2007 Fiscal Year Final Research Report Summary
Multifunctional therapeutic strategy for malignant gliomas targeting cathepsin D
| Project/Area Number |
18591577
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Chiba University |
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Principal Investigator |
IWADATE Yasuo Chiba University, Graduate School of Medicine, Instructor (70272309)
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| Co-Investigator(Kenkyū-buntansha) |
HIWASA Takaki Chiba University, Graduate School of Medicine, Associate Professor (30260251)
TAGAWA Masatoshi Chiba Cancer Center, Research Institute, Director (20171572)
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| Project Period (FY) |
2006 – 2007
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| Keywords | glioma / cathepsin D / invasion / proteases / proteomics |
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| Research Abstract |
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.
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Research Products
(26 results)
