A Novel Transforming Growth Factor β Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma

Kawajiri, Hidemi; Yashiro, Masakazu; Shinto, Osamu; Nakamura, Kazunori; Tendo, Masashige; Takemura, Susumu; Node, Manabu; Hamashima, Yoshio; Kajimoto, Tetsuya; Sawada, Tetsuji; Ohira, Masaichi; Hirakawa, Kosei

doi:10.1158/1078-0432.ccr-07-1634

Cited by 38 publications

(32 citation statements)

References 31 publications

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“…In the present study, we established a peritoneal carcinomatosis model by using human scirrhous gastric cancer cell line OCUM2MD3. It was previously reported that these cells, intraperitoneally inoculaed, had developed peritoneal metastasis accompanied by stromal fibrosis of the peritoneum in nude mice (22,23). The result of our in vivo study supports the assumption that AT1 receptor blockade therapy provides a new strategy for peritoneal carcinomatosis through suppression of both tumor growth and stromal fibrosis.…”

Section: Discussionsupporting

confidence: 88%

“…The gastric cancer cell lines used in this study were human gastric cancer cell line, OCUM2MD3 which was kindly supplied by Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan, and MKN28, AZ521, TMK1, MKN45 which were purchased from American Type Culture Collection (Rockville, MD, USA). OUUM2MD3 is a human scirrhous gastric cancer cell line and it has a strong ability to metastasize into the peritoneum in nude mice (22,23). This cell line was maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco-BRL, USA) supplemented with 10% fetal bovine serum (FBS; Iwaki, Japan), 2 mM glutamine (Nissui Pharmaceutical, Tokyo, Japan), 10 U/ml penicillin-streptomycin (Gibco-BRL) and the other cell lines were maintained in RPMI-1640 medium (Nissui Pharmaceutical) supplemented with the same chemicals.…”

Section: Methodsmentioning

confidence: 99%

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Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

Koyama

Fushida²,

Harada³

et al. 2009

Int J Oncol

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Abstract. Angiotensin II is a main effector peptide in renin-angiotensin system, acting as a growth promoter via angiotensin II type 1 (AT1) receptor. The present study examined intrinsic angiotensin II generating system in gastric cancer and potential roles of angiotensin II in cellular proliferation and survival. The expression of AT1 receptor was examined in gastric cancer cell lines and tissues. In addition, we measured angiotensin II concentration in tissues from twenty gastric cancer and corresponding normal region using the florisil method. In vitro, we investigated the potential roles of angiotensin II in cellular proliferation and cell survival in cultured human gastric cancer cell line. The effects of AT1 receptor blocker candesartan were evaluated in a mouse model of peritoneal carcinomatosis. AT1 receptor protein was expressed in gastric cancer cell lines and tissues. Angiotensin II concentration in tumor region (1447±624 pg/g wet) was significantly higher than those of normal region (775±320 pg/g wet) (p<0.05). Angiotensin II stimulates the cell proliferation in the AT1 receptor-positive OCUM2MD3 gastric cancer cell line and this proliferative effect of angiotensin II was inhibited by a specific AT1 receptor antagonist, candesartan. We also confirmed the angiotensin II stimulated ERK1/2, nuclear transcript factor-κB (NF-κB) and surviving activation, which are central molecules of cellular proliferation and survival in OCUM2MD3 cells. Candesartan significantly prolonged survival time in a mouse model of peritoneal carcinomatosis compared with control group (p=0.0.197, log-rank test). Our data provide in vivo evidence of intrinsic angiotensin II generating system in gastric cancer and indicate locally formed angiotensin II is involved in cellular proliferation and survival.

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

Koyama

Fushida²,

Harada³

et al. 2009

Int J Oncol

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“…The attachment of GC cells to the peritoneum is an important step in the initial phases of metastatic dissemination (10)(11)(12). The results of the present study showed that only a small subset of GC cells have potential metastatic ability in the peritoneum.…”

Section: Discussionsupporting

confidence: 47%

Role of integrin α1 subunits in gastric cancer patients with peritoneal dissemination

et al. 2011

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Abstract. The interaction between gastric cancer (GC) cells and the peritoneum is a critical event in peritoneal dissemination. The molecular mechanisms of this dissemination, however, remain unclear. Integrins are heterodimeric cell adhesion molecules consisting of α and β subunits that serve as adhesion receptors for extracellular matrix proteins and cellular ligands, and may participate in GC peritoneal dissemination. In this study, we isolated fresh GC cells from a patient with peritoneal metastasis and examined them for integrin expression and investigated the role of integrin α1 subunit molecules in GC. Five clones (KGC1C2, KGC1F3, KGC1H3, KGC1E8, KGC1G10) were established from the clinical GC sample and used in an in vitro adhesion model using a single cell culture method. Each clone was transplanted into the peritoneal cavity of SCID mice, where each clone formed tumors and caused conglutination of organs in the abdominal cavity. We analyzed the expression of integrin subunits for each clone by flow cytometry and found that the expression ratio of α1 subunits paired with β1 subunits was detected at higher levels than other subunits. To verify that anti-integrin α1 subunit (CD49a) antibody inhibits cell adhesion in an in vitro adhesion assay, each clone was treated with anti-CD49a antibody, which significantly inhibited cell adhesion compared to the untreated group. Characterization of α1 subunit expression in GC may be useful in optimizing treatments for different individuals. Having high metastatic abilities, these 5 new GC clones may be beneficial for analyzing integrin function in tumor metastasis.

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“…In this same study, patients with high levels of ␣5-integrin died 9 months earlier than those displaying low ␣5-integrin expression. 33 Following a similar rational, Kawajiri et al 34 recently showed that the transforming growth factor-␤-R inhibitor, A-77, decreased the adhesive and invasive abilities of diffuse gastric cancer cells to the mice peritoneum, as well as the size and number of metastatic nodes, and demonstrated that this effect was mediated by decreased expression of integrins.…”

Section: Discussionmentioning

confidence: 87%

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

et al. 2009

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Background & Aims:Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients. Methods: Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry. Results: Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P ‫؍‬ .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample. Conclusion: The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.

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A Novel Transforming Growth Factor β Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma

Cited by 38 publications

References 31 publications

Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

Role of integrin α1 subunits in gastric cancer patients with peritoneal dissemination

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

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