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Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events

机译:肿瘤缺氧及其下游分子事件的纵向和多峰体内成像

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摘要

Tumor hypoxia and the hypoxia-inducible factors (HIFs) play a central role in the development of cancer. To study the relationship between tumor growth, tumor hypoxia, the stabilization of HIF-1α, and HIF transcriptional activity, we have established an in vivo imaging tool that allows longitudinal and noninvasive monitoring of these processes in a mouse C51 allograft tumor model. We used positron emission tomography (PET) with the hypoxia-sensitive tracer [~(18)F]-fluoromisonidazole (FMISO) to measure tumor hypoxia over 14 days. Stabilization of HIF-1 a and HIF transcriptional activity were assessed by bioluminescence imaging using the reporter constructs HIF-1α-luciferase and hypoxia response element-lucif-erase, respectively, stably expressed in C51 cells. Interestingly, we did not observe any major change in the level of tumor hypoxia throughout the observation period whereas HIF-1α levels and HIF activity showed drastic temporal variations. When comparing the readouts as a function of time we found a good correlation between HIF-1α levels and HIF activity. In contrast, there was no significant correlation between the [~(18)F]-FMISO PET and HIF readouts. The tool developed in this work allows for the longitudinal study of tumor hypoxia and HIF-1α in cancer in an individual animal and will be of value when monitoring the efficacy of therapeutical interventions targeting the HIF pathway.
机译:肿瘤缺氧和缺氧诱导因子(HIFs)在癌症的发展中起着核心作用。为了研究肿瘤生长,肿瘤缺氧,HIF-1α的稳定化和HIF转录活性之间的关系,我们建立了一种体内成像工具,可以在小鼠C51同种异体移植肿瘤模型中纵向和无创地监测这些过程。我们使用正电子发射断层扫描(PET)和缺氧敏感示踪剂[〜(18)F]-氟代咪唑(FMISO)来测量14天以上的肿瘤缺氧。通过使用分别在C51细胞中稳定表达的报道基因构建体HIF-1α-荧光素酶和缺氧反应元件-lucif-酶的生物发光成像来评估HIF-1α和HIF转录活性的稳定性。有趣的是,我们在整个观察期内均未观察到肿瘤缺氧水平的任何重大变化,而HIF-1α水平和HIF活性则表现出剧烈的时间变化。比较读数与时间的关系时,我们发现HIF-1α水平与HIF活性之间存在良好的相关性。相反,[〜(18)F] -FMISO PET与HIF读数之间没有显着相关性。在这项工作中开发的工具可以对动物体内的肿瘤缺氧和HIF-1α进行纵向研究,并且在监测针对HIF途径的治疗性干预措施的疗效时将具有重要的价值。

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  • 作者单位

    Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;

    Institutes of Physiology, University of Zurich, 8057 Zurich, Switzerland;

    Institute for Pharmaceutical Sciences, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;

    Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;

    Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;

    Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;

    Institutes of Physiology, University of Zurich, 8057 Zurich, Switzerland;

    Institute for Pharmaceutical Sciences, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;

    Institutes of Physiology, University of Zurich, 8057 Zurich, Switzerland;

    Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland Institutes of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    hypoxia-inducibie factor; positron emission tomography; bioluminescence; reporter gene; tumor allograft model;

    机译:缺氧诱导因子正电子发射断层扫描生物发光报告基因肿瘤同种异体移植模型;

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