showed that HIF-1alpha exerts unfavorable effects 
      on anoikis resistance and adhesion to extracellular matrix. Angiogenesis and 
      vascular invasion were more aggressive in the SC gastric tumors. Vascular 
      invasion was present in the intratumoral regions of the disseminated nodules in 
      the SC o.i., but not the i.p., mice. HIF-1alpha was found to be crucial for the 
      development of peritoneal dissemination in o.i. model, which mimics natural 
      metastasis. In contrast, HIF-1alpha played an inhibitory role in suppressing 
      peritoneal dissemination in the i.p. model. These results indicate that 
      peritoneal dissemination in o.i. mice may not act through a seeding mechanism. An 
      immunohistochemical analysis demonstrated HIF-1alpha-activated angiogenesis and 
      vascular invasion in stomach tumors. Furthermore, the results showed that the 
      disseminated nodules observed in SC o.i. mice were formed via extravasation of 
      cancer cells. We provide a possible mechanism in which peritoneal dissemination 
      of gastric cancer develops via a vascular network whereby HIF-1alpha activates tumor 
      angiogenesis.
FAU - Miyake, Shuusuke
AU  - Miyake S
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
FAU - Kitajima, Yoshihiko
AU  - Kitajima Y
FAU - Nakamura, Jun
AU  - Nakamura J
FAU - Kai, Keita
AU  - Kai K
FAU - Yanagihara, Kazuyoshi
AU  - Yanagihara K
FAU - Tanaka, Tomokazu
AU  - Tanaka T
FAU - Hiraki, Masatsugu
AU  - Hiraki M
FAU - Miyazaki, Kohji
AU  - Miyazaki K
FAU - Noshiro, Hirokazu
AU  - Noshiro H
LA  - eng
PT  - Journal Article
DEP - 20130821
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Adenocarcinoma, Scirrhous/genetics/metabolism/*pathology
MH  - Animals
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Cell Adhesion
MH  - Cell Proliferation
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Immunoenzyme Techniques
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - *Neovascularization, Pathologic
MH  - Peritoneal Neoplasms/genetics/metabolism/*secondary
MH  - RNA, Messenger/genetics
MH  - RNA, Small Interfering/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Stomach Neoplasms/genetics/metabolism/*pathology
EDAT- 2013/08/24 06:00
MHDA- 2014/05/20 06:00
CRDT- 2013/08/24 06:00
PHST- 2013/05/27 00:00 [received]
PHST- 2013/07/02 00:00 [accepted]
PHST- 2013/08/24 06:00 [entrez]
PHST- 2013/08/24 06:00 [pubmed]
PHST- 2014/05/20 06:00 [medline]
AID - 10.3892/ijo.2013.2068 [doi]
PST - ppublish
SO  - Int J Oncol. 2013 Nov;43(5):1431-40. doi: 10.3892/ijo.2013.2068. Epub 2013 Aug 
      21.