The Role of CD147 in Glioblastoma Invasiveness
CD147 在胶质母细胞瘤侵袭中的作用
基本信息
- 批准号:9254829
- 负责人:
- 金额:$ 3.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-18 至 2021-10-15
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAdultAstrocytesBrainBrain NeoplasmsCarcinomaCellsClinicalConditioned Culture MediaEnvironmentExcisionExtracellular MatrixFibroblastsGlioblastomaGliomaGoalsIn VitroInvadedIonizing radiationKnowledgeMalignant NeoplasmsMalignant neoplasm of central nervous systemMatrix MetalloproteinasesMediatingMediator of activation proteinMessenger RNAMicrogliaMigration AssayNeoplasm MetastasisNormal CellOperative Surgical ProceduresOutcomePatientsPlayPrimary Brain NeoplasmsPrimary carcinoma of the liver cellsProcessProductionProteinsRadiationRadiation exposureRadiation therapyRecurrenceResearchRoentgen RaysRoleSignal PathwaySystemTestingTherapeutic InterventionTumor Cell InvasionTumor VolumeVesicleWorkX-Ray Computed Tomographycancer cellcancer typechemoradiationexperimental studyextracellular vesiclesimage guidedimprovedimproved outcomein vivoin vivo Modelinhibitor/antagonistintercellular communicationirradiationknock-downmouse modelneoplastic celloverexpressionpreventradiation responsestandard caretumor
项目摘要
Glioblastoma is a primary cancer of the central nervous system. Unfortunately, current treatments are
unable to control the invasiveness of the tumor, leading to a 95% recurrence rate. Moreover, although radiation
therapy has produced the largest improvement in survival for these patients, it is also associated with
increased tumor invasiveness, perhaps contributing to the high recurrence rate. Our preliminary work suggests
that CD147, a protein which is commonly overexpressed in glioblastoma, may contribute to this invasion, in
particular the increased invasion after radiation exposure. Interestingly, CD147 works to promote invasion in
cancer cells via intercellular communication: carcinomas secrete CD147 to induce neighboring fibroblasts to
produce matrix metalloproteinases (MMPs), which degrade the extracellular matrix. In glioblastoma, we have
found that extracellular vesicles from glioblastoma cells not only contain CD147, but their CD147 levels are
higher if the cells are irradiated. Similarly, we found that glioblastoma cells release extracellular vesicles that
increase MMP production in astrocytes, and that MMP production is further increased if the extracellular
vesicles are from irradiated glioblastoma cells. Together, these studies suggest that CD147 may play a key
role in both the invasiveness of glioblastoma tumors and the increased invasion observed following irradiation.
Therefore, this study proposes two specific aims to test the central hypothesis that glioblastoma cells use
extracellular vesicles containing CD147 to mediate a pro-invasive environment. We further hypothesize that
radiation increases the levels of CD147 in extracellular vesicles, resulting in increased invasiveness.
In Aim 1, we will examine in vitro whether CD147 in the extracellular vesicles of glioblastoma cells can
induce astrocytes and microglia to promote invasion through MMP production, and whether radiation enhances
this process. Through knockdown of CD147, we will examine how CD147 controls drivers of invasion by
analyzing the MMP protein and mRNA levels, the amount and activity of secreted MMPs, and the signaling
pathways leading to MMP production. We will also test the effects of CD147 on functional endpoints using
invasion and migration assays. In Aim 2, we will demonstrate in vivo that CD147 is an important mediator of
tumor invasiveness, in particular after radiation exposure. We will use an orthotopic mouse model of glioma
consisting of wild-type and CD147-knockdown tumor cells. Using a state-of-the-art system that mimics clinical
therapy, we will perform specific CT-image guided X-ray irradiation of the tumors. We will examine differences
in survival, number of metastases in the brain, and immunohistological endpoints. Radiation is expected to
increase invasion in the CD147 wild-type tumors, relative to non-irradiated controls. However, we predict that
the combination of radiation and CD147 knockdown will act synergistically to generate the lowest level of
invasion among the groups. These results may suggest CD147 inhibitors as an important adjuvant to radiation
therapy, contributing to reduced invasion and thus improved patient survival.
胶质母细胞瘤是一种中枢神经系统的原发性癌症。不幸的是,目前的治疗方法是
项目成果
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