Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice.
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 microm in diameter. 18F-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.
Serganova
Inna
I
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Doubrovin
Michael
M
Vider
Jelena
J
Ponomarev
Vladimir
V
Soghomonyan
Suren
S
Beresten
Tatiana
T
Ageyeva
Ludmila
L
Serganov
Alexander
A
Cai
Shangde
S
Balatoni
Julius
J
Blasberg
Ronald
R
Gelovani
Juri
J
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000235:genetics*; D049452:Green Fluorescent Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D019275:Radiopharmaceuticals; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D014055:Tomography, Emission-Computed; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D005462:Fluorine Radioisotopes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D001086:Arabinofuranosyluracil; C054103:2'-fluoro-5-ethylarabinosyluracil; D013937:Thymidine Kinase; D010100:Oxygen