Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice Journal Article
| Authors: | Serganova, I.; Doubrovin, M.; Vider, J.; Ponomarev, V.; Soghomonyan, S.; Beresten, T.; Ageyeva, L.; Serganov, A.; Cai, S.; Balatoni, J.; Blasberg, R.; Gelovani, J. |
| Article Title: | Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice |
| Abstract: | 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 μm in diameter. 18F-2′-fluoro- 2′deoxy-1β-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. |
| Keywords: | signal transduction; controlled study; vascular endothelial growth factor a; unclassified drug; nonhuman; positron emission tomography; glioma; radiopharmaceuticals; animal cell; mouse; animals; mice; gene; oxygen; animal experiment; animal model; molecular imaging; cell line, tumor; diagnostic imaging; genetic vectors; luminescent proteins; transcription factors; cell heterogeneity; hypoxia; gene expression regulation, neoplastic; transcription regulation; recombinant fusion proteins; xenograft; ischemia; glioma cell; retrovirus vector; arabinofuranosyluracil; reporter gene; green fluorescent proteins; thymidine kinase; cell hypoxia; genes, reporter; rats; tumor; non invasive measurement; retroviridae; cobalt chloride; hypoxia-inducible factor 1, alpha subunit; tomography, emission-computed; fluorine radioisotopes; tumor blood flow; reperfusion injury; hypoxia inducible factor 1; trans-activation (genetics); clevudine; spheroid cell; priority journal; article; 2' fluoro 2' deoxy 1beta dextro arabionofuranosyl 5 ethyl uracil fluorine 18; hif 1 gene |
| Journal Title: | Cancer Research |
| Volume: | 64 |
| Issue: | 17 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2004-09-01 |
| Start Page: | 6101 |
| End Page: | 6108 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-04-0842 |
| PROVIDER: | scopus |
| PUBMED: | 15342393 |
| DOI/URL: | |
| Notes: | Cancer Res. -- Cited By (since 1996):128 -- Export Date: 16 June 2014 -- CODEN: CNREA -- Source: Scopus |
