Novel target therapy for the HGF/cMET axis and HB-EGF in gastric cancer

胃癌 HGF/cMET 轴和 HB-EGF 的新型靶向治疗

• 批准号: 23591921
• 负责人: YASUMOTO Kazuo
• 金额: $ 3.24万
• 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: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591921/
• 关键词: 胃癌; がん性腹膜炎; HGF/MET axis; 分子標的治療; MET/HGF; 癌性腹膜炎; スキルス胃癌; パラクリン活性経路; MET TKI; パラクリン経路; MET; HGF

Scirrhous gastric cancer frequently develops into peritoneal carcinomatosis with malignant ascites. We investigated the role of the HGF/MET axis in peritoneal carcinomatosis in scirrhous cancer. Scirrhous cell lines produced peritoneal carcinomatosis with massive ascites after intraperitoneal injection in nude mice. Their proliferation was stimulated by exogenous HGF in vitro. MET-TKIs inhibited HGF-stimulated proliferation of scirrhous cells. Furthermore, MET-TKIs prolonged the survival of mice bearing established tumors by scirrhous cells. In clinical specimens, HGF was markedly produced by stromal fibroblasts in scirrous cancer. Our results strongly suggest that paracrine HGF-induced activation of MET-mediated signaling pathways plays an important role in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer.Thus, MET signaling pathway may be a potential therapeutic target for peritoneal carcinomatosis of gastric cancer, even without MET amplification.

硬化性胃癌常发展为腹膜癌病伴恶性腹水。我们研究了HGF/MET轴在硬癌腹膜癌转移中的作用。硬癌细胞株腹腔注射裸鼠后产生大量腹水的腹膜癌病。在体外，外源性HGF可刺激细胞增殖。MET-TKI抑制HGF刺激的硬结细胞增殖。此外，MET-TKI延长了通过硬化细胞建立的肿瘤小鼠的生存期。在临床标本中，肝细胞生长因子由硬癌中的间质成纤维细胞显着产生。我们的研究结果表明旁分泌HGF激活MET信号通路在硬化性胃癌腹膜癌转移的发病机制中起重要作用，因此，MET信号通路可能是治疗胃癌腹膜癌转移的潜在靶点，即使没有MET扩增。

项目成果

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

• DOI: 10.1158/1078-0432.ccr-10-2475
• 发表时间: 2011-06-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Yasumoto, Kazuo;Yamada, Tadaaki;Yano, Seiji
• 通讯作者: Yano, Seiji

EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition

• DOI: 10.1158/0008-5472.can-12-3479
• 发表时间: 2013-04-15
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Nakagawa, Takayuki;Takeuchi, Shinji;Yano, Seiji
• 通讯作者: Yano, Seiji