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Multifunctional therapeutic strategy for malignant gliomas targeting cathepsin D

以组织蛋白酶 D 为靶点的恶性胶质瘤多功能治疗策略

基本信息

批准号：
18591577
负责人：
IWADATE Yasuo
金额：
$ 2.23万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591577/
关键词：
glioma cathepsin D invasion proteases proteomics 腫瘍マーカー

项目摘要

We investigated efficacies of the novel therapeutic approaches for malignant gliomas targeting one of the aspartic protease, cathpsin D. We have reported that glioblastoma patients with high gene expression of cathepsin D frequently had leptomeningeal dissemination and they lived significantly shorter than those with low expression. Measurement of the serum cathepsin D concentrations by enzyme-linked immunosorbent assay (ELISA) demonstrated a significant increase in the patients with high-grade gliomas as compared with the low-grade tumors, which suggests that this protease would be useful as a glioma biomarker. We first knocked down the gene expression of cathpsin D in glioma cell lines (U87MG, U138MG, U251MG, U373MG; A172) using RNA interference. Effective down-regulations of cathepsin D was achieved in U87MG and A172 which originally express high levels of cathepsin D, the invasive abilities of these cell lines were accordingly dcreased. Then we used a rat glioma model using 9L gliosarcoma cells and serial MRI monitoring system. For this model, the peripheral vaccination with whole tumor cells inactivated by irradiation and intracerebral administration of IL-2 gene transduced vectors could induce complete rejection of established brain tumors. When cathepsin D was used as subcutaneous vaccine, the treatment efficacies against a rat glioma model did not reach those obtained by the inactivated whole tumor cell vaccine. Immunohistochemical analysis revealed that IL-2 was sufficiently expressed in the brain tumors, but the CD4^+ T cells and CD8^+ T cells were abundantly infiltrated. During the 3-month follow-up period, no adverse effect was observed. More glioma-specific proteins would be desirable for vaccination against gliomas.

我们研究了针对天冬氨酸蛋白酶之一组织蛋白酶 D 的恶性胶质瘤新治疗方法的疗效。我们报道了组织蛋白酶 D 高基因表达的胶质母细胞瘤患者经常发生软脑膜播散，并且他们的寿命明显短于低表达的患者。通过酶联免疫吸附测定 (ELISA) 测量的血清组织蛋白酶 D 浓度表明，与低级别肿瘤相比，高级别胶质瘤患者的血清组织蛋白酶 D 浓度显着增加，这表明该蛋白酶可用作胶质瘤生物标志物。我们首先使用 RNA 干扰技术敲低神经胶质瘤细胞系（U87MG、U138MG、U251MG、U373MG；A172）中组织蛋白酶 D 的基因表达。在原本表达高水平组织蛋白酶D的U87MG和A172中实现了组织蛋白酶D的有效下调，这些细胞系的侵袭能力相应降低。然后我们使用 9L 胶质肉瘤细胞和串行 MRI 监测系统建立大鼠胶质瘤模型。对于该模型，用通过辐射灭活的整个肿瘤细胞进行外周疫苗接种以及脑内施用IL-2基因转导载体可以诱导已建立的脑肿瘤的完全排斥。当使用组织蛋白酶D作为皮下疫苗时，对大鼠神经胶质瘤模型的治疗效果未达到灭活全肿瘤细胞疫苗所获得的效果。免疫组织化学分析显示，IL-2在脑肿瘤中充分表达，但CD4^+T细胞和CD8^+T细胞大量浸润。 3个月随访期间，未观察到不良反应。对于针对神经胶质瘤的疫苗接种，需要更多的神经胶质瘤特异性蛋白质。