Lehmann Steffi, Stiehl Daniel P, Honer Michael, Dominietto Marco, Keist Ruth, Kotevic Ivana, Wollenick Kristin, Ametamey Simon, Wenger Roland H, Rudin Markus
Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14004-9. doi: 10.1073/pnas.0901194106. Epub 2009 Jul 31.
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-1alpha, 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-1alpha and HIF transcriptional activity were assessed by bioluminescence imaging using the reporter constructs HIF-1alpha-luciferase and hypoxia response element-luciferase, 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-1alpha levels and HIF activity showed drastic temporal variations. When comparing the readouts as a function of time we found a good correlation between HIF-1alpha 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-1alpha in cancer in an individual animal and will be of value when monitoring the efficacy of therapeutical interventions targeting the HIF pathway.
肿瘤缺氧和缺氧诱导因子（HIFs）在癌症发展过程中起着核心作用。为了研究肿瘤生长、肿瘤缺氧、HIF-1α的稳定性以及HIF转录活性之间的关系，我们建立了一种体内成像工具，可在小鼠C51同种异体移植肿瘤模型中对这些过程进行纵向和非侵入性监测。我们使用对缺氧敏感的示踪剂[（18）F] -氟米索硝唑（FMISO）进行正电子发射断层扫描（PET），以在14天内测量肿瘤缺氧情况。分别使用在C51细胞中稳定表达的报告构建体HIF-1α-荧光素酶和缺氧反应元件-荧光素酶，通过生物发光成像评估HIF-1α的稳定性和HIF转录活性。有趣的是，在整个观察期内，我们未观察到肿瘤缺氧水平有任何重大变化，而HIF-1α水平和HIF活性则呈现出剧烈的时间变化。当将读数作为时间的函数进行比较时，我们发现HIF-1α水平与HIF活性之间具有良好的相关性。相比之下，[（18）F] -FMISO PET与HIF读数之间没有显著相关性。这项工作中开发的工具允许在个体动物中对癌症中的肿瘤缺氧和HIF-1α进行纵向研究，并且在监测针对HIF途径的治疗干预效果时将具有价值。
