The pathophysiology of malignant glioma and of treatment strategies

恶性胶质瘤的病理生理学和治疗策略

• 批准号: 14370439
• 负责人: KURATSU Jun-ichi
• 金额: $ 8.96万
• 依托单位: Kumamoto University (2004)Kagoshima University (2002-2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370439/
• 关键词: glioma; macrophage; apoptosis; integrin; MCP-1; NF1; angiogenesis; グリオーマ; インテグリン; PTEN; ドコサヘキサエンサン; アポトーシス; c-kit; 胚細胞腫; NF-1; p53; EGF-R; NO; ケモカイン; トロンビン; 血管新生; 浸潤

1.Vascular endothelial growth factor(VEGF) play an important role in the angiogenesis of glioma. We found that there are two mechanisms of angiogenesis by VEGF in malignant glioma, one is via VEGF produced by macrophages infiltrated by monocyte chemoattractant protein 1(MCP-1) derived from glioma cells and the other is via VEGF stimulated by thrombin converted from pro-thrombin derived from glioma cells. Furthermore, we found that docosahexaenoic acid contained in the necrotic tissue suppressed the antitumor activity of macrophages infiltrated in the glioma.2.We reported that the increased activity and expression of Integrin-linked kinase(ILK) activity is regulated by PTEN. The transfection into the glioblastoma cells altered the localization of ILK in the cell membrane ; transfection with PTEN down-regulated PKB/Akt phosphorylation of ILK-singnaling. We assume that ILK is critical for the PTEN-sensitive regulation of PKB/Akt-dependent cell survival. The COX-2 inhibitor was capable of down-regulating ILK and PKB/Akt phosphorylation.3.We retrospectively analyzed the relationship between treatment outcomes and EGF-R gene, homozygous deletion of p16 gene in newly diagnosed glioblastoma adult patients. We found that EGF-R and homozygous deletion of p16 gene are of significant prognostic value for predicting survival in glioblastoma patients.4.Neurofibromin which is a NF1 gene product. We found the mutural regulation of cellular neurofibromin is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.

1.血管内皮生长因子(VEGF)在胶质瘤血管生成中发挥重要作用。我们发现恶性胶质瘤中 VEGF 的血管生成有两种机制，一种是通过来自胶质瘤细胞的单核细胞趋化蛋白 1（MCP-1）浸润的巨噬细胞产生 VEGF，另一种是通过前体转化的凝血酶刺激 VEGF。源自神经胶质瘤细胞的凝血酶。此外，我们发现坏死组织中所含的二十二碳六烯酸抑制了胶质瘤中浸润的巨噬细胞的抗肿瘤活性。2.我们报道了整合素连接激酶（ILK）活性的增加和表达受PTEN调节。转染到胶质母细胞瘤细胞中改变了ILK在细胞膜中的定位； PTEN 转染下调了 ILK 信号传导的 PKB/Akt 磷酸化。我们假设 ILK 对于 PTEN 敏感的 PKB/Akt 依赖性细胞存活调节至关重要。 COX-2抑制剂能够下调ILK和PKB/Akt磷酸化。3.我们回顾性分析了初诊成人胶质母细胞瘤患者的治疗结果与EGF-R基因、p16基因纯合缺失的关系。我们发现EGF-R和p16基因纯合缺失对于预测胶质母细胞瘤患者的生存具有重要的预后价值。4.神经纤维蛋白，是NF1基因的产物。我们发现细胞神经纤维蛋白的相互调节对于正常神经元分化至关重要，并且神经元细胞的异常调节可能与 NF1 相关的学习和记忆障碍有关。

项目成果

N.Shinojima: "Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme."Cancer Res.. 63・20. 6962-6970 (2003)

N.Shinojima：“表皮生长因子受体对多形性胶质母细胞瘤患者的预后价值”。Cancer Res.63・20（2003）。

Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GAP function toward Ras.

神经纤维瘤病 I 型肿瘤抑制神经纤维蛋白通过其针对 Ras 的 GAP 功能调节神经元分化。

• 发表时间: 2003
• 期刊: J.Biol.Chem. 278
• 作者: S.Yunoue;H.Tokuo;K.Fukunaga;L.Feng;T.Ozawa;T.Nishi;A.Kikuchi;S.Hattori;J.Kuratsu;H.Saya;N.Araki
• 通讯作者: N.Araki

Pathodynamics of nitric oxide production within implanted glioma studied with an in vivo microdialysis technique and immunohistochemistry.

• DOI: 10.1254/jphs.91.15
• 发表时间: 2003
• 期刊: Journal of pharmacological sciences
• 影响因子: 3.5
• 作者: T. Oyoshi;M. Nomoto;H. Hirano;J. Kuratsu

Osamu Miyanohara: "Diagnostic signficance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors"Journal of Neurosurgery. 97. 177-183 (2002)

Osamu Miyanohara：“生殖细胞肿瘤患者脑脊液中可溶性 c-kit 的诊断意义”神经外科杂志。

Takahiro Kimura: "Expression of lymphocyte-spectic chemokines in human malignant glioma : Essential role of LARC in cellular immunity of malignant glioma"International Journal of Oncology. 21. 707-715 (2002)

Takahiro Kimura：“人恶性神经胶质瘤中淋巴细胞特异性趋化因子的表达：LARC 在恶性神经胶质瘤细胞免疫中的重要作用”国际肿瘤学杂志。