Studies on Helicobacter species on gastric MALT lymphoma and effect of molecular target drugs

幽门螺杆菌对胃MALT淋巴瘤的影响及分子靶向药物的研究

• 批准号: 22590690
• 负责人: NAKAMURA Masahiko
• 金额: $ 2.91万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590690/
• 关键词: 上部消化管学(食道、胃、十二指腸); Helicobacter heilmannii; 胃MALTリンパ腫; 胃癌; hepatocyte growth factor; c-MET; HGF activator; high endothelial venule; 胃マルトリンパ腫; ヘリコバクター; 鳥肌胃炎; VEGF; Flt-1; Flk-1; in situ hybridization法; PCR法; ヘリコバクターハイルマニイ; ヘリコバクターピロリ

By the investigation of the specimens obtained from the upper gastrointestinal endoscopy of the patients suffering from chronic gastritis, gastric ulcer, gastric polyp, gastric cancer and gastric MALT lymphoma, 7 MALT lymphoma cases out of 18 (38%) were found to be positive to Helicobacter heilmannii, while only 2% were positive in other gastric diseases. By the cluster analysis using GENENTYC-MAC UPGMA, these cases were found to be infected by Helicobacter heilmannii and suis. Among other gastric diseases, nodular gastritis patents were found to be highly positive to H. heilmannii, suggesting the possible interaction with the gastric cancer. In H. heilmannii positive cases, more than half cases were found to show the positivity to H. pylori as well.By the in vivo study using the infection model using C57BL/6 mice, VEGF-related immunoreactities were recognized in the MALT lymphoma, suggesting the VEGF-mediated angiogenesis was closely related to the expansion of the tumor. The administration of Flt-4 and Flt-1 antibody suppressed the tumor, supporting this hypothesis. c-Met immunoreactivity was found in the lymphocytes composing the MALT lymphoma, and HGF immunoreactivity was recognized mostly in the endothelial cells and macrophages. HGFA was localized on mesenchymal cells other than the lymphocytes. The administration of antibodies against c-Met to the infected mice induced the significant suppression of hepatic and pulmonary lesions as well as the gastric MALT lymphoma.In conclusion, HGF and c-Met pathway were suggested to contribute to the lymphomagenesis in the liver and lung after Helicobacter heilmannii infection.

通过对慢性胃炎、胃溃疡、胃息肉、胃癌及胃MALT淋巴瘤患者上消化道内镜标本的调查，发现18例MALT淋巴瘤中有7例（38%）检出Helicobacterheilmannii，而其他胃病中仅2%检出Helicobacterheilmannii。应用GENENTYC-MAC UPGMA聚类分析，发现这些病例均为海尔曼螺杆菌和猪螺杆菌感染。在其他胃疾病中，结节性胃炎患者被发现对H。Heilmannii，提示可能与胃癌相互作用。In H. Heilmannii阳性例中，半数以上为H.通过使用C57 BL/6小鼠的感染模型的体内研究，在MALT淋巴瘤中识别VEGF相关的免疫反应性，表明VEGF介导的血管生成与肿瘤的扩展密切相关。Flt-4和Flt-1抗体的给药抑制了肿瘤，支持了这一假设。在构成MALT淋巴瘤的淋巴细胞中发现c-Met免疫反应性，并且HGF免疫反应性主要在内皮细胞和巨噬细胞中被识别。HGFA定位于间充质细胞而不是淋巴细胞。抗c-Met抗体可明显抑制Heilmannii感染小鼠的肝、肺病变及胃MALT淋巴瘤的发生，提示HGF和c-Met通路参与了Heilmannii感染后肝、肺淋巴瘤的发生。

项目成果

Suppression of lymphangiogenesis induced by Flt-4 antibody in gastric low-grade mucosa-associated lymphoid tissue lymphoma by Helicobacter heilmannii infection

• DOI: 10.1111/j.1440-1746.2010.06230.x
• 发表时间: 2010-05-01
• 期刊: JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
• 影响因子: 4.1
• 作者: Nakamura, Masahiko;Matsui, Hidenori;Tsuchimoto, Kanji
• 通讯作者: Tsuchimoto, Kanji

胃リンパ腫をターゲットとした各種モノクローナル抗体による抗腫瘍効果について。シンポジウム4消化管疾患の病態生理と治療薬の開発

关于各种针对胃淋巴瘤的单克隆抗体的抗肿瘤作用。

• 发表时间: 2011
• 作者: Nakamura;M.;中村正彦
• 通讯作者: 中村正彦

Helicobacter heilmannii can induce gastric lymphoid follicles in mice via a Peyer's patch-independent pathway

• DOI: 10.1111/j.1574-695x.2010.00731.x
• 发表时间: 2010-11-01
• 期刊: FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY
• 作者: Nobutani, Kentaro;Yoshida, Masaru;Azuma, Takeshi
• 通讯作者: Azuma, Takeshi

New pharmaceutical treatment of gastric MALT lymphoma: anti-angiogenesis treatment using VEGF receptor antibodies and celecoxib.

• DOI: 10.2174/13816128113199990420
• 发表时间: 2014
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: Nakamura M;Takahashi T;Matsui H;Takahashi S;Murayama SY;Suzuki H;Tsuchimoto K
• 通讯作者: Tsuchimoto K

Angiogenesis and Lymphangiogenesis in Malignancy: Lesson from Gastric MALT Lymphoma Model

恶性肿瘤中的血管生成和淋巴管生成：胃 MALT 淋巴瘤模型的教训

• 发表时间: 2013
• 期刊: Current Medicinal Chemistry
• 影响因子: 4.1
• 作者: Fukui H;Zhang X;Sun C;Yamasaki T;Kondo T;Ikehara H;Tomita T;Oshima T;横山展子;Masahiko Nakamura
• 通讯作者: Masahiko Nakamura