VITRONECTIN IN THE MALIGNANCY OF GLIOBLASTOMA

玻连蛋白在胶质母细胞瘤恶性肿瘤中的作用

• 批准号: 2100567
• 负责人: Candece L Gladson
• 金额: $ 16.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-14 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2100567
• 关键词: antireceptor antibody; astrocytoma; athymic mouse; biomarker; biopsy; cell adhesion; cell motility; clone cells; glioblastoma multiforme; human subject; immunocytochemistry; in situ hybridization; integrins; molecular oncology; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplasm /cancer invasiveness; receptor expression; transfection; vitronectin

Tumor invasion is potentiated by adhesive interactions between tumor cells and extracellular matrix proteins. We have recently demonstrated that the adhesive protein vitronectin (VN) is a marker of highly malignant astrocytomas, also known as glioblastoma (GBM) tumors and potentiates cellular adhesion events in these tumors. The overall goals of this research are to determine if VN or its receptors can be used in the diagnosis of GBM tumors, and to characterize the molecular basis of VN-mediated adhesion and its significance in the proliferation of, and local invasion by, GBM tumors. Recent data has demonstrated VN mRNA both in human GBm tumors and in tumors. In addition, we have identified expression of the avB3 and the avB5 VN receptor intergrins in GBM tumors. In contrast, normal adult brain glial cells failed to express protein or mRNA for intergrins avB3 and avB5, suggesting that these VN receptor intergrins are induced in transformed glial cells and that this regulation occurs at the level of transcription. Our mapping of mRNA and protein expression for the avB3 and avB5 receptor intergrins in GBM tumors has demonstrated distinct cellular localizations, implying they serve discrete functions in situ. This proposal will focus on three specific objectives. First, to determine the source of VN in GBM tumors employing in situ hybridization and immunohistochemical analysis of glioma biopsies, including GBM tumor biopsies VN receptor intergrins expressed on various grade glial tumor biopsies and an intracerebral athymia nude mouse model of human GBM tumors. Second, to characterize the repertoire of VN receptor intergrins expressed on various grade glial tumor biopsies and on cultured cell lines by immunochemical and in situ hybridization analyses. The results on the differential expression of VN and its receptors will be used to determine if they can be used as markers of the malignant glial cell. In addition, the function of the identified VN receptor integrins in GBM tumor cell adhesion and motility will be determined. Third, the role of the VN receptor integrins in the biologic properties of GB tumors will be investigated. The cDNA encoding the beta3 subunit of the VN receptor will be transfected into a GBN cell line that proliferates minimally in vivo and is deficient in this gene product, and in addition a GBM cell line deficient in the av subunit VN receptor gene product will be selected. These will be characterized in vitro, analyzed for in vivo proliferation, reculture and characterized in vitro. GBM tumors are diagnosed in approximately 9,000 individuals per year and they have an increased incidence in the fifth and sixth decades, as well as an extremely poor prognosis (100% mortality). This project is designed to determine the molecular basis for GBM tumor cell adhesion, proliferation, motility and tumor invasiveness. As such, basis for the design of a therapeutic strategy for this disease. As adhesive interactions between proliferating cells and extracellular matrix proteins are of relevance to embryonic cell proliferation, the findings from this research will be of significance to understanding integrin function in situ in brain development.

肿瘤的肿瘤相互作用增强了肿瘤的侵袭 细胞和细胞外基质蛋白。 我们最近证明了 粘附蛋白玻染蛋白（VN）是高度的标记 恶性星形胶质细胞瘤，也称为胶质母细胞瘤（GBM）肿瘤和 增强这些肿瘤中的细胞粘附事件。 总体目标 这项研究是为了确定VN或其受体是否可以用于 GBM肿瘤的诊断，并表征 VN介导的粘附及其在增殖中的重要性， GBM肿瘤的局部入侵。 最近的数据证明了VN mRNA 在人类GBM肿瘤和肿瘤中。 此外，我们已经确定了 GBM肿瘤中AVB3和AVB5 VN受体间的表达。 相反，正常的成年脑胶质细胞无法表达蛋白质或 Grins Intergrins AVB3和AVB5的mRNA，表明这些VN受体 在转化的神经胶质细胞中诱导了包蛋白，这是 调节发生在转录水平。 我们的mrna映射和 GBM中AVB3和AVB5受体间的蛋白质表达 肿瘤表现出明显的细胞局部局部化，这意味着它们 原位服务离散功能。 该建议将集中在三个特定目标上。 首先，到 确定采用原位杂交的GBM肿瘤中的VN来源 以及包括GBM肿瘤在内的神经胶质瘤活检的免疫组织化学分析 活检VN受体间的围林在各种级神经胶质肿瘤上表达 活检和人GBM的脑裸鼠裸鼠模型 肿瘤。 其次，要表征VN受体间格林的曲目 在各种级别的神经胶质肿瘤活检和培养细胞上表达 通过免疫化学和原位杂交分析的线。 结果 关于VN及其受体的差分表达将用于 确定它们是否可以用作恶性神经胶质细胞的标记。 此外，GBM中已鉴定的VN受体整联蛋白的功能 将确定肿瘤细胞粘附和运动。 第三，角色 GB肿瘤生物学特性中的VN受体整合蛋白将 被调查。 编码VN受体的β3亚基的cDNA 将转染到GBN细胞系中，该细胞系在最小的 体内并且在该基因产物中不足，另外还有GBM细胞 AV亚基VN受体基因产物中缺陷的线路将是 选定。 这些将在体外表征，分析体内 增殖，再培养和体外表征。 GBM肿瘤每年大约9,000名诊断出 他们在第五和第六十年的发生率也增加了 作为极度差的预后（100％死亡率）。 这个项目是 设计用于确定GBM肿瘤细胞粘附的分子基础， 增殖，运动和肿瘤的侵袭性。 因此， 设计这种疾病的治疗策略。 作为粘合剂 增殖细胞与细胞外基质之间的相互作用 蛋白质与胚胎细胞增殖相关，结果 从这项研究中，对于了解整合素的意义将具有重要意义 在大脑发育中起作用。