Development of molecular target therapy for gastric cancer targeted for the CXCR4/CXCL12 axis and HB-EGF

针对CXCR4/CXCL12轴和HB-EGF的胃癌分子靶向治疗的开发

• 批准号: 20591565
• 负责人: YASUMOTO Kazuo
• 金额: $ 2.91万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591565/
• 关键词: 胃十二指腸外科学; 胃癌; 腹膜播種(癌性腹膜炎); CXCR4/CXCL12 axis; Amphiregulin; HB-EGF; EGFR ligands; 癌微小環境; HER4; 癌性腹膜炎; CXCR4; CXCL12 axis; 分子標的治療; EGF; EGFR

In this study, we showed that the EGFR ligands, amphiregulin and HB-EGF, are abundant in malignant ascites. Amphiregulin strongly enhanced the proliferation of CXCR4-expressing human gastric cancer NUGC4 cells, whereas HB-EGF markedly induced migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNF□-converting enzyme (TACE)-dependent amphiregulin shedding from functional CXCR4-expressing NUGC4 cells. Cetuximab, an anti-EGFR monoclonal antibody, effectively reduced tumor growth and ascites formation, and therefore dramatically prolonged survival in nude mice inoculated with NUGC4 cells. Our findings provide a novel insight into treatments that target tumor cells and their microenvironments during the development of peritoneal carcinomatosis from gastric cancer (Clin Cancer Res 2011 in press).

在这项研究中，我们发现在恶性腹水中有丰富的EGFR配体，即双调节蛋白和HB-EGF。双调蛋白显著促进表达CXCR4的人胃癌NUGC4细胞的增殖，而HB-EGF显著诱导成纤维细胞迁移。此外，HB-EGF和CXCL12共同促进表达CXCR4的NUGC4细胞分泌依赖于TACE的两调节素。西妥昔单抗是一种抗EGFR的单抗，可以有效地减少肿瘤生长和腹水形成，从而显著延长接种NUGC4细胞的裸鼠的生存时间。我们的发现为在胃癌腹膜癌病发展过程中针对肿瘤细胞及其微环境的治疗提供了新的见解(《临床癌症研究报告2011》)。

项目成果

Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma cells with EGF receptor mutations.

肝细胞生长因子诱导具有EGF受体突变的肺腺癌细胞对吉非替尼耐药。

• 发表时间: 2008
• 期刊: Cancer Res 68
• 作者: Yano S;et al.
• 通讯作者: et al.

The molecular mechanisms of gastric cancer metastases : Role of the themokine receptor CXCR4 and its ligand CXCL12 in peritoneal carcinomatosis

胃癌转移的分子机制：热因子受体CXCR4及其配体CXCL12在腹膜癌转移中的作用

• 发表时间: 2010
• 期刊: Transworld Research Network
• 作者: Kazuo Yasumoto;Seiji Yano
• 通讯作者: Seiji Yano

胃癌癌性腹膜炎成立へのEGFRリガンド

EGFR配体促进胃癌腹膜炎的形成

• 发表时间: 2010
• 作者: 佐藤史顕;戸井雅和;安本和生
• 通讯作者: 安本和生

Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement

• DOI: 10.1016/j.canlet.2008.02.018
• 发表时间: 2008-06-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Ogino, Hirokazu;Yano, Seiji;Sone, Saburo
• 通讯作者: Sone, Saburo

HGF-MET in resistance to EGFR tyrosine kinase inhibitors in lung cancer. Hepatocyte growth factor and its receptor signaling and the therapeutic implications.

HGF-MET 对肺癌中 EGFR 酪氨酸激酶抑制剂的耐药性。

• 发表时间: 2011
• 期刊: Curr Signal Transd T (in press)
• 作者: Yano S;et al.
• 通讯作者: et al.