Microenvironment: Imaging/Implications in Brain Tumors

微环境：脑肿瘤的成像/影响

• 批准号: 6903023
• 负责人: Sydney M. Evans
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903023
• 关键词: apoptosis; bioimaging /biomedical imaging; biological signal transduction; biomarker; biopsy; brain imaging /visualization /scanning; brain neoplasms; cell proliferation; clinical research; diffusion; fluorine; glioma; human subject; hypoxia; immunofluorescence technique; microarray technology; neoplasm /cancer classification /staging; neoplasm /cancer invasiveness; neoplastic growth; outcomes research; perfusion; pharmacokinetics; positron emission tomography; protein quantitation /detection; radiotracer

DESCRIPTION (provided by applicant): The effects of hypoxia on tumor physiology and response to radiation therapy have been extensively described using in vitro studies, pre-clinical models and in human tumors. Investigations regarding the modulation of molecular signaling by hypoxia are less advanced, with the conclusions of the majority of published studies performed in cellular or subcellular systems. Despite the observation of abnormal blood vessels and regions of pseudopalisading necrosis in high-grade glial brain tumors, little attention has been given to the role of hypoxia in the mechanism of their progression. Recently however, the central role of hypoxia in brain tumor progression and aggressiveness has been hypothesized based on pathological examination of WHO Grade 4 glial tumors by Brat et al. Their studies and conclusions were based upon HIF-1? staining in regions of pseudopalisading necrosis. We have developed the methodology to directly and more specifically measure hypoxia in tissue from all grades of human brain cancer using biopsy-based immunohistochemical (IHC) analysis of EF5 binding. The current application proposes to extend our biopsy-based analyses to PET studies of [F-18]-EF5 and compare patient outcome with [F-18]-EF5 data and IHC-based endpoints (Specific Aim 1). In our second Specific Aim, the tissues obtained from these patients, as well as tissues archived from patients previously treated with EF5 will be used to study the physiologic and molecular hypoxia-dependent mechanisms that result in tumor resistance or cellular hypoxia tolerance. Analyses using software for fluorescence images, developed in our lab, will be performed on frozen sections stained for EF5, PECAM/CD31 (blood vessels), TUNEL (apoptosis) and Ki67 (proliferation). In our third Specific Aim, tissue microarrays (TMAs) will be constructed to assess the impact of microenvironment on molecular signaling pathways. At the completion of this grant we will have compared a validated, quantitative IHC-based marker of hypoxia (EF5) to the non-invasive assay using the identical compound ([18-F]-EF5 PET) and determined the mechanisms and situations under which hypoxia is important in human glial tumors, based upon clinical outcome.

描述（由申请人提供）：缺氧对肿瘤生理学和放射治疗反应的影响已通过体外研究、临床前模型和人类肿瘤进行了广泛描述。关于缺氧调节分子信号传导的研究还不太先进，大多数已发表的研究的结论都是在细胞或亚细胞系统中进行的。尽管在高级别神经胶质脑肿瘤中观察到异常血管和假栅栏坏死区域，但很少有人关注缺氧在其进展机制中的作用。然而最近，Brat 等人根据 WHO 4 级神经胶质瘤的病理检查，推测缺氧在脑肿瘤进展和侵袭性中的核心作用。他们的研究和结论是基于HIF-1？假栅栏坏死区域的染色。我们开发了一种方法，使用基于活检的 EF5 结合免疫组织化学 (IHC) 分析来直接、更具体地测量所有级别的人脑癌组织中的缺氧情况。当前的申请建议将我们基于活检的分析扩展到 [F-18]-EF5 的 PET 研究，并将患者结果与 [F-18]-EF5 数据和基于 IHC 的终点进行比较（具体目标 1）。在我们的第二个具体目标中，从这些患者获得的组织以及从先前接受 EF5 治疗的患者存档的组织将用于研究导致肿瘤抵抗或细胞缺氧耐受的生理和分子缺氧依赖性机制。使用我们实验室开发的荧光图像软件对 EF5、PECAM/CD31（血管）、TUNEL（细胞凋亡）和 Ki67（增殖）染色的冷冻切片进行分析。在我们的第三个具体目标中，将构建组织微阵列（TMAs）来评估微环境对分子信号传导途径的影响。完成本次资助后，我们将比较经过验证的基于 IHC 的定量缺氧标志物 (EF5) 与使用相同化合物 ([18-F]-EF5 PET) 的非侵入性测定，并确定以下机制和情况根据临床结果，缺氧在人类神经胶质瘤中很重要。