Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice
Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice
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DOI：
10.1158/0008-5472.can-04-0842
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Gelovani, J
中科院分区：
文献类型：
--
作者：
Serganova, I;Doubrovin, M;Gelovani, J
肿瘤缺氧是一种时空异质性现象，是肿瘤和宿主组织特异性过程共同作用的结果。为了研究缺氧诱导因子-1（HIF-1）特异性转录活性在肿瘤中的动态和空间异质性，我们使用重复的非侵入性正电子发射断层扫描（PET）成像在活体小鼠肿瘤中缺氧诱导的HIF-1转录活性。这种方法使用了一种新的逆转录病毒载体，携带HIF-1诱导的“传感器”报告基因（HSV1-tk/GFP融合）和组成型表达的“信标”报告基因（DsRed2/XPRT）。C6神经胶质瘤细胞转导与此多报告系统揭示了剂量依赖性模式的时间动态的HIF-1的转录活性诱导的氯化钴或降低大气中的氧浓度。当直径> 350 μ m时，C6报告细胞的多细胞球状体形成缺氧核心。F-18 - 2'-氟-2'-脱氧-1 β-D-阿拉伯呋喃糖基-5-乙基-尿嘧啶（FEAU）PET显示，小鼠报告异种移植物中HIF-1转录活性的空间异质性是大小或缺血-再灌注损伤的函数。随着肿瘤直径的增加（> 3mm），在肿瘤的核心区域观察到HIF-1转录活性的显著增加。即使是在小的C6肿瘤中的中度缺血再灌注损伤也会引起HIF-1转录活性的快速诱导，这种诱导持续很长时间，因为C6肿瘤无法快速补偿肿瘤微循环的急性变化。
Tumor hypoxia is a spatially and temporally heterogeneous phenomenon, which results from several tumor and host tissue-specific processes. To study the dynamics and spatial heterogeneity of hypoxia-inducible factor-1 (HIF-1)-specific transcriptional activity in tumors, we used repetitive noninvasive positron emission tomography (PET) imaging of hypoxia-induced HIF-1 transcriptional activity in tumors in living mice. This approach uses a novel retroviral vector bearing a HIF-1-inducible "sensor" reporter gene (HSV1-tk/GFP fusion) and a constitutively expressed "beacon" reporter gene (DsRed2/XPRT). C6 glioma cells transduced with this multireporter system revealed dose-dependent patterns in temporal dynamics of HIF-1 transcriptional activity induced by either CoCl2 or decreased atmospheric oxygen concentration. Multicellular spheroids of C6 reporter cells developed a hypoxic core when >350 mum in diameter. F-18-2'-fluoro-2'deoxy-1beta-D-arabionofuranosyl-5-ethyl-uracil (FEAU) PET revealed spatial heterogeneity of HIF-1 transcriptional activity in reporter xenografts in mice as a function of size or ischemia-reperfusion injury. With increasing tumor diameter (>3 mm), a marked increase in HIF-1 transcriptional activity was observed in the core regions of tumors. Even a moderate ischemia-reperfusion injury in small C6 tumors caused a rapid induction of HIF-1 transcriptional activity, which persisted for a long time because of the inability of C6 tumors to rapidly compensate acute changes in tumor microcirculation.