Radiation effects of MMPs in glioma angiogenesis

MMPs 在胶质瘤血管生成中的放射效应

• 批准号: 7010032
• 负责人: SANJEEVA MOHANAM
• 金额: $ 24.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010032
• 关键词: Adenoviridae; angiogenesis; antisense nucleic acid; apoptosis; athymic mouse; cell cell interaction; cell line; collagenase; enzyme activity; enzyme induction /repression; gamma radiation; genetic promoter element; glioblastoma multiforme; mixed tissue /cell culture; molecular oncology; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; neoplastic cell; neoplastic growth; radiobiology; tissue inhibitor of metalloproteinases; transfection /expression vector; vascular endothelium

DESCRIPTION (provided by applicant): Radiotherapy remains as a major component of treatment modalities for controlling tumor progression and the majority of glioblastoma multiforme (GBM) tumors recur within or at the margin of the radiation field. The unexpected biological effect of irradiation involves an altered profile of MMP-2 and MMP-9 expression and activity and provides evidence of a scenario where irradiation might promote angiogenic and invasion-related gene expression, thereby increasing invasive and angiogenic glioma cell behavior. To elucidate the interactions between radiation and MMPs in glioblastomas, we propose the following specific aims: Specific Aim 1. Determine the effects of irradiation on MMPs/TEMPs in human endothelial and glioblastoma cells, a) Increases in MMP expression and activity during radiation therapy have potential therapeutic implications. We will determine the effects of radiation and glioblastoma-endothelial interactions on MMPs/TIMPs expression, secretion and angiogenesis in vitro in endothelial cells, b) Increased expression and activity of MMPs in irradiated tumor and endothelial cells will be modulated by antagonists and antisense RNAs of MMP-2 and MMP-9 through expression plasmids and adenoviral vectors and will be evaluated in co-cultures for the modulation of angiogenesis in vitro in endothelial cells with and without irradiation. Specific Aim 2. Determine the effects of antisense MMP-2 and MMP-9 inhibition on glioma angiogenesis in vivo. Malignant glioma is one of the most radioresistant tumor types and tumor vascular endothelium is resilient to cytotoxic effects of ionizing radiation. In this aim, we will study the effect of a) adenoviral-mediated antisense suppression of MMP-9 expression under the control of a radiation-responsive (Erg/CMV) chimeric promoter with and without radiation treatment and b) adenoviral-mediated antisense suppression of MMP-9 expression under the control of an endothelial-specific (flt-1) promoter on tumor growth delay, microvessel density, apoptotic index and relative MMPs/TIMPs levels in tumors during tumor growth in the mouse brain. The proposed studies should generate major insights into the pathogenesis of radiation-induced alterations in GBM tumors and, in turn, demonstrate that MMPs inhibition during radiotherapy may represent a new therapeutic approach in improving the therapeutic efficacy of radiotherapy for malignant gliomas.

描述（由申请人提供）：放疗仍然是控制肿瘤进展的治疗方式的主要组成部分，并且大多数胶质母细胞瘤多形（GBM）肿瘤在辐射场的边缘内或在辐射场的边缘内复发。辐照的意外生物学作用涉及MMP-2和MMP-9表达和活性的变化，并提供了一种情况，即辐射可能促进血管生成和侵袭相关的基因表达，从而增加了浸润性和血管生成性神经瘤细胞的行为。为了阐明胶质母细胞瘤中辐射与MMP之间的相互作用，我们提出以下特定目的：特定目的1。确定辐射对人内皮细胞和胶质母细胞瘤细胞中MMP/TEMP的影响，a）在放射治疗过程中MMP表达和活性的增加具有潜在的治疗疗法。我们将确定辐射和胶质母细胞瘤 - 内皮相互作用对内皮细胞体外体外的MMP/TIMP表达，分泌和血管生成的影响，b）b）在辐射的肿瘤和内皮细胞中MMP的表达和活性增加，将由MMP-2和MMP-2和MMP-2的反义rnas进行调节，并通过对拮抗剂和抗浓度的RNA进行调节。在内皮细胞中调节体外血管生成的共培养。具体目标2。确定反义MMP-2和MMP-9抑制对体内神经胶质瘤血管生成的影响。恶性神经胶质瘤是最放射耐药的肿瘤类型之一，肿瘤血管内皮对电离辐射的细胞毒性作用有弹性。 In this aim, we will study the effect of a) adenoviral-mediated antisense suppression of MMP-9 expression under the control of a radiation-responsive (Erg/CMV) chimeric promoter with and without radiation treatment and b) adenoviral-mediated antisense suppression of MMP-9 expression under the control of an endothelial-specific (flt-1) promoter on tumor growth delay, microvessel density,小鼠脑中肿瘤生长过程中肿瘤中的凋亡指数和相对MMP/TIMP水平。拟议的研究应产生对辐射诱导的GBM肿瘤改变的发病机理的重大见解，进而证明，放疗过程中MMPS抑制作用可能代表了一种新的治疗方法，以提高恶性肿瘤的放射治疗的治疗功效。